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BabyScreen+ newborn screening v0.2074 SORD Zornitza Stark Gene: sord has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2074 SORD Zornitza Stark Classified gene: SORD as Red List (low evidence)
BabyScreen+ newborn screening v0.2074 SORD Zornitza Stark Gene: sord has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2073 SORD Zornitza Stark Tag treatable tag was added to gene: SORD.
Tag metabolic tag was added to gene: SORD.
BabyScreen+ newborn screening v0.2073 SOX3 Zornitza Stark Marked gene: SOX3 as ready
BabyScreen+ newborn screening v0.2073 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2073 SOX3 Zornitza Stark Classified gene: SOX3 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2073 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2072 SOX3 Zornitza Stark Tag for review tag was added to gene: SOX3.
Tag treatable tag was added to gene: SOX3.
Tag endocrine tag was added to gene: SOX3.
BabyScreen+ newborn screening v0.2072 SOX3 Zornitza Stark reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Panhypopituitarism, X-linked MIM#312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Marked gene: SOX3 as ready
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Classified gene: SOX3 as Amber List (moderate evidence)
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v0.31 SOX3 Zornitza Stark Tag SV/CNV tag was added to gene: SOX3.
Pituitary hormone deficiency v0.31 SOX3 Zornitza Stark reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Panhypopituitarism, X-linked, MIM# 312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
BabyScreen+ newborn screening v0.2072 STAT1 Zornitza Stark Marked gene: STAT1 as ready
BabyScreen+ newborn screening v0.2072 STAT1 Zornitza Stark Gene: stat1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2072 STAT1 Zornitza Stark Mode of inheritance for gene: STAT1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2071 STAT1 Zornitza Stark Classified gene: STAT1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2071 STAT1 Zornitza Stark Gene: stat1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2070 STAT1 Zornitza Stark Tag treatable tag was added to gene: STAT1.
Tag immunological tag was added to gene: STAT1.
BabyScreen+ newborn screening v0.2070 STAT1 Zornitza Stark reviewed gene: STAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive, MIM# 613796; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2070 STIM1 Zornitza Stark Marked gene: STIM1 as ready
BabyScreen+ newborn screening v0.2070 STIM1 Zornitza Stark Gene: stim1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2070 STIM1 Zornitza Stark Classified gene: STIM1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2070 STIM1 Zornitza Stark Gene: stim1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2069 STIM1 Zornitza Stark Tag treatable tag was added to gene: STIM1.
Tag immunological tag was added to gene: STIM1.
BabyScreen+ newborn screening v0.2069 STIM1 Zornitza Stark reviewed gene: STIM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 10 MIM612783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2069 STK4 Zornitza Stark Marked gene: STK4 as ready
BabyScreen+ newborn screening v0.2069 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2069 STK4 Zornitza Stark Classified gene: STK4 as Green List (high evidence)
BabyScreen+ newborn screening v0.2069 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2068 STK4 Zornitza Stark Tag treatable tag was added to gene: STK4.
Tag immunological tag was added to gene: STK4.
BabyScreen+ newborn screening v0.2068 STK4 Zornitza Stark reviewed gene: STK4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM#614868; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.93 IL2RB Aimee Huynh gene: IL2RB was added
gene: IL2RB was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: IL2RB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL2RB were set to 31040184, 31040185
Phenotypes for gene: IL2RB were set to immunodeficiency; autoimmune enteropathy
Penetrance for gene: IL2RB were set to unknown
Review for gene: IL2RB was set to AMBER
gene: IL2RB was marked as current diagnostic
Added comment: 3 homozygous mutations in the IL2RB gene of 8 individuals from 4 consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and CMV disease. 4/5 children had severe diarrhea and infectious/autoimmune enteropathy. Endoscopy of patient B1 showed villous atrophy, and gastrointestinal biopsies revealed chronic inflammatory infiltration of the duodenum and rectum.
Sources: Expert Review
BabyScreen+ newborn screening v0.2068 STX16 Zornitza Stark Marked gene: STX16 as ready
BabyScreen+ newborn screening v0.2068 STX16 Zornitza Stark Gene: stx16 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2068 STX16 Zornitza Stark Classified gene: STX16 as Green List (high evidence)
BabyScreen+ newborn screening v0.2068 STX16 Zornitza Stark Gene: stx16 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2067 STX16 Zornitza Stark Tag treatable tag was added to gene: STX16.
Tag endocrine tag was added to gene: STX16.
BabyScreen+ newborn screening v0.2067 SYT2 Zornitza Stark Marked gene: SYT2 as ready
BabyScreen+ newborn screening v0.2067 SYT2 Zornitza Stark Gene: syt2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2067 SYT2 Zornitza Stark Mode of inheritance for gene: SYT2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2066 SYT2 Zornitza Stark Classified gene: SYT2 as Green List (high evidence)
BabyScreen+ newborn screening v0.2066 SYT2 Zornitza Stark Gene: syt2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2065 SYT2 Zornitza Stark Tag treatable tag was added to gene: SYT2.
Tag neurological tag was added to gene: SYT2.
BabyScreen+ newborn screening v0.2065 TBL1X Zornitza Stark Marked gene: TBL1X as ready
BabyScreen+ newborn screening v0.2065 TBL1X Zornitza Stark Gene: tbl1x has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2065 TBL1X Zornitza Stark Classified gene: TBL1X as Green List (high evidence)
BabyScreen+ newborn screening v0.2065 TBL1X Zornitza Stark Gene: tbl1x has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2064 TBL1X Zornitza Stark Tag treatable tag was added to gene: TBL1X.
Tag endocrine tag was added to gene: TBL1X.
Inflammatory bowel disease v0.93 IL21 Aimee Huynh gene: IL21 was added
gene: IL21 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: IL21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL21 were set to 24746753
Phenotypes for gene: IL21 were set to immunodeficiency; inflammatory bowel disease
Penetrance for gene: IL21 were set to unknown
Review for gene: IL21 was set to AMBER
gene: IL21 was marked as current diagnostic
Added comment: IL-21 deficiency - a novel monogenetic cause of severe, early-onset IBD associated with a CVID-like primary immunodeficiency. One case of a turkish boy born to consanguinous parents, diagnosed with IBD in early years (diarrhea from 2 months of age, worsened over time, biopsy typical of Crohn's). This proband had 2 siblings who had early onset IBD before age 1 year and died.
Sources: Expert Review
BabyScreen+ newborn screening v0.2064 TF Zornitza Stark Marked gene: TF as ready
BabyScreen+ newborn screening v0.2064 TF Zornitza Stark Gene: tf has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2064 TF Zornitza Stark Classified gene: TF as Green List (high evidence)
BabyScreen+ newborn screening v0.2064 TF Zornitza Stark Gene: tf has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2063 TF Zornitza Stark Tag treatable tag was added to gene: TF.
Tag haematological tag was added to gene: TF.
Inflammatory bowel disease v0.93 DKC1 Chris Richmond gene: DKC1 was added
gene: DKC1 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: DKC1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DKC1 were set to 21284747
Phenotypes for gene: DKC1 were set to Dyskeratosis congenita
Penetrance for gene: DKC1 were set to unknown
Review for gene: DKC1 was set to GREEN
gene: DKC1 was marked as current diagnostic
Added comment: 2 unrelated infants with infant-onset DKC - the most prominent clinical finding was the presence of a severe, chronic, non-infectious enteropathy leading to malabsorption and nutrient deficiencies . Histological abnormalities included inflammation and mucosal apoptosis (identical to gut GVHD) in the esophagus, small bowel, or colon. Phenotypic overlap with IBD. Review with Dr. Peter McNaughton (immunologist QCH).
Sources: Expert Review
Stickler Syndrome v1.5 SLC29A3 Krithika Murali changed review comment from: Phenotypic features can overlap with Stickler syndrome (presentation VCGS Dysmorphology meeting 24.3.23)
Sources: Expert list, Literature; to: Phenotypic features can overlap with Stickler syndrome (presentation VCGS Dysmorphology meeting 24.3.23, suggested adding gene to Stickler panel)
Sources: Expert list, Literature
Stickler Syndrome v1.5 SLC29A3 Krithika Murali gene: SLC29A3 was added
gene: SLC29A3 was added to Stickler Syndrome. Sources: Expert list,Literature
Mode of inheritance for gene: SLC29A3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC29A3 were set to Histiocytosis-lymphadenopathy plus syndrome - MIM#602782
Review for gene: SLC29A3 was set to GREEN
Added comment: Phenotypic features can overlap with Stickler syndrome (presentation VCGS Dysmorphology meeting 24.3.23)
Sources: Expert list, Literature
Mendeliome v1.743 STX4 Achchuthan Shanmugasundram reviewed gene: STX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 36355422; Phenotypes: Hearing impairment, HP:0000365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram edited their review of gene: ARF1: Changed publications: 36345169
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram reviewed gene: ARF1: Rating: ; Mode of pathogenicity: None; Publications: 3634516; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.2063 SARS Lilian Downie gene: SARS was added
gene: SARS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to PMID:34570399, PMID: 34194004
Phenotypes for gene: SARS were set to Neurodevelopmental disorder with microcephaly, ataxia, and seizures MIM#617709
Review for gene: SARS was set to RED
Added comment: developmental delay, deafness, cardiomyopathy, epilepsy, and severe febrile decompensations
Rx serine supplementation - limited evidence and sounds supportive only
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SCARB2 Lilian Downie gene: SCARB2 was added
gene: SCARB2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SCARB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCARB2 were set to PMID: 34337151, PMID: 35346091, PMID: 26677510
Phenotypes for gene: SCARB2 were set to Epilepsy, progressive myoclonic 4, with or without renal failure MIM#254900
Review for gene: SCARB2 was set to RED
Added comment: Onset not <5
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SERPING1 Lilian Downie gene: SERPING1 was added
gene: SERPING1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SERPING1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SERPING1 were set to PMID: 32898710
Phenotypes for gene: SERPING1 were set to Angioedema, hereditary, 1 and 2 MIM#106100
Review for gene: SERPING1 was set to RED
Added comment: episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts.

Age of onset not typically <5

Treatment Purified C1 inhibitor concentrate (Cinryze, Berinert, HAEGARDA, or Ruconest), Ecallantide (Kalbitor), Icatibant (Firazyr), Lanadelumab, Orladeyo (berotralstat), FFP or solvent-detergent treated plasma, antisense oligonucleotide treatment (donidalorsen)
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SGPL1 Lilian Downie gene: SGPL1 was added
gene: SGPL1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SGPL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGPL1 were set to PMID: 28165343
Phenotypes for gene: SGPL1 were set to Nephrotic syndrome, type 14 MIM#617575
Review for gene: SGPL1 was set to RED
Added comment: infancy or early childhood with progressive renal dysfunction associated with focal segmental glomerulosclerosis (FSGS), resulting in end-stage renal disease within a few years. Other infants present with primary adrenal insufficiency. Some patients present in utero with fetal hydrops and fetal demise. Additional features of the disorder can include ichthyosis, acanthosis, adrenal insufficiency, immunodeficiency, and neurologic defects

Rx Hydrocortisone, kidney transplant (treatment doesn't fit screening model as would need to have ESRD before you had it?)
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SLC1A3 Lilian Downie gene: SLC1A3 was added
gene: SLC1A3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SLC1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC1A3 were set to PMID: 32754645
Phenotypes for gene: SLC1A3 were set to Episodic ataxia, type 6 MIM#612656
Review for gene: SLC1A3 was set to RED
Added comment: ataxia occurs with febrile illnesses
Episodic attacks lasted 2 to 3 hours and were often associated with nausea, vomiting, photophobia, phonophobia, vertigo, diplopia, and/or slurred speech
Not consistently in children <5 and variable severity

Suggested Rx acetazolamide
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SMARCD2 Lilian Downie gene: SMARCD2 was added
gene: SMARCD2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SMARCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMARCD2 were set to PubMed: 28369036, 33279574, 33025377
Phenotypes for gene: SMARCD2 were set to Specific granule deficiency 2 MIM#617475
Review for gene: SMARCD2 was set to GREEN
Added comment: recurrent infections due to defective neutrophil development. Bone marrow findings include paucity of neutrophil granulocytes, absence of granule proteins in neutrophils, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. The disorder is apparent from infancy, and patients may die in early childhood unless they undergo hematopoietic stem cell transplantation. Most patients have additional findings, including delayed development, mild dysmorphic features, tooth abnormalities, and distal skeletal defects

Rx bone marrow transplant
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SNX10 Lilian Downie gene: SNX10 was added
gene: SNX10 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SNX10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNX10 were set to PMID: 30885997, PMID: 22499339
Phenotypes for gene: SNX10 were set to Osteopetrosis, autosomal recessive 8 MIM#615085
Review for gene: SNX10 was set to GREEN
Added comment: macrocephaly
failure to thrive
osteopetrosis

Rx bone marrow tranplant
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SORD Lilian Downie gene: SORD was added
gene: SORD was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SORD were set to PMID: 32367058
Phenotypes for gene: SORD were set to Sorbitol dehydrogenase deficiency with peripheral neuropathy MIM#618912
Review for gene: SORD was set to RED
Added comment: Slowly progressive, onset not consistently <5

Rx epalrestat and ranirestat
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SOX3 Lilian Downie gene: SOX3 was added
gene: SOX3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SOX3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SOX3 were set to PMID: 31678974, PMID: 15800844
Phenotypes for gene: SOX3 were set to Panhypopituitarism, X-linked MIM#312000
Review for gene: SOX3 was set to AMBER
Added comment: Amber in our mendeliome - reviewed for ID
Green in pituitary disorders

Xq27.1 duplication most common mechanism - inclusion might be a question of whether we can detect CNV's in this region

neonatal hypoglycemia and growth hormone deficiency in addition to variable deficiencies of other pituitary hormones. Brain hypoplasia of the anterior pituitary with hypoplasia or absence of the lower half of the infundibulum

Rx Growth hormone, levothyroxine, hydrocortisone
Sources: Expert list
BabyScreen+ newborn screening v0.2063 STAT1 Lilian Downie gene: STAT1 was added
gene: STAT1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STAT1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: STAT1 were set to PMID: 31512162, PMID: 27117246
Phenotypes for gene: STAT1 were set to Immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive MIM#613796
Review for gene: STAT1 was set to GREEN
Added comment: combined immunodeficiency
autosomal recessive (AR) complete STAT1 deficiency, AR partial STAT1 deficiency, autosomal dominant (AD) STAT1 deficiency, and AD STAT1 gain-of-function.
gain of function mutations - treat rituxomab
complete - treat BMT
Sources: Expert list
BabyScreen+ newborn screening v0.2063 STIM1 Lilian Downie gene: STIM1 was added
gene: STIM1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STIM1 were set to PMID: 26469693, PMID: 30949876, PMID: 26560041
Phenotypes for gene: STIM1 were set to Immunodeficiency 10 MIM612783
Review for gene: STIM1 was set to GREEN
Added comment: recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta

Rx bone marrow transpant

Age of onset is consistently <5 but the severity of infections is highly variable - treatment if the phenotype is severe
Sources: Expert list
BabyScreen+ newborn screening v0.2063 STK4 Lilian Downie gene: STK4 was added
gene: STK4 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STK4 were set to PMID: 22294732
Phenotypes for gene: STK4 were set to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM#614868
Review for gene: STK4 was set to GREEN
Added comment: primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, autoimmune manifestations, and cardiac malformations, including atrial septal defect

Rx bone marrow transplant
Sources: Expert list
BabyScreen+ newborn screening v0.2063 STX16 Lilian Downie gene: STX16 was added
gene: STX16 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STX16 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: STX16 were set to PMID: 33247854, PMID: 34477200, PMID: 29072892
Phenotypes for gene: STX16 were set to Pseudohypoparathyroidism, type IB MIM#603233
Review for gene: STX16 was set to GREEN
Added comment: characterized clinically by isolated renal PTH resistance manifest as hypocalcemia, hyperphosphatemia, and increased serum PTH
without other features of Albright hereditary osteodystrophy
Rx Calcium, calcitriol, levothyroxine, growth hormone
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SYT2 Lilian Downie gene: SYT2 was added
gene: SYT2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SYT2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SYT2 were set to PMID: 32250532, 32776697
Phenotypes for gene: SYT2 were set to Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461
Review for gene: SYT2 was set to GREEN
Added comment: Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function.

Only report biallelic for newborn screening ?
monoallelic causes a later onset distal weakness/neuropathy phenotype - still childhood but variable or not clear - not consistently <5yrs
Sources: Expert list
BabyScreen+ newborn screening v0.2063 TBL1X Lilian Downie gene: TBL1X was added
gene: TBL1X was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TBL1X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: TBL1X were set to PMID: 27603907
Phenotypes for gene: TBL1X were set to Hypothyroidism, congenital, nongoitrous, 8 MIM#301033
Review for gene: TBL1X was set to GREEN
Added comment: Small thyroid gland
Detected on newborn screening
Can affect carrier females but more mildly
Association with deafness

Rx thyroxine
Sources: Expert list
BabyScreen+ newborn screening v0.2063 TF Lilian Downie gene: TF was added
gene: TF was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TF were set to PMID: 32028041, PMID: 19579082, PMID: 11110675
Phenotypes for gene: TF were set to Atransferrinemia MIM#209300
Review for gene: TF was set to GREEN
Added comment: Hypochromic microcytic anaemia from absent transferrin - presents in infancy


Rx Red cell transfusions, deferoxamine
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SAR1B Zornitza Stark Marked gene: SAR1B as ready
BabyScreen+ newborn screening v0.2063 SAR1B Zornitza Stark Gene: sar1b has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2063 SAR1B Zornitza Stark Classified gene: SAR1B as Green List (high evidence)
BabyScreen+ newborn screening v0.2063 SAR1B Zornitza Stark Gene: sar1b has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2062 SAR1B Zornitza Stark gene: SAR1B was added
gene: SAR1B was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, gastrointestinal tags were added to gene: SAR1B.
Mode of inheritance for gene: SAR1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SAR1B were set to Chylomicron retention disease, MIM# 246700
Review for gene: SAR1B was set to GREEN
Added comment: Chylomicron retention disease is an autosomal recessive disorder of severe fat malabsorption associated with failure to thrive in infancy. Well established gene-disease association.

Congenital onset.

Treatment: low-fat diet with supplementation of fat-soluble vitamins (A, D, E, and K) and oral essential fatty acid supplementation

Non-genetic confirmatory testing: total cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol
Sources: Expert list
BabyScreen+ newborn screening v0.2061 SAMD9L Zornitza Stark Marked gene: SAMD9L as ready
BabyScreen+ newborn screening v0.2061 SAMD9L Zornitza Stark Gene: samd9l has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2061 SAMD9L Zornitza Stark Classified gene: SAMD9L as Green List (high evidence)
BabyScreen+ newborn screening v0.2061 SAMD9L Zornitza Stark Gene: samd9l has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2060 SAMD9L Zornitza Stark gene: SAMD9L was added
gene: SAMD9L was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological, haematological tags were added to gene: SAMD9L.
Mode of inheritance for gene: SAMD9L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD9L were set to 31306780
Phenotypes for gene: SAMD9L were set to Ataxia-pancytopenia syndrome, MIM# 159550
Review for gene: SAMD9L was set to GREEN
Added comment: At least three unrelated families reported, some postulate GoF whereas others postulate LoF as mechanism.

Ataxia-pancytopenia syndrome (ATXPC) is an autosomal dominant disorder characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to bone marrow failure and myeloid leukemia. The germline genetic defect is associated with somatic loss of chromosome 7 (monosomy 7) resulting in the deletion of several genes on chromosome 7 that may predispose to the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML).

Treatment: BMT.

Non-genetic confirmatory testing: no.
Sources: Expert list
BabyScreen+ newborn screening v0.2059 SAMD9 Zornitza Stark Marked gene: SAMD9 as ready
BabyScreen+ newborn screening v0.2059 SAMD9 Zornitza Stark Gene: samd9 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2059 SAMD9 Zornitza Stark Classified gene: SAMD9 as Green List (high evidence)
BabyScreen+ newborn screening v0.2059 SAMD9 Zornitza Stark Gene: samd9 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2058 SAMD9 Zornitza Stark gene: SAMD9 was added
gene: SAMD9 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SAMD9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD9 were set to 31306780
Phenotypes for gene: SAMD9 were set to MIRAGE syndrome, MIM# 617053
Review for gene: SAMD9 was set to GREEN
Added comment: MIRAGE syndrome (MIRAGE) is a form of syndromic adrenal hypoplasia, characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. The condition is often fatal within the first decade of life, usually as a result of invasive infection.

Treatment: BMT.

Non-genetic confirmatory testing: no.
Sources: Expert list
Mendeliome v1.743 THAP11 Zornitza Stark Marked gene: THAP11 as ready
Mendeliome v1.743 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Mendeliome v1.743 THAP11 Zornitza Stark gene: THAP11 was added
gene: THAP11 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to 28449119
Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Review for gene: THAP11 was set to RED
Added comment: Single individual reported with homozygous missense variant, supportive functional data.
Sources: Expert Review
BabyScreen+ newborn screening v0.2057 THAP11 Zornitza Stark Marked gene: THAP11 as ready
BabyScreen+ newborn screening v0.2057 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2057 THAP11 Zornitza Stark Phenotypes for gene: THAP11 were changed from Combined methylmalonic acidemia and homocystinuria, cblX like 2 to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
BabyScreen+ newborn screening v0.2056 THAP11 Zornitza Stark Classified gene: THAP11 as Red List (low evidence)
BabyScreen+ newborn screening v0.2056 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.26 THAP11 Zornitza Stark Marked gene: THAP11 as ready
Miscellaneous Metabolic Disorders v1.26 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.26 THAP11 Zornitza Stark gene: THAP11 was added
gene: THAP11 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to 28449119
Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Review for gene: THAP11 was set to RED
Added comment: Single individual reported with homozygous missense variant, supportive functional data.
Sources: Expert Review
BabyScreen+ newborn screening v0.2055 TMEM165 Zornitza Stark Marked gene: TMEM165 as ready
BabyScreen+ newborn screening v0.2055 TMEM165 Zornitza Stark Gene: tmem165 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2055 TMEM165 Zornitza Stark Classified gene: TMEM165 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2055 TMEM165 Zornitza Stark Gene: tmem165 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2054 TMEM165 Zornitza Stark Tag metabolic tag was added to gene: TMEM165.
BabyScreen+ newborn screening v0.2054 TMEM165 Zornitza Stark reviewed gene: TMEM165: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IIk MIM#614727; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2054 TNFRSF13B Zornitza Stark Marked gene: TNFRSF13B as ready
BabyScreen+ newborn screening v0.2054 TNFRSF13B Zornitza Stark Gene: tnfrsf13b has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2054 TNFRSF13B Zornitza Stark Classified gene: TNFRSF13B as Red List (low evidence)
BabyScreen+ newborn screening v0.2054 TNFRSF13B Zornitza Stark Gene: tnfrsf13b has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2053 TNFRSF13B Zornitza Stark Tag treatable tag was added to gene: TNFRSF13B.
Tag immunological tag was added to gene: TNFRSF13B.
BabyScreen+ newborn screening v0.2053 TNFAIP3 Zornitza Stark Marked gene: TNFAIP3 as ready
BabyScreen+ newborn screening v0.2053 TNFAIP3 Zornitza Stark Gene: tnfaip3 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2053 TNFAIP3 Zornitza Stark Classified gene: TNFAIP3 as Red List (low evidence)
BabyScreen+ newborn screening v0.2053 TNFAIP3 Zornitza Stark Gene: tnfaip3 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2052 TNFAIP3 Zornitza Stark Tag treatable tag was added to gene: TNFAIP3.
Tag immunological tag was added to gene: TNFAIP3.
BabyScreen+ newborn screening v0.2052 THAP11 Lilian Downie gene: THAP11 was added
gene: THAP11 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to PMID: 28449119, PMID: 31905202
Phenotypes for gene: THAP11 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 2
Review for gene: THAP11 was set to RED
Added comment: Single patient?
Not in our mendeliome
Not enough gene disease validity
Sources: Expert list
BabyScreen+ newborn screening v0.2052 TMEM165 Lilian Downie gene: TMEM165 was added
gene: TMEM165 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TMEM165 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM165 were set to PMID: 28323990, PMID: 35693943, PMID: 22683087
Phenotypes for gene: TMEM165 were set to Congenital disorder of glycosylation, type IIk MIM#614727
Review for gene: TMEM165 was set to AMBER
Added comment: Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Serum transferrin analysis shows a CDG type II pattern

Rx D-galactose (single paper, 2 unrelated patients and an in vitro study) ?inadequete evidence for treatment? Might need to check with JC if we would offer it maybe include
Sources: Expert list
BabyScreen+ newborn screening v0.2052 TNFRSF13B Lilian Downie gene: TNFRSF13B was added
gene: TNFRSF13B was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFRSF13B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TNFRSF13B were set to PMID: 31681716, PMID: 18981294
Phenotypes for gene: TNFRSF13B were set to Immunodeficiency, common variable, 2 MIM#240500
Review for gene: TNFRSF13B was set to RED
Added comment: hypogammaglobulinemia with low serum IgG, IgM, and IgA, and recurrent infections, including otitis media, respiratory tract infections, and gastrointestinal tract infections. Serum IgG and IgA were low, and serum antibody response to immunization with pneumococcal vaccine was decreased, although T cell-dependent response to tetanus toxin was normal.

I think the age of onset is too variable .

Rx immunoglobulin
Sources: Expert list
BabyScreen+ newborn screening v0.2052 TNFAIP3 Lilian Downie gene: TNFAIP3 was added
gene: TNFAIP3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFAIP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNFAIP3 were set to PMID: 31587140, PMID: 33101300
Phenotypes for gene: TNFAIP3 were set to Autoinflammatory syndrome, familial, Behcet-like 1 MIM#616744
Review for gene: TNFAIP3 was set to RED
Added comment: Average age of onset 5yrs - too variable re age of onset.

painful and recurrent mucosal ulceration affecting the oral mucosa, gastrointestinal tract, and genital areas. The onset of symptoms is usually in the first decade, although later onset has been reported. Additional more variable features include skin rash, uveitis, and polyarthritis, consistent with a systemic hyperinflammatory state. Many patients have evidence of autoimmune disease. Rare patients may also have concurrent features of immunodeficiency, including recurrent infections with low numbers of certain white blood cells or impaired function of immune cells.

Treatment: Colchicine, glucocorticoid, mesalazine, cyclosporine, methotrexate, azathioprine, anakinra, rituximab, tocilizumab, infliximab
Sources: Expert list
BabyScreen+ newborn screening v0.2052 RNPC3 Zornitza Stark Marked gene: RNPC3 as ready
BabyScreen+ newborn screening v0.2052 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2052 RNPC3 Zornitza Stark Classified gene: RNPC3 as Green List (high evidence)
BabyScreen+ newborn screening v0.2052 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2051 RNPC3 Zornitza Stark gene: RNPC3 was added
gene: RNPC3 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: RNPC3.
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 29866761; 32462814; 33650182
Phenotypes for gene: RNPC3 were set to Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Review for gene: RNPC3 was set to GREEN
Added comment: Three unrelated individuals reported with combined and isolated pituitary hormone deficiencies, including GH and TSH.

Onset: congenital.

Treatment: GH, thyroxine.

Non-genetic confirmatory testing: hormone levels.
Sources: Expert list
Mendeliome v1.742 RNPC3 Zornitza Stark Phenotypes for gene: RNPC3 were changed from Growth hormone deficiency; Intellectual disability to Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Mendeliome v1.741 RNPC3 Zornitza Stark edited their review of gene: RNPC3: Changed phenotypes: Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
BabyScreen+ newborn screening v0.2050 RASGRP1 Zornitza Stark Marked gene: RASGRP1 as ready
BabyScreen+ newborn screening v0.2050 RASGRP1 Zornitza Stark Gene: rasgrp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2050 RASGRP1 Zornitza Stark Classified gene: RASGRP1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2050 RASGRP1 Zornitza Stark Gene: rasgrp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2049 RASGRP1 Zornitza Stark gene: RASGRP1 was added
gene: RASGRP1 was added to Baby Screen+ newborn screening. Sources: Literature
treatable, immunological tags were added to gene: RASGRP1.
Mode of inheritance for gene: RASGRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RASGRP1 were set to Immunodeficiency 64 (MIM#618534)
Review for gene: RASGRP1 was set to GREEN
Added comment: Immunodeficiency-64 with lymphoproliferation (IMD64) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show variably decreased numbers of T cells, with lesser deficiencies of B and NK cells. There is impaired T-cell proliferation and activation; functional defects in B cells and NK cells may also be observed. Patients have increased susceptibility to EBV infection and may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity.

Severe disorder, fatal outcomes reported in childhood.

Treatment: BMT.

Non-genetic confirmatory testing: no.
Sources: Literature
Arthrogryposis v0.392 NALCN Zornitza Stark Marked gene: NALCN as ready
Arthrogryposis v0.392 NALCN Zornitza Stark Gene: nalcn has been classified as Green List (High Evidence).
Arthrogryposis v0.392 SLC35A3 Zornitza Stark Marked gene: SLC35A3 as ready
Arthrogryposis v0.392 SLC35A3 Zornitza Stark Gene: slc35a3 has been classified as Green List (High Evidence).
Arthrogryposis v0.392 LIFR Zornitza Stark Marked gene: LIFR as ready
Arthrogryposis v0.392 LIFR Zornitza Stark Gene: lifr has been classified as Green List (High Evidence).
Arthrogryposis v0.392 KY Zornitza Stark Marked gene: KY as ready
Arthrogryposis v0.392 KY Zornitza Stark Gene: ky has been classified as Green List (High Evidence).
Arthrogryposis v0.392 KIF5C Zornitza Stark Marked gene: KIF5C as ready
Arthrogryposis v0.392 KIF5C Zornitza Stark Gene: kif5c has been classified as Green List (High Evidence).
Arthrogryposis v0.392 CNTN1 Zornitza Stark Marked gene: CNTN1 as ready
Arthrogryposis v0.392 CNTN1 Zornitza Stark Gene: cntn1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.392 CNTN1 Zornitza Stark Classified gene: CNTN1 as Amber List (moderate evidence)
Arthrogryposis v0.392 CNTN1 Zornitza Stark Gene: cntn1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.391 CNTN1 Zornitza Stark reviewed gene: CNTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 12, OMIM #612540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v0.391 CACNA1S Zornitza Stark Marked gene: CACNA1S as ready
Arthrogryposis v0.391 CACNA1S Zornitza Stark Gene: cacna1s has been classified as Green List (High Evidence).
Arthrogryposis v0.391 B3GALT6 Zornitza Stark Marked gene: B3GALT6 as ready
Arthrogryposis v0.391 B3GALT6 Zornitza Stark Gene: b3galt6 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.391 VRK1 Zornitza Stark Marked gene: VRK1 as ready
Arthrogryposis v0.391 VRK1 Zornitza Stark Gene: vrk1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.391 PPP3CA Zornitza Stark Marked gene: PPP3CA as ready
Arthrogryposis v0.391 PPP3CA Zornitza Stark Gene: ppp3ca has been classified as Green List (High Evidence).
Arthrogryposis v0.391 PMM2 Zornitza Stark Marked gene: PMM2 as ready
Arthrogryposis v0.391 PMM2 Zornitza Stark Gene: pmm2 has been classified as Green List (High Evidence).
Arthrogryposis v0.391 LMNA Zornitza Stark Marked gene: LMNA as ready
Arthrogryposis v0.391 LMNA Zornitza Stark Gene: lmna has been classified as Green List (High Evidence).
Arthrogryposis v0.391 FLVCR2 Zornitza Stark Marked gene: FLVCR2 as ready
Arthrogryposis v0.391 FLVCR2 Zornitza Stark Gene: flvcr2 has been classified as Green List (High Evidence).
Arthrogryposis v0.391 BIN1 Zornitza Stark Marked gene: BIN1 as ready
Arthrogryposis v0.391 BIN1 Zornitza Stark Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.391 TMEM5 Zornitza Stark Marked gene: TMEM5 as ready
Arthrogryposis v0.391 TMEM5 Zornitza Stark Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.391 TMEM5 Zornitza Stark Phenotypes for gene: TMEM5 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, MIM# 615041
Arthrogryposis v0.390 TMEM5 Zornitza Stark Mode of inheritance for gene: TMEM5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v0.389 FAM20C Zornitza Stark Marked gene: FAM20C as ready
Arthrogryposis v0.389 FAM20C Zornitza Stark Gene: fam20c has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.389 FAM20C Zornitza Stark Mode of inheritance for gene: FAM20C was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v0.388 FAM20C Zornitza Stark Phenotypes for gene: FAM20C were changed from to Raine syndrome, MIM# 259775
Arthrogryposis v0.387 DAG1 Zornitza Stark Marked gene: DAG1 as ready
Arthrogryposis v0.387 DAG1 Zornitza Stark Gene: dag1 has been classified as Red List (Low Evidence).
Arthrogryposis v0.387 DAG1 Zornitza Stark Phenotypes for gene: DAG1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9 (MIM#616538)
Arthrogryposis v0.386 B3GALNT2 Zornitza Stark Marked gene: B3GALNT2 as ready
Arthrogryposis v0.386 B3GALNT2 Zornitza Stark Gene: b3galnt2 has been classified as Red List (Low Evidence).
Arthrogryposis v0.386 B3GALNT2 Zornitza Stark Phenotypes for gene: B3GALNT2 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 11, MIM# 615181
Arthrogryposis v0.385 SLC35A3 Chirag Patel Classified gene: SLC35A3 as Green List (high evidence)
Arthrogryposis v0.385 SLC35A3 Chirag Patel Gene: slc35a3 has been classified as Green List (High Evidence).
Arthrogryposis v0.384 LIFR Chirag Patel Classified gene: LIFR as Green List (high evidence)
Arthrogryposis v0.384 LIFR Chirag Patel Gene: lifr has been classified as Green List (High Evidence).
Arthrogryposis v0.384 SLC35A3 Chirag Patel gene: SLC35A3 was added
gene: SLC35A3 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: SLC35A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35A3 were set to PMID: 28777481, 24031089, 28328131, 33416188
Phenotypes for gene: SLC35A3 were set to Arthrogryposis, impaired intellectual development, and seizures, OMIM #615553
Review for gene: SLC35A3 was set to GREEN
Added comment: Arthrogryposis, impaired intellectual development, and seizures (AMRS) is an autosomal recessive disorder characterized by skeletal abnormalities, including arthrogryposis, short limbs, and vertebral malformations, impaired intellectual development, and seizures consistent with early-onset epileptic encephalopathy in some patients. Other features may include cleft palate, micrognathia, posterior embryotoxon, talipes valgus, rocker-bottom feet, and dysmorphic facies.

4 families with 12 affected individuals reported with biallelic variants in SLC35A3 gene. Functional studies in one family showed patient cells showed no normal transcript, indicating that they had no functional SLC35A3 protein. Golgi vesicles derived from patient fibroblasts showed significantly reduced transport of UDP-GlcNAc compared to controls.
Sources: Expert list
Arthrogryposis v0.383 LIFR Chirag Patel gene: LIFR was added
gene: LIFR was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: LIFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIFR were set to PMID: 9674905, 9674906, 14740318, 24988918, 35663789
Phenotypes for gene: LIFR were set to Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, OMIM #601559
Review for gene: LIFR was set to GREEN
Added comment: Patients reported as having either neonatal SJS or STWS presented a combination of a severe, prenatal-onset neuromuscular disorder with congenital joint contractures, respiratory and feeding difficulties, tendency to hyperthermia, and frequent death in infancy and a distinct campomelic-metaphyseal skeletal dysplasia. Multiple families with biallelic variants in LIFR gene reported.
Sources: Expert list
Arthrogryposis v0.382 KY Chirag Patel Classified gene: KY as Green List (high evidence)
Arthrogryposis v0.382 KY Chirag Patel Gene: ky has been classified as Green List (High Evidence).
Arthrogryposis v0.381 KIF5C Chirag Patel Classified gene: KIF5C as Green List (high evidence)
Arthrogryposis v0.381 KIF5C Chirag Patel Gene: kif5c has been classified as Green List (High Evidence).
Arthrogryposis v0.381 KY Chirag Patel gene: KY was added
gene: KY was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: KY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KY were set to PMID: 27484770, 27485408, 30591934, 35752288
Phenotypes for gene: KY were set to Myopathy, myofibrillar, 7, OMIM #617114
Review for gene: KY was set to GREEN
Added comment: Myofibrillar myopathy-7 (MFM7) is an autosomal recessive muscle disorder characterized by early childhood onset of slowly progressive muscle weakness that primarily affects the lower limbs and is associated with joint contractures. 4 families with 6 affected individuals, with homozygous variants in KY gene. Immunostaining showed absence of the KY protein in patient muscle, consistent with a loss of function in one family.
Sources: Expert list
Arthrogryposis v0.380 KIF5C Chirag Patel gene: KIF5C was added
gene: KIF5C was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: KIF5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KIF5C were set to Cortical dysplasia, complex, with other brain malformations 2, OMIM #615282
Review for gene: KIF5C was set to GREEN
Added comment: 2 families with 5 affecteds with severe malformations of cortical development. One family with 4 siblings with severe arthrogryposis. Same heterozygous missense variant found in both families (E237V) in KIF5C gene.

Family 1: unaffected mother was determined to be germline mosaic for the mutation. In vitro functional expression studies in E. coli and COS-7 cells showed that the mutant protein had a complete loss of ATP hydrolysis activity. In COS-7 cells, mutant KIF5C heavily colocalized with microtubules throughout the cell, but did not appear as puncta or accumulate in cortical clusters as did the wildtype protein. Poirier et al. (2013) postulated a dominant-negative effect. The findings extended the association between microtubule-based cellular processes and proper cortical development.
Sources: Expert list
Arthrogryposis v0.379 CACNA1S Chirag Patel Classified gene: CACNA1S as Green List (high evidence)
Arthrogryposis v0.379 CACNA1S Chirag Patel Gene: cacna1s has been classified as Green List (High Evidence).
Arthrogryposis v0.378 CNTN1 Chirag Patel gene: CNTN1 was added
gene: CNTN1 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: CNTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTN1 were set to PMID:19026398
Phenotypes for gene: CNTN1 were set to Congenital myopathy 12, OMIM #612540
Review for gene: CNTN1 was set to RED
Added comment: Congenital myopathy-12 (CMYP12) is an autosomal recessive disorder characterized by severe neonatal hypotonia resulting in feeding difficulties and respiratory failure within the first months of life. There is evidence of the disorder in utero, with decreased fetal movements and polyhydramnios. Additional features may include high-arched palate and contractures. Skeletal muscle biopsy shows myopathic changes with disrupted sarcomeres and minicore-like structures. One family reported with homozygous mutation in the CNTN1 gene.
Sources: Expert list
Arthrogryposis v0.377 CACNA1S Chirag Patel gene: CACNA1S was added
gene: CACNA1S was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: CACNA1S was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA1S were set to PMID: 33060286, 31227654, 28012042
Phenotypes for gene: CACNA1S were set to Congenital myopathy 18 due to dihydropyridine receptor defect, OMIM #620246
Review for gene: CACNA1S was set to GREEN
Added comment: Congenital myopathy-18 (CMYP18) is a disorder of the skeletal muscle characterized by the onset of symptoms of muscle weakness in early childhood, including in utero and infancy. There is clinical heterogeneity in the manifestations and severity, ranging from fetal akinesia sequence causing early death to onset of symptoms in adulthood.
Sources: Expert list
Arthrogryposis v0.376 B3GALT6 Chirag Patel Classified gene: B3GALT6 as Amber List (moderate evidence)
Arthrogryposis v0.376 B3GALT6 Chirag Patel Gene: b3galt6 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.376 VRK1 Chirag Patel Classified gene: VRK1 as Amber List (moderate evidence)
Arthrogryposis v0.376 VRK1 Chirag Patel Gene: vrk1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.375 B3GALT6 Chirag Patel gene: B3GALT6 was added
gene: B3GALT6 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: B3GALT6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B3GALT6 were set to PMID: 29443383, 25149931
Phenotypes for gene: B3GALT6 were set to Al-Gazali syndrome, OMIM #609465
Review for gene: B3GALT6 was set to AMBER
Added comment: Al-Gazali syndrome (ALGAZ) is characterized by prenatal growth retardation, skeletal anomalies including joint contractures, camptodactyly, and bilateral talipes equinovarus, small mouth, anterior segment eye anomalies, and early lethality.

In an infant with Al-Gazali syndrome, Sellars et al. (2014) identified compound heterozygous missense mutations in the B3GALT6 gene. The mutation, which was found by exome sequencing, segregated with the disorder in the family.

In 1 of the Palestinian infants with Al-Gazali syndrome reported by al-Gazali et al. (1999), Ben-Mahmoud et al. (2018) identified homozygosity for a missense mutation in the B3GALT6 gene. The parents were heterozygous for the mutation.
Sources: Expert list
Arthrogryposis v0.374 VRK1 Chirag Patel gene: VRK1 was added
gene: VRK1 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: VRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VRK1 were set to PMID: 21937992, 21937992
Phenotypes for gene: VRK1 were set to Pontocerebellar hypoplasia type 1A, OMIM# 607596
Review for gene: VRK1 was set to AMBER
Added comment: contractures reported and mutation found in 2 families
Sources: Expert list
Arthrogryposis v0.373 PPP3CA Chirag Patel Classified gene: PPP3CA as Green List (high evidence)
Arthrogryposis v0.373 PPP3CA Chirag Patel Gene: ppp3ca has been classified as Green List (High Evidence).
Arthrogryposis v0.372 PMM2 Chirag Patel Classified gene: PMM2 as Green List (high evidence)
Arthrogryposis v0.372 PMM2 Chirag Patel Gene: pmm2 has been classified as Green List (High Evidence).
Arthrogryposis v0.372 PPP3CA Chirag Patel gene: PPP3CA was added
gene: PPP3CA was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: PPP3CA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP3CA were set to PMID: 29432562
Phenotypes for gene: PPP3CA were set to Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, OMIM #618265
Review for gene: PPP3CA was set to GREEN
Added comment: 2 unrelated patients with arthrogryposis, cleft palate, craniosynostosis, micrognathia, short stature, and impaired intellectual development. Whole-exome sequencing (+ Sanger confirmation) found de novo heterozygous mutations in the autoinhibitory domain of PPP3CA gene. Using a yeast model, the mutations were found to be constitutively activating.
Sources: Expert list
Arthrogryposis v0.371 PMM2 Chirag Patel gene: PMM2 was added
gene: PMM2 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PMM2 were set to Congenital disorder of glycosylation, type Ia, OMIM #212065
Review for gene: PMM2 was set to GREEN
Added comment: Arthrogryposis reported
Sources: Expert list
Arthrogryposis v0.370 LMNA Chirag Patel Classified gene: LMNA as Green List (high evidence)
Arthrogryposis v0.370 LMNA Chirag Patel Gene: lmna has been classified as Green List (High Evidence).
Arthrogryposis v0.369 LMNA Chirag Patel gene: LMNA was added
gene: LMNA was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: LMNA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNA were set to PMID:18551513
Phenotypes for gene: LMNA were set to Muscular dystrophy, congenital, OMIM #613205
Review for gene: LMNA was set to GREEN
Added comment: Arthrogryposis reported
Sources: Expert list
Arthrogryposis v0.368 FLVCR2 Chirag Patel Classified gene: FLVCR2 as Green List (high evidence)
Arthrogryposis v0.368 FLVCR2 Chirag Patel Gene: flvcr2 has been classified as Green List (High Evidence).
Arthrogryposis v0.367 FLVCR2 Chirag Patel gene: FLVCR2 was added
gene: FLVCR2 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: FLVCR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR2 were set to PMID: 20206334, 20014121, 20014121
Phenotypes for gene: FLVCR2 were set to Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome, OMIM #225790
Review for gene: FLVCR2 was set to GREEN
Added comment: Severe arthrogryposis disorder
Sources: Expert list
Arthrogryposis v0.366 BIN1 Chirag Patel Classified gene: BIN1 as Green List (high evidence)
Arthrogryposis v0.366 BIN1 Chirag Patel Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.366 BIN1 Chirag Patel Classified gene: BIN1 as Green List (high evidence)
Arthrogryposis v0.366 BIN1 Chirag Patel Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.366 BIN1 Chirag Patel Classified gene: BIN1 as Green List (high evidence)
Arthrogryposis v0.366 BIN1 Chirag Patel Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.365 BIN1 Chirag Patel gene: BIN1 was added
gene: BIN1 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: BIN1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BIN1 were set to Centronuclear myopathy 2; OMIM #255200
Review for gene: BIN1 was set to GREEN
Added comment: Arthrogryposis reported
Sources: Expert list
Arthrogryposis v0.364 TMEM5 Chirag Patel Classified gene: TMEM5 as Red List (low evidence)
Arthrogryposis v0.364 TMEM5 Chirag Patel Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.364 TMEM5 Chirag Patel Classified gene: TMEM5 as Red List (low evidence)
Arthrogryposis v0.364 TMEM5 Chirag Patel Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.364 TMEM5 Chirag Patel Classified gene: TMEM5 as Red List (low evidence)
Arthrogryposis v0.364 TMEM5 Chirag Patel Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.363 TMEM5 Chirag Patel reviewed gene: TMEM5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.363 FAM20C Chirag Patel Classified gene: FAM20C as Amber List (moderate evidence)
Arthrogryposis v0.363 FAM20C Chirag Patel Gene: fam20c has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.362 FAM20C Chirag Patel reviewed gene: FAM20C: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.362 DAG1 Chirag Patel Classified gene: DAG1 as Red List (low evidence)
Arthrogryposis v0.362 DAG1 Chirag Patel Gene: dag1 has been classified as Red List (Low Evidence).
Arthrogryposis v0.361 DAG1 Chirag Patel reviewed gene: DAG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.361 B4GAT1 Chirag Patel Classified gene: B4GAT1 as Red List (low evidence)
Arthrogryposis v0.361 B4GAT1 Chirag Patel Gene: b4gat1 has been classified as Red List (Low Evidence).
Arthrogryposis v0.360 B4GAT1 Chirag Patel reviewed gene: B4GAT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.360 B3GALNT2 Chirag Patel Classified gene: B3GALNT2 as Red List (low evidence)
Arthrogryposis v0.360 B3GALNT2 Chirag Patel Gene: b3galnt2 has been classified as Red List (Low Evidence).
Arthrogryposis v0.359 B3GALNT2 Chirag Patel reviewed gene: B3GALNT2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
BabyScreen+ newborn screening v0.2048 RAC2 Zornitza Stark Marked gene: RAC2 as ready
BabyScreen+ newborn screening v0.2048 RAC2 Zornitza Stark Gene: rac2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2048 RAC2 Zornitza Stark Phenotypes for gene: RAC2 were changed from Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986 to Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopenia MIM# 618986
BabyScreen+ newborn screening v0.2047 RAC2 Zornitza Stark Classified gene: RAC2 as Green List (high evidence)
BabyScreen+ newborn screening v0.2047 RAC2 Zornitza Stark Gene: rac2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2046 RAC2 Zornitza Stark gene: RAC2 was added
gene: RAC2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: RAC2.
Mode of inheritance for gene: RAC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RAC2 were set to Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986
Review for gene: RAC2 was set to GREEN
Added comment: Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia
13 individuals from 8 unrelated families; mono-allelic; gain of function; multiple mouse models

Mono-allelic missense variants were reported in each individual (5 x De Novo) and resulted in a gain-of -function. (E62K, P34H, N92T, G12R)

These individuals typically presented in infancy with frequent infections, profound leukopaenia, lymphopaenia diarrhoea and hypogammaglobulinaemia.

SCID-like phenotype.

Treatment: IVIG, BMT

Note evidence for the other two immunodeficiency disorders associated with this gene is limited.
Sources: Expert list
BabyScreen+ newborn screening v0.2045 PLS3 Zornitza Stark Marked gene: PLS3 as ready
BabyScreen+ newborn screening v0.2045 PLS3 Zornitza Stark Gene: pls3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2045 PLS3 Zornitza Stark Classified gene: PLS3 as Green List (high evidence)
BabyScreen+ newborn screening v0.2045 PLS3 Zornitza Stark Gene: pls3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2044 PLS3 Zornitza Stark Tag treatable tag was added to gene: PLS3.
Tag skeletal tag was added to gene: PLS3.
BabyScreen+ newborn screening v0.2044 PLS3 Zornitza Stark gene: PLS3 was added
gene: PLS3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: PLS3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PLS3 were set to 32655496; 25209159; 29736964; 29884797; 28777485; 24088043
Phenotypes for gene: PLS3 were set to Bone mineral density QTL18, osteoporosis - MIM#300910
Review for gene: PLS3 was set to GREEN
Added comment: Females mildly affected: exclude from screening.

Presentation in males similar to OI, though also variable in severity.

Treatment: safe handling techniques, bisphosphonates, pamidronate, zoledronic acid, teriparatide, denosumab, alendronate

Non-genetic confirmatory testing: skeletal survey
Sources: Expert list
BabyScreen+ newborn screening v0.2043 OTULIN Zornitza Stark Marked gene: OTULIN as ready
BabyScreen+ newborn screening v0.2043 OTULIN Zornitza Stark Gene: otulin has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2043 OTULIN Zornitza Stark Classified gene: OTULIN as Green List (high evidence)
BabyScreen+ newborn screening v0.2043 OTULIN Zornitza Stark Gene: otulin has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2042 OTULIN Zornitza Stark gene: OTULIN was added
gene: OTULIN was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: OTULIN.
Mode of inheritance for gene: OTULIN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: OTULIN were set to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099
Review for gene: OTULIN was set to GREEN
Added comment: Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) is an autosomal recessive autoinflammatory disease characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy. Additional features may include diarrhea, increased serum C-reactive protein (CRP), leukocytosis, and neutrophilia in the absence of any infection.

Onset is generally in infancy.

Treatment: inflixiimab, anakinra, etanercept, corticosteroids.

Non-genetic confirmatory testing: no.
Sources: Expert list
BabyScreen+ newborn screening v0.2041 OAS1 Zornitza Stark Marked gene: OAS1 as ready
BabyScreen+ newborn screening v0.2041 OAS1 Zornitza Stark Gene: oas1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2041 OAS1 Zornitza Stark Classified gene: OAS1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2041 OAS1 Zornitza Stark Gene: oas1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2040 OAS1 Zornitza Stark gene: OAS1 was added
gene: OAS1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: OAS1.
Mode of inheritance for gene: OAS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OAS1 were set to 34145065; 29455859
Phenotypes for gene: OAS1 were set to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinaemia, MIM#618042
Review for gene: OAS1 was set to GREEN
Added comment: Immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100) is primarily a lung disorder characterized by onset of respiratory insufficiency due to pulmonary alveolar proteinosis (PAP) in the first months of life. Affected individuals may have normal respiratory function at birth. Development of the disorder appears to be influenced or triggered by viral infection, manifest as progressive respiratory insufficiency, confluent consolidations on lung imaging, and diffuse collection of periodic acid-Schiff (PAS)-positive material in pulmonary alveoli associated with small and nonfoamy alveolar macrophages. Patients also have hypogammaglobulinemia, leukocytosis, and splenomegaly. Many patients die of respiratory failure in infancy or early childhood.

Treatment: IVIG; BMT is curative.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
Inflammatory bowel disease v0.93 NLRC4 Zornitza Stark Marked gene: NLRC4 as ready
Inflammatory bowel disease v0.93 NLRC4 Zornitza Stark Gene: nlrc4 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.93 NLRC4 Zornitza Stark Phenotypes for gene: NLRC4 were changed from Infantile onset enterocolitis and autoinflammation to Autoinflammation with infantile enterocolitis, MIM# 616050
Inflammatory bowel disease v0.92 NLRC4 Zornitza Stark Publications for gene: NLRC4 were set to PMID: 25217960
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark edited their review of gene: NLRC4: Changed publications: 25217959, 25217960
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark edited their review of gene: NLRC4: Changed publications: 25217959
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark Classified gene: NLRC4 as Amber List (moderate evidence)
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark Gene: nlrc4 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.90 NLRC4 Zornitza Stark reviewed gene: NLRC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 25217960; Phenotypes: Autoinflammation with infantile enterocolitis 616050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5192 TAB2 Lucy Spencer gene: TAB2 was added
gene: TAB2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAB2 were set to 35971781
Phenotypes for gene: TAB2 were set to Congenital heart defects, multiple types, 2 MONDO:0014000
Review for gene: TAB2 was set to GREEN
Added comment: PMID: 35971781 - expansion of the phenotype, 14 patients with TAB2 variants 6 have dev delay and 4 are also listed as having ID along with other phenotype features associated with this gene.

Note- there is a previous review of this paper in the mendeilome as amber
Sources: Literature
BabyScreen+ newborn screening v0.2039 NFKBIA Zornitza Stark Marked gene: NFKBIA as ready
BabyScreen+ newborn screening v0.2039 NFKBIA Zornitza Stark Gene: nfkbia has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2039 NFKBIA Zornitza Stark Classified gene: NFKBIA as Green List (high evidence)
BabyScreen+ newborn screening v0.2039 NFKBIA Zornitza Stark Gene: nfkbia has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2038 NFKBIA Zornitza Stark gene: NFKBIA was added
gene: NFKBIA was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: NFKBIA.
Mode of inheritance for gene: NFKBIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NFKBIA were set to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132
Review for gene: NFKBIA was set to GREEN
Added comment: 12 heterozygous variants were identified in 15 unrelated individuals (de novo in 14 individuals and somatic mosaicism in 1 individual).

Functional studies & two mouse models; demonstrate reported NFKBIA gain-of-function variants resulting in impaired NFKB1 activity.

The majority of individuals displayed recurrent infections, chronic diarrhoea, agammaglobulinaemia, increased IgM, and defects in teeth (hair, nail, sweat glands).

Onset is generally in infancy.

Treatment: BMT.

Non-genetic confirmatory testing: no
Sources: Expert list
BabyScreen+ newborn screening v0.2037 NAXE Zornitza Stark Marked gene: NAXE as ready
BabyScreen+ newborn screening v0.2037 NAXE Zornitza Stark Gene: naxe has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2037 NAXE Zornitza Stark gene: NAXE was added
gene: NAXE was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: NAXE.
Mode of inheritance for gene: NAXE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXE were set to 27122014; 27616477; 31758406
Phenotypes for gene: NAXE were set to Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186
Review for gene: NAXE was set to RED
Added comment: Early-onset progressive encephalopathy with brain oedema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported.

Treatment: niacin

However, single case reported. Treatment not established.
Sources: Expert list
BabyScreen+ newborn screening v0.2036 NAXD Zornitza Stark Marked gene: NAXD as ready
BabyScreen+ newborn screening v0.2036 NAXD Zornitza Stark Gene: naxd has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2036 NAXD Zornitza Stark Classified gene: NAXD as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2036 NAXD Zornitza Stark Gene: naxd has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2035 NAXD Zornitza Stark gene: NAXD was added
gene: NAXD was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: NAXD.
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to 30576410; 31755961; 32462209; 35231119
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321
Review for gene: NAXD was set to AMBER
Added comment: Seven unrelated cases, episodes of fever/infection prior to deterioration reported. Variable phenotype: one patient reported with neurodevelopmental disorder, autism spectrum disorder and a muscular-dystrophy-like myopathy; another with progressive encephalopathy with brain oedema. Patient cells and muscle biopsies also showed impaired mitochondrial function, higher sensitivity to metabolic stress, and decreased mitochondrial reactive oxygen species production. In vitro functional assays also conducted.

Treatment: niacin

However, only two cases reported. Treatment not established.
Sources: Expert list
BabyScreen+ newborn screening v0.2034 MYD88 Zornitza Stark Marked gene: MYD88 as ready
BabyScreen+ newborn screening v0.2034 MYD88 Zornitza Stark Gene: myd88 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2034 MYD88 Zornitza Stark Classified gene: MYD88 as Green List (high evidence)
BabyScreen+ newborn screening v0.2034 MYD88 Zornitza Stark Gene: myd88 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2033 MYD88 Zornitza Stark gene: MYD88 was added
gene: MYD88 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: MYD88.
Mode of inheritance for gene: MYD88 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYD88 were set to 18669862; 20538326; 31301515
Phenotypes for gene: MYD88 were set to Immunodeficiency 68, MIM# 612260
Review for gene: MYD88 was set to GREEN
Added comment: Immunodeficiency-68 (IMD68) is an autosomal recessive primary immunodeficiency characterized by severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common organisms implicated are Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas, although other organisms may be observed.

At least 7 families and a mouse model.

Treatment: Prophylactic antibiotic treatment, pneumococcal, meningococcal, haemophilus influenzae vaccines, and immunoglobulin replacement.

Non-genetic confirmatory testing: toll-like receptor function
Sources: Expert list
BabyScreen+ newborn screening v0.2032 MTHFS Zornitza Stark Marked gene: MTHFS as ready
BabyScreen+ newborn screening v0.2032 MTHFS Zornitza Stark Gene: mthfs has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2032 MTHFS Zornitza Stark gene: MTHFS was added
gene: MTHFS was added to Baby Screen+ newborn screening. Sources: Expert list
metabolic tags were added to gene: MTHFS.
Mode of inheritance for gene: MTHFS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFS were set to 30031689; 31844630; 22303332
Phenotypes for gene: MTHFS were set to Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367
Review for gene: MTHFS was set to RED
Added comment: Established gene-disease association.

Onset in infancy. Severe disorder.

Treatment: single report of some improvement with combination of oral L-5- methyltetrahydrofolate and intramuscular methylcobalamin
Sources: Expert list
BabyScreen+ newborn screening v0.2031 MTHFD1 Zornitza Stark Marked gene: MTHFD1 as ready
BabyScreen+ newborn screening v0.2031 MTHFD1 Zornitza Stark Gene: mthfd1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2031 MTHFD1 Zornitza Stark Classified gene: MTHFD1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2031 MTHFD1 Zornitza Stark Gene: mthfd1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2030 MTHFD1 Zornitza Stark gene: MTHFD1 was added
gene: MTHFD1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological, haematological tags were added to gene: MTHFD1.
Mode of inheritance for gene: MTHFD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFD1 were set to 32414565; 19033438
Phenotypes for gene: MTHFD1 were set to Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinaemia MIM # 617780
Review for gene: MTHFD1 was set to GREEN
Added comment: 8 individuals from 4 unrelated families have been reported; multiple mouse models

7 individuals were Compound heterozygous (nonsense & missense) and 1 was homozygous (missense) for MTHFD1 variants often resulting in alteration of highly conserved residues in binding-sites.

Individuals typically present with megaloblastic anaemia, atypical hemolytic uremic syndrome, hyperhomocysteinaemia, microangiopathy, recurrent infections and autoimmune diseases.

Treatment: hydroxocobalamin, folinic acid and betaine

Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, complete blood count with MCV, plasma homocysteine and methylmalonic acid levels, CSF
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.5192 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder, MONDO:0700092, UBE3C-related to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Intellectual disability syndromic and non-syndromic v0.5191 UBE3C Zornitza Stark edited their review of gene: UBE3C: Changed phenotypes: Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.741 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder, MONDO:0700092, UBE3C-related to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.740 UBE3C Zornitza Stark edited their review of gene: UBE3C: Changed phenotypes: Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Angelman Rett like syndromes v1.8 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder, MONDO:0700092, UBE3C-related to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Angelman Rett like syndromes v1.7 UBE3C Zornitza Stark edited their review of gene: UBE3C: Changed phenotypes: Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.740 MS4A1 Zornitza Stark Publications for gene: MS4A1 were set to 20038800
Mendeliome v1.739 MS4A1 Zornitza Stark Classified gene: MS4A1 as Amber List (moderate evidence)
Mendeliome v1.739 MS4A1 Zornitza Stark Gene: ms4a1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2029 MNX1 Zornitza Stark Marked gene: MNX1 as ready
BabyScreen+ newborn screening v0.2029 MNX1 Zornitza Stark Gene: mnx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2029 MNX1 Zornitza Stark Classified gene: MNX1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2029 MNX1 Zornitza Stark Gene: mnx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2028 MNX1 Zornitza Stark gene: MNX1 was added
gene: MNX1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: MNX1.
Mode of inheritance for gene: MNX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MNX1 were set to 36586106
Phenotypes for gene: MNX1 were set to Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Review for gene: MNX1 was set to GREEN
Added comment: Three unrelated families reported. Presentation is in newborn period.

Treatment: insulin.

Non-genetic confirmatory testing: glucose tolerance test, hemoglobin A1C, insulin level, glucose level
Sources: Expert list
Mendeliome v1.738 MNX1 Zornitza Stark Phenotypes for gene: MNX1 were changed from Currarino syndrome, MIM# 176450 to Currarino syndrome, MIM# 176450; Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Mendeliome v1.737 MNX1 Zornitza Stark Mode of inheritance for gene: MNX1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic Diabetes v0.38 MNX1 Zornitza Stark Marked gene: MNX1 as ready
Monogenic Diabetes v0.38 MNX1 Zornitza Stark Gene: mnx1 has been classified as Green List (High Evidence).
Monogenic Diabetes v0.38 MNX1 Zornitza Stark Phenotypes for gene: MNX1 were changed from to Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Monogenic Diabetes v0.37 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586106; Phenotypes: Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.736 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586106; Phenotypes: Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2027 MALT1 Zornitza Stark Marked gene: MALT1 as ready
BabyScreen+ newborn screening v0.2027 MALT1 Zornitza Stark Gene: malt1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2027 MALT1 Zornitza Stark Classified gene: MALT1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2027 MALT1 Zornitza Stark Gene: malt1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2026 MALT1 Zornitza Stark gene: MALT1 was added
gene: MALT1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: MALT1.
Mode of inheritance for gene: MALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MALT1 were set to Immunodeficiency 12 MIM# 615468
Review for gene: MALT1 was set to GREEN
Added comment: 5 individuals from 3 unrelated families with immunodeficiency phenotype have reported variants in MALT1; two MALT1-knockout mouse models displaying primary T- and B-cell lymphocyte deficiency.

Variants identified were homozygous missense variants resulting in the alteration of highly conserved residue domains.

All individuals reported onset in infancy of recurrent bacterial/ fungal/ viral infections leading to bronchiectasis and poor T-cell proliferation.

Treatment: prophylactic antibiotics, IVIG, BMT.

Non-genetic confirmatory testing: no
Sources: Expert list
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Marked gene: RIPK4 as ready
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Gene: ripk4 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Classified gene: RIPK4 as Green List (high evidence)
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Gene: ripk4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2025 MAGT1 Zornitza Stark Marked gene: MAGT1 as ready
BabyScreen+ newborn screening v0.2025 MAGT1 Zornitza Stark Gene: magt1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2025 MAGT1 Zornitza Stark Classified gene: MAGT1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2025 MAGT1 Zornitza Stark Gene: magt1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2024 MAGT1 Zornitza Stark gene: MAGT1 was added
gene: MAGT1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: MAGT1.
Mode of inheritance for gene: MAGT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MAGT1 were set to 31036665; 31714901
Phenotypes for gene: MAGT1 were set to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853)
Review for gene: MAGT1 was set to GREEN
Added comment: XMEN is an X-linked recessive immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. Affected individuals have chronic Epstein-Barr virus (EBV) infection and are susceptible to the development of EBV-associated B-cell lymphoproliferative disorders.

Variable age of onset, including in early childhood.

Treatment: Mg supplementation; IVIG, BMT.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile, Carbohydrate deficient glycosylation profile
Sources: Expert list
BabyScreen+ newborn screening v0.2023 LRBA Zornitza Stark Marked gene: LRBA as ready
BabyScreen+ newborn screening v0.2023 LRBA Zornitza Stark Gene: lrba has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2023 LRBA Zornitza Stark Classified gene: LRBA as Green List (high evidence)
BabyScreen+ newborn screening v0.2023 LRBA Zornitza Stark Gene: lrba has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2022 LRBA Zornitza Stark gene: LRBA was added
gene: LRBA was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: LRBA.
Mode of inheritance for gene: LRBA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRBA were set to 22608502; 22721650; 25468195; 26206937; 33155142; 31887391
Phenotypes for gene: LRBA were set to Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700
Review for gene: LRBA was set to GREEN
Added comment: Well established gene-disease association.

Generally childhood onset with recurrent infections and autoimmune phenomena.

Treatment: abatacept, BMT.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
BabyScreen+ newborn screening v0.2021 LIG1 Zornitza Stark Marked gene: LIG1 as ready
BabyScreen+ newborn screening v0.2021 LIG1 Zornitza Stark Gene: lig1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2021 LIG1 Zornitza Stark Classified gene: LIG1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2021 LIG1 Zornitza Stark Gene: lig1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2020 LIG1 Zornitza Stark gene: LIG1 was added
gene: LIG1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: LIG1.
Mode of inheritance for gene: LIG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG1 were set to 30395541
Phenotypes for gene: LIG1 were set to Immunodeficiency 96, MIM# 619774
Review for gene: LIG1 was set to GREEN
Added comment: Established gene-disease association.

Onset is generally in early childhood.

Presents with recurrent severe infections.

Treatment: IVIG, BMT.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile, complete blood count
Sources: Expert list
BabyScreen+ newborn screening v0.2019 LEP Zornitza Stark Marked gene: LEP as ready
BabyScreen+ newborn screening v0.2019 LEP Zornitza Stark Gene: lep has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2019 LEP Zornitza Stark Classified gene: LEP as Green List (high evidence)
BabyScreen+ newborn screening v0.2019 LEP Zornitza Stark Gene: lep has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2018 LEP Zornitza Stark gene: LEP was added
gene: LEP was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: LEP.
Mode of inheritance for gene: LEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LEP were set to 26567097
Phenotypes for gene: LEP were set to Obesity, morbid, due to leptin deficiency (MIM#614962)
Review for gene: LEP was set to GREEN
Added comment: Established gene-disease association.

Onset is in infancy/early childhood. Similar disorders included.

Treatment: metreleptin.

Non-genetic confirmatory testing: leptin level.
Sources: Expert list
BabyScreen+ newborn screening v0.2017 JAGN1 Zornitza Stark Marked gene: JAGN1 as ready
BabyScreen+ newborn screening v0.2017 JAGN1 Zornitza Stark Gene: jagn1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2017 JAGN1 Zornitza Stark Classified gene: JAGN1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2017 JAGN1 Zornitza Stark Gene: jagn1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2016 JAGN1 Zornitza Stark gene: JAGN1 was added
gene: JAGN1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: JAGN1.
Mode of inheritance for gene: JAGN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JAGN1 were set to 25129144
Phenotypes for gene: JAGN1 were set to Neutropenia, severe congenital, 6, autosomal recessive, MIM# 616022
Review for gene: JAGN1 was set to GREEN
Added comment: Established gene-disease association.

Typically presents in early childhood with severe infections.

Treatment: G-CSF, BMT.

Non-genetic confirmatory testing: complete blood count, bone marrow aspiration and biopsy
Sources: Expert list
BabyScreen+ newborn screening v0.2015 TNFRSF13C Zornitza Stark Marked gene: TNFRSF13C as ready
BabyScreen+ newborn screening v0.2015 TNFRSF13C Zornitza Stark Gene: tnfrsf13c has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2015 TNFRSF13C Zornitza Stark Classified gene: TNFRSF13C as Red List (low evidence)
BabyScreen+ newborn screening v0.2015 TNFRSF13C Zornitza Stark Gene: tnfrsf13c has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2014 ITK Zornitza Stark Marked gene: ITK as ready
BabyScreen+ newborn screening v0.2014 ITK Zornitza Stark Gene: itk has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2014 ITK Zornitza Stark Classified gene: ITK as Green List (high evidence)
BabyScreen+ newborn screening v0.2014 ITK Zornitza Stark Gene: itk has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2013 ITK Zornitza Stark gene: ITK was added
gene: ITK was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: ITK.
Mode of inheritance for gene: ITK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ITK were set to Lymphoproliferative syndrome 1, MIM# 613011
Review for gene: ITK was set to GREEN
Added comment: 7 individuals from 5 unrelated families reported homozygous (missense/ nonsense) ITK variants consistent with Lymphoproliferative syndrome phenotype. Triggered by EBV infection.

Two ITK-deficient mouse models demonstrated reduced T cells (CD4+), causing decreased CD4 to CD8 ratio.

Patients displayed early onset of features typically including fever, lymphadenopathy, autoimmune disorders, low immunoglobulins and high EBV viral load.

Fatal without BMT.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile.
Sources: Expert list
BabyScreen+ newborn screening v0.2012 IRS4 Zornitza Stark changed review comment from: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.

Most identified through standard NBS.
Sources: Expert list; to: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.

Most identified through standard NBS.

Treatment: thyroxine.
Sources: Expert list
BabyScreen+ newborn screening v0.2012 IRS4 Zornitza Stark Marked gene: IRS4 as ready
BabyScreen+ newborn screening v0.2012 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2012 IRS4 Zornitza Stark Classified gene: IRS4 as Green List (high evidence)
BabyScreen+ newborn screening v0.2012 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2011 IRS4 Zornitza Stark gene: IRS4 was added
gene: IRS4 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: IRS4.
Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IRS4 were set to 30061370
Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Review for gene: IRS4 was set to GREEN
Added comment: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.

Most identified through standard NBS.
Sources: Expert list
Mendeliome v1.736 IRS4 Zornitza Stark Marked gene: IRS4 as ready
Mendeliome v1.736 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Mendeliome v1.736 IRS4 Zornitza Stark Classified gene: IRS4 as Green List (high evidence)
Mendeliome v1.736 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Mendeliome v1.735 IRS4 Zornitza Stark gene: IRS4 was added
gene: IRS4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IRS4 were set to 30061370
Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Review for gene: IRS4 was set to GREEN
Added comment: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.
Sources: Expert Review
Congenital hypothyroidism v0.38 IRS4 Zornitza Stark Marked gene: IRS4 as ready
Congenital hypothyroidism v0.38 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.38 IRS4 Zornitza Stark Phenotypes for gene: IRS4 were changed from Congenital central hypothyroidism to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Congenital hypothyroidism v0.37 IRS4 Zornitza Stark reviewed gene: IRS4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30061370; Phenotypes: Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
BabyScreen+ newborn screening v0.2010 TNFRSF13C Lilian Downie gene: TNFRSF13C was added
gene: TNFRSF13C was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFRSF13C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFRSF13C were set to PMID: 19666484, PMID: 27250108, PMID: 18025937
Phenotypes for gene: TNFRSF13C were set to Immunodeficiency, common variable, 4 MIM#613494
Review for gene: TNFRSF13C was set to RED
Added comment: Amber in our mendeliome
Later childhood or adult onset.
BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.
Sources: Expert list
BabyScreen+ newborn screening v0.2010 IL36RN Zornitza Stark Marked gene: IL36RN as ready
BabyScreen+ newborn screening v0.2010 IL36RN Zornitza Stark Gene: il36rn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2010 IL36RN Zornitza Stark Classified gene: IL36RN as Green List (high evidence)
BabyScreen+ newborn screening v0.2010 IL36RN Zornitza Stark Gene: il36rn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2009 IL36RN Zornitza Stark gene: IL36RN was added
gene: IL36RN was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL36RN.
Mode of inheritance for gene: IL36RN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL36RN were set to 31286990
Phenotypes for gene: IL36RN were set to Psoriasis 14, pustular, MIM# 614204
Review for gene: IL36RN was set to GREEN
Added comment: Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein.

Variable age of onset but predominantly in infancy/early childhood.

Treatment: ustekinumab, secukinumab, etanercept.
Sources: Expert list
BabyScreen+ newborn screening v0.2008 IL2RA Zornitza Stark Marked gene: IL2RA as ready
BabyScreen+ newborn screening v0.2008 IL2RA Zornitza Stark Gene: il2ra has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2008 IL2RA Zornitza Stark Classified gene: IL2RA as Green List (high evidence)
BabyScreen+ newborn screening v0.2008 IL2RA Zornitza Stark Gene: il2ra has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2007 IL2RA Zornitza Stark gene: IL2RA was added
gene: IL2RA was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL2RA.
Mode of inheritance for gene: IL2RA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IL2RA were set to Immunodeficiency 41 with lymphoproliferation and autoimmunity, MIM# 606367
Review for gene: IL2RA was set to GREEN
Added comment: Immunodeficiency-41 is a disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation.

At least 4 unrelated families reported.

Treatment: rapamycin, bone marrow transplant.

Confirmatory non-genetic testing: flow cytometric analysis.
Sources: Expert list
BabyScreen+ newborn screening v0.2006 IL21R Zornitza Stark Marked gene: IL21R as ready
BabyScreen+ newborn screening v0.2006 IL21R Zornitza Stark Gene: il21r has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2006 IL21R Zornitza Stark Classified gene: IL21R as Green List (high evidence)
BabyScreen+ newborn screening v0.2006 IL21R Zornitza Stark Gene: il21r has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2005 IL21R Zornitza Stark gene: IL21R was added
gene: IL21R was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL21R.
Mode of inheritance for gene: IL21R was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IL21R were set to Immunodeficiency 56, MIM# 615207
Review for gene: IL21R was set to GREEN
Added comment: Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections.

More than 20 individuals reported. Recent series of 13 individuals: the main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinaemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients.

Onset: infancy/early childhood.

Treatment: BMT.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
BabyScreen+ newborn screening v0.2004 IL1RN Zornitza Stark Marked gene: IL1RN as ready
BabyScreen+ newborn screening v0.2004 IL1RN Zornitza Stark Gene: il1rn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2004 IL1RN Zornitza Stark Classified gene: IL1RN as Green List (high evidence)
BabyScreen+ newborn screening v0.2004 IL1RN Zornitza Stark Gene: il1rn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2003 IL1RN Zornitza Stark gene: IL1RN was added
gene: IL1RN was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL1RN.
Mode of inheritance for gene: IL1RN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IL1RN were set to Interleukin 1 receptor antagonist deficiency, MIM# 612852
Review for gene: IL1RN was set to GREEN
Added comment: Severe immunodeficiency, onset in infancy. Multi-system involvement, can be fatal if untreated.

Treatment: anakinra, etanercept, methotrexate, corticosteroid
Sources: Expert list
BabyScreen+ newborn screening v0.2002 IKZF1 Zornitza Stark Marked gene: IKZF1 as ready
BabyScreen+ newborn screening v0.2002 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2002 IKZF1 Zornitza Stark Classified gene: IKZF1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2002 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2001 IKZF1 Zornitza Stark Tag treatable tag was added to gene: IKZF1.
Tag immunological tag was added to gene: IKZF1.
BabyScreen+ newborn screening v0.2001 IKZF1 Zornitza Stark edited their review of gene: IKZF1: Changed rating: GREEN
BabyScreen+ newborn screening v0.2001 IKZF1 Zornitza Stark gene: IKZF1 was added
gene: IKZF1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: IKZF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: IKZF1 were set to Immunodeficiency, common variable, 13 MIM# 616873
Added comment: Over 25 individuals from 9 unrelated families with variants in IKZF1 displaying Immunodeficiency; three mouse models Heterozygous missense, frameshift and deletion variants in IKZF1 gene resulting in loss or alteration of a zinc finger DNA contact site cause LoF. Typically presents with recurrent bacterial respiratory infections, hypogammaglobulinaemia and low Ig levels; variable age of onset.

PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation.

Included primarily for LoF phenotype.

Treatment: IVIG and BMT.

Non-genetic confirmatory testing: immunoglobulin levels
Sources: Expert list
BabyScreen+ newborn screening v0.2000 IKBKB Zornitza Stark changed review comment from: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells.

Treatment: bone marrow transplant.
Sources: Expert list; to: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells.

Treatment: bone marrow transplant.

Limited evidence for mono-allelic disease.
Sources: Expert list
BabyScreen+ newborn screening v0.2000 IKBKB Zornitza Stark Marked gene: IKBKB as ready
BabyScreen+ newborn screening v0.2000 IKBKB Zornitza Stark Gene: ikbkb has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2000 IKBKB Zornitza Stark Classified gene: IKBKB as Green List (high evidence)
BabyScreen+ newborn screening v0.2000 IKBKB Zornitza Stark Gene: ikbkb has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1999 IKBKB Zornitza Stark gene: IKBKB was added
gene: IKBKB was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IKBKB.
Mode of inheritance for gene: IKBKB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IKBKB were set to Immunodeficiency 15B, MIM# 615592
Review for gene: IKBKB was set to GREEN
Added comment: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells.

Treatment: bone marrow transplant.
Sources: Expert list
BabyScreen+ newborn screening v0.1998 IFNGR2 Zornitza Stark Marked gene: IFNGR2 as ready
BabyScreen+ newborn screening v0.1998 IFNGR2 Zornitza Stark Gene: ifngr2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1998 IFNGR2 Zornitza Stark Classified gene: IFNGR2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1998 IFNGR2 Zornitza Stark Gene: ifngr2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1997 IFNGR2 Zornitza Stark gene: IFNGR2 was added
gene: IFNGR2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IFNGR2.
Mode of inheritance for gene: IFNGR2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IFNGR2 were set to Immunodeficiency 28, mycobacteriosis, MIM# 614889
Review for gene: IFNGR2 was set to AMBER
Added comment: At least 5 unrelated families reported.

Commonest trigger is BCG vaccination, which is not part of the routine schedule in Australia, therefore exclude.

Treatment: BMT; avoidance of BCG.
Sources: Expert list
BabyScreen+ newborn screening v0.1996 IFNGR1 Zornitza Stark Marked gene: IFNGR1 as ready
BabyScreen+ newborn screening v0.1996 IFNGR1 Zornitza Stark Gene: ifngr1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1996 IFNGR1 Zornitza Stark Classified gene: IFNGR1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1996 IFNGR1 Zornitza Stark Gene: ifngr1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1995 IFNGR1 Zornitza Stark Tag treatable tag was added to gene: IFNGR1.
Tag immunological tag was added to gene: IFNGR1.
BabyScreen+ newborn screening v0.1995 IFNGR1 Zornitza Stark gene: IFNGR1 was added
gene: IFNGR1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: IFNGR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: IFNGR1 were set to Immunodeficiency 27A, mycobacteriosis, AR, MIM# 209950; Immunodeficiency 27B, mycobacteriosis, AD, MIM# 615978
Review for gene: IFNGR1 was set to AMBER
Added comment: Variable age of onset. Most common precipitant is BCG vaccination, which is not part of the routine schedule in Australia, therefore exclude.

Treatment: BMT; avoidance of BCG.
Sources: Expert list
BabyScreen+ newborn screening v0.1994 IFITM5 Zornitza Stark Marked gene: IFITM5 as ready
BabyScreen+ newborn screening v0.1994 IFITM5 Zornitza Stark Gene: ifitm5 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1994 IFITM5 Zornitza Stark Classified gene: IFITM5 as Green List (high evidence)
BabyScreen+ newborn screening v0.1994 IFITM5 Zornitza Stark Gene: ifitm5 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1993 IFITM5 Zornitza Stark gene: IFITM5 was added
gene: IFITM5 was added to Baby Screen+ newborn screening. Sources: Expert list
5'UTR, treatable, skeletal tags were added to gene: IFITM5.
Mode of inheritance for gene: IFITM5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFITM5 were set to 22863190; 22863195; 32383316; 24519609
Phenotypes for gene: IFITM5 were set to Osteogenesis imperfecta, type V MIM#610967
Review for gene: IFITM5 was set to GREEN
Added comment: A recurrent c.-14C>T variant has been reported in many patients with type V OI. It introduces an alternative in-frame start codon upstream that is stronger than the reference start codon in transfected HEK cells (PMIDs: 22863190, 22863195). However, the effect of mutant protein (5 amino acids longer) remains unknown but neomorphic mechanism is a widely accepted hypothesis (PMIDs: 25251575, 32383316).

Variable severity, including within families. However, severe perinatal presentations reported.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
BabyScreen+ newborn screening v0.1992 ICOS Zornitza Stark Marked gene: ICOS as ready
BabyScreen+ newborn screening v0.1992 ICOS Zornitza Stark Gene: icos has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1992 ICOS Zornitza Stark Classified gene: ICOS as Green List (high evidence)
BabyScreen+ newborn screening v0.1992 ICOS Zornitza Stark Gene: icos has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1991 ICOS Zornitza Stark gene: ICOS was added
gene: ICOS was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: ICOS.
Mode of inheritance for gene: ICOS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ICOS were set to Immunodeficiency, common variable, 1 MIM# 607594
Review for gene: ICOS was set to GREEN
Added comment: 15 affected individuals from 8 unrelated families reported with ICOS variants and displayed immunodeficiency, common variable, 1 phenotype; three mouse models.

Homozygous and compound heterozygous deletion and missense variants, with the most frequent variant being a 442 nucleotide deletion.

Patients typically presented with recurrent bacterial respiratory & gastrointestinal infections and low IgG/IgA.

Congenital onset.

Treatment: replacement immunoglobulin treatment, bone marrow transplant.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
BabyScreen+ newborn screening v0.1990 IARS Zornitza Stark Marked gene: IARS as ready
BabyScreen+ newborn screening v0.1990 IARS Zornitza Stark Gene: iars has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1990 IARS Zornitza Stark Classified gene: IARS as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1990 IARS Zornitza Stark Gene: iars has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1989 IARS Zornitza Stark Tag treatable tag was added to gene: IARS.
Tag metabolic tag was added to gene: IARS.
BabyScreen+ newborn screening v0.1989 IARS Zornitza Stark gene: IARS was added
gene: IARS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: IARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IARS were set to 27426735; 34194004
Phenotypes for gene: IARS were set to Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, MIM#617093
Review for gene: IARS was set to AMBER
Added comment: Established gene-disease association.

Congenital, multi-system metabolic disorder.

N=1 study of Isoleucine supplementation and protein fortification (2.5mg/kg/day, during illness 3.5 g/kg/day) with some clinical improvement.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.5191 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder, MONDO:0700092, HECTD4-related to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Intellectual disability syndromic and non-syndromic v0.5190 HECTD4 Zornitza Stark edited their review of gene: HECTD4: Changed phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Mendeliome v1.734 HECTD4 Zornitza Stark Marked gene: HECTD4 as ready
Mendeliome v1.734 HECTD4 Zornitza Stark Gene: hectd4 has been classified as Green List (High Evidence).
Mendeliome v1.734 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM# to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Mendeliome v1.733 HECTD4 Zornitza Stark reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Angelman Rett like syndromes v1.7 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder, MONDO:0700092, HECTD4-related to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Angelman Rett like syndromes v1.6 HECTD4 Zornitza Stark edited their review of gene: HECTD4: Changed phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Disorders of immune dysregulation v0.167 TNFRSF9 Zornitza Stark Phenotypes for gene: TNFRSF9 were changed from EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection to Immunodeficiency 109 with lymphoproliferation, MIM# 620282; EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection
Disorders of immune dysregulation v0.166 TNFRSF9 Zornitza Stark edited their review of gene: TNFRSF9: Changed phenotypes: Immunodeficiency 109 with lymphoproliferation, MIM# 620282, EBV lymphoproliferation, B-cell lymphoma, Chronic active EBV infection
Mendeliome v1.733 TNFRSF9 Zornitza Stark Phenotypes for gene: TNFRSF9 were changed from EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection to Immunodeficiency 109 with lymphoproliferation, MIM# 620282; EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection
Mendeliome v1.732 TNFRSF9 Zornitza Stark edited their review of gene: TNFRSF9: Changed phenotypes: Immunodeficiency 109 with lymphoproliferation, MIM# 620282, EBV lymphoproliferation, B-cell lymphoma, Chronic active EBV infection
BabyScreen+ newborn screening v0.1988 TNFRSF1A Zornitza Stark Marked gene: TNFRSF1A as ready
BabyScreen+ newborn screening v0.1988 TNFRSF1A Zornitza Stark Gene: tnfrsf1a has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1988 TNFRSF1A Zornitza Stark Classified gene: TNFRSF1A as Red List (low evidence)
BabyScreen+ newborn screening v0.1988 TNFRSF1A Zornitza Stark Gene: tnfrsf1a has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1987 TOP2B Zornitza Stark Marked gene: TOP2B as ready
BabyScreen+ newborn screening v0.1987 TOP2B Zornitza Stark Gene: top2b has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1987 TOP2B Zornitza Stark Classified gene: TOP2B as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1987 TOP2B Zornitza Stark Gene: top2b has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1986 TOP2B Zornitza Stark reviewed gene: TOP2B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: B-cell immunodeficiency, distal limb anomalies, and urogenital malformations MIM#609296; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1986 TPK1 Zornitza Stark Marked gene: TPK1 as ready
BabyScreen+ newborn screening v0.1986 TPK1 Zornitza Stark Gene: tpk1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1986 TPK1 Zornitza Stark Classified gene: TPK1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1986 TPK1 Zornitza Stark Gene: tpk1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1985 TPK1 Zornitza Stark Tag treatable tag was added to gene: TPK1.
Tag metabolic tag was added to gene: TPK1.
BabyScreen+ newborn screening v0.1985 TRNT1 Zornitza Stark Marked gene: TRNT1 as ready
BabyScreen+ newborn screening v0.1985 TRNT1 Zornitza Stark Gene: trnt1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1985 TRNT1 Zornitza Stark Classified gene: TRNT1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1985 TRNT1 Zornitza Stark Gene: trnt1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1984 TRNT1 Zornitza Stark Tag treatable tag was added to gene: TRNT1.
Tag immunological tag was added to gene: TRNT1.
BabyScreen+ newborn screening v0.1984 TRNT1 Zornitza Stark reviewed gene: TRNT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay MIM#616084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1984 TRPM6 Zornitza Stark Marked gene: TRPM6 as ready
BabyScreen+ newborn screening v0.1984 TRPM6 Zornitza Stark Gene: trpm6 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1984 TRPM6 Zornitza Stark Classified gene: TRPM6 as Green List (high evidence)
BabyScreen+ newborn screening v0.1984 TRPM6 Zornitza Stark Gene: trpm6 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1983 TRPM6 Zornitza Stark Tag treatable tag was added to gene: TRPM6.
Tag endocrine tag was added to gene: TRPM6.
BabyScreen+ newborn screening v0.1983 UCP2 Zornitza Stark Marked gene: UCP2 as ready
BabyScreen+ newborn screening v0.1983 UCP2 Zornitza Stark Gene: ucp2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1983 UCP2 Zornitza Stark Publications for gene: UCP2 were set to
BabyScreen+ newborn screening v0.1982 TNFRSF1A Lilian Downie gene: TNFRSF1A was added
gene: TNFRSF1A was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFRSF1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNFRSF1A were set to PMID: 11175303, PMID: 32066461, PMID: 29773275, PMID: 32831641
Phenotypes for gene: TNFRSF1A were set to Periodic fever, familial MIM#142680
Penetrance for gene: TNFRSF1A were set to Incomplete
Review for gene: TNFRSF1A was set to RED
Added comment: Strong gene disease association
Childhood onset but age not consistently under 5 and cases of adult onset
reports of variable penetrance
Rx
NSAIDs, corticosteroids, Etanercept , anakinra, canakinumab, tocilizumab

because there is no non-molecular confirmatory test I think should be red for variability of age of onset and severity of symptoms.
Sources: Expert list
BabyScreen+ newborn screening v0.1982 TOP2B Lilian Downie gene: TOP2B was added
gene: TOP2B was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TOP2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TOP2B were set to PMID: 31409799, PMID: 35063500, PMID: 32128574, PMID: 33459963
Phenotypes for gene: TOP2B were set to B-cell immunodeficiency, distal limb anomalies, and urogenital malformations MIM#609296
Review for gene: TOP2B was set to AMBER
Added comment: congenital onset
humoral immunodeficiency with undetectable B cells, distal limb anomalies, dysmorphic facial features, and urogenital malformations

Treatment immunoglobulin (only partially treats phenotype) no literature for evidence around immunoglobulin treatment.

Suggest RED but maybe discuss with immunologist?
Sources: Expert list
BabyScreen+ newborn screening v0.1982 TPK1 Lilian Downie gene: TPK1 was added
gene: TPK1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TPK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPK1 were set to PMID: 33086386, 32679198, 22152682, PMID: 33231275
Phenotypes for gene: TPK1 were set to Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) MIM#614458
Review for gene: TPK1 was set to GREEN
Added comment: Strong gene disease association
Variable age of onset but always under 5years

Thiamine metabolism dysfunction syndrome-5 (THMD5) is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (Mayr et al., 2011).

Biotin and thiamine therapy - newer evidence (2021) suggests early thiamine therapy may prevent any neurologic deficits.
Sources: Expert list
BabyScreen+ newborn screening v0.1982 TRNT1 Lilian Downie gene: TRNT1 was added
gene: TRNT1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TRNT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRNT1 were set to PMID: 25193871, PMID: 23553769, PMID: 33936027, PMID: 26494905
Phenotypes for gene: TRNT1 were set to Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay MIM#616084
Review for gene: TRNT1 was set to AMBER
Added comment: Onset infancy
Strong gene disease association

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by Wiseman et al., 2013).

Bone marrow transplant (hematopoietic stem cell transplantation (HSCT)), replacement immunoglobulin treatment

Allelic disease: Retinitis pigmentosa and erythrocytic microcytosis MIM#616959. Also AR.
DeLuca et al. (2016) concluded that hypomorphic TRNT1 mutations can cause a recessive disease that is almost entirely limited to the retina - this has teenage onset and is not treatable. can we exclude these variants?
Sources: Expert list
BabyScreen+ newborn screening v0.1982 TRPM6 Lilian Downie gene: TRPM6 was added
gene: TRPM6 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TRPM6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRPM6 were set to PMID: 35903165, PMID: 18818955
Phenotypes for gene: TRPM6 were set to Hypomagnesemia 1, intestinal MIM#602014
Review for gene: TRPM6 was set to GREEN
Added comment: Hypomagnaesemia and hypocalcaemia
Hypocalcemia is a secondary consequence of parathyroid failure and parathyroid hormone resistance as a result of severe magnesium deficiency. The disease typically manifests during the first months of life with generalized convulsions or signs of increased neuromuscular excitability, such as muscle spasms or tetany. Untreated, the disease may be fatal or lead to severe neurologic damage. Treatment includes immediate administration of magnesium, usually intravenously, followed by life-long high-dose oral magnesium (review by Knoers, 2009).
Sources: Expert list
BabyScreen+ newborn screening v0.1982 UCP2 Lilian Downie reviewed gene: UCP2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 28681398, PMID: 27967291; Phenotypes: UCP2 associated hyperinsulinism; Mode of inheritance: None
Hereditary Neuropathy_CMT - isolated v1.29 SPTLC1 Zornitza Stark Phenotypes for gene: SPTLC1 were changed from HSAN/SFN; Hereditary Sensory and Autonomic Neuropathy, Type II; Neuropathy, hereditary sensory and autonomic, type IA, 162400 to Juvenile amyotrophic lateral sclerosis-27, MIM#620285; HSAN/SFN; Hereditary Sensory and Autonomic Neuropathy, Type II; Neuropathy, hereditary sensory and autonomic, type IA, 162400
Hereditary Neuropathy_CMT - isolated v1.28 SPTLC1 Zornitza Stark edited their review of gene: SPTLC1: Changed phenotypes: Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400, Juvenile amyotrophic lateral sclerosis-27, MIM#620285
Mendeliome v1.732 SPTLC1 Zornitza Stark Phenotypes for gene: SPTLC1 were changed from Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis) to Juvenile amyotrophic lateral sclerosis-27, MIM#620285; Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v1.731 SPTLC1 Zornitza Stark edited their review of gene: SPTLC1: Changed phenotypes: Juvenile amyotrophic lateral sclerosis-27, MIM#620285, Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400, Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Hyperinsulinism v1.9 GLUD1 Zornitza Stark Mode of inheritance for gene: GLUD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hyperinsulinism v1.8 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fatty Acid Oxidation Defects v1.10 GLUD1 Zornitza Stark Mode of inheritance for gene: GLUD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fatty Acid Oxidation Defects v1.9 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.731 GLUD1 Zornitza Stark Mode of inheritance for gene: GLUD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.730 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.730 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1982 UNG Zornitza Stark Marked gene: UNG as ready
BabyScreen+ newborn screening v0.1982 UNG Zornitza Stark Gene: ung has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1982 UNG Zornitza Stark Classified gene: UNG as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1982 UNG Zornitza Stark Gene: ung has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1981 UNG Zornitza Stark Tag treatable tag was added to gene: UNG.
Tag immunological tag was added to gene: UNG.
BabyScreen+ newborn screening v0.1981 UNG Zornitza Stark reviewed gene: UNG: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency with hyper IgM, type 5 MIM#608106; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1981 UMPS Zornitza Stark Marked gene: UMPS as ready
BabyScreen+ newborn screening v0.1981 UMPS Zornitza Stark Gene: umps has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1981 UMPS Zornitza Stark Classified gene: UMPS as Green List (high evidence)
BabyScreen+ newborn screening v0.1981 UMPS Zornitza Stark Gene: umps has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1980 UMPS Zornitza Stark Tag for review tag was added to gene: UMPS.
Tag treatable tag was added to gene: UMPS.
Tag metabolic tag was added to gene: UMPS.
Neurodegeneration with brain iron accumulation v0.22 BCAS3 Zornitza Stark Marked gene: BCAS3 as ready
Neurodegeneration with brain iron accumulation v0.22 BCAS3 Zornitza Stark Gene: bcas3 has been classified as Green List (High Evidence).
Neurodegeneration with brain iron accumulation v0.22 BCAS3 Zornitza Stark Phenotypes for gene: BCAS3 were changed from spasticity; intellectual disability; global developmental delay; microcephaly; short stature to Hengel-Maroofian-Schols syndrome, MIM# 619641
Neurodegeneration with brain iron accumulation v0.21 BCAS3 Zornitza Stark Publications for gene: BCAS3 were set to DOI:10.1002/mds.28915 Corpus ID: 245670502
Neurodegeneration with brain iron accumulation v0.20 BCAS3 Zornitza Stark Classified gene: BCAS3 as Green List (high evidence)
Neurodegeneration with brain iron accumulation v0.20 BCAS3 Zornitza Stark Gene: bcas3 has been classified as Green List (High Evidence).
Neurodegeneration with brain iron accumulation v0.19 BCAS3 Zornitza Stark reviewed gene: BCAS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34981858; Phenotypes: Hengel-Maroofian-Schols syndrome, MIM# 619641; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurodegeneration with brain iron accumulation v0.19 AFG3L2 Zornitza Stark Marked gene: AFG3L2 as ready
Neurodegeneration with brain iron accumulation v0.19 AFG3L2 Zornitza Stark Gene: afg3l2 has been classified as Red List (Low Evidence).
Neurodegeneration with brain iron accumulation v0.19 AFG3L2 Zornitza Stark Phenotypes for gene: AFG3L2 were changed from ataxia; visual impairment; neuroregression to Spastic ataxia 5, autosomal recessive, MIM# 614487; Spinocerebellar ataxia 28, MIM# 610246
Neurodegeneration with brain iron accumulation v0.18 AFG3L2 Zornitza Stark Classified gene: AFG3L2 as Red List (low evidence)
Neurodegeneration with brain iron accumulation v0.18 AFG3L2 Zornitza Stark Gene: afg3l2 has been classified as Red List (Low Evidence).
Neurodegeneration with brain iron accumulation v0.17 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive, MIM# 614487, Spinocerebellar ataxia 28, MIM# 610246; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegeneration with brain iron accumulation v0.17 GTPBP2 Zornitza Stark Marked gene: GTPBP2 as ready
Neurodegeneration with brain iron accumulation v0.17 GTPBP2 Zornitza Stark Gene: gtpbp2 has been classified as Amber List (Moderate Evidence).
Neurodegeneration with brain iron accumulation v0.17 GTPBP2 Zornitza Stark Phenotypes for gene: GTPBP2 were changed from dystonia; ataxia; cognitive dysfunction; motor neuropathy; retinal abnormalities; sparse thin and brittle hair to Jaberi-Elahi syndrome, MIM# 617988
Neurodegeneration with brain iron accumulation v0.16 GTPBP2 Zornitza Stark Classified gene: GTPBP2 as Amber List (moderate evidence)
Neurodegeneration with brain iron accumulation v0.16 GTPBP2 Zornitza Stark Gene: gtpbp2 has been classified as Amber List (Moderate Evidence).
Neurodegeneration with brain iron accumulation v0.15 GTPBP2 Zornitza Stark reviewed gene: GTPBP2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Jaberi-Elahi syndrome, MIM# 617988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1980 NLGN4X Zornitza Stark Marked gene: NLGN4X as ready
BabyScreen+ newborn screening v0.1980 NLGN4X Zornitza Stark Gene: nlgn4x has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1980 NLGN4X Zornitza Stark Phenotypes for gene: NLGN4X were changed from Autism to Intellectual developmental disorder, X-linked MIM#300495
BabyScreen+ newborn screening v0.1979 NLGN4X Zornitza Stark Mode of inheritance for gene: NLGN4X was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
BabyScreen+ newborn screening v0.1978 NLGN4X Zornitza Stark reviewed gene: NLGN4X: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked MIM#300495; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.730 NLGN4X Zornitza Stark Classified gene: NLGN4X as Green List (high evidence)
Mendeliome v1.730 NLGN4X Zornitza Stark Gene: nlgn4x has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5190 Zornitza Stark removed gene:MTSS1 from the panel
Microcephaly v1.195 Zornitza Stark removed gene:MTSS1 from the panel
Mendeliome v1.729 Zornitza Stark removed gene:MTSS1 from the panel
Autism v0.188 NLGN4X Elena Savva commented on gene: NLGN4X
Autism v0.188 NLGN4X Elena Savva Classified gene: NLGN4X as Green List (high evidence)
Autism v0.188 NLGN4X Elena Savva Gene: nlgn4x has been classified as Green List (High Evidence).
Mendeliome v1.728 TAB2 Achchuthan Shanmugasundram reviewed gene: TAB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35971781; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
BabyScreen+ newborn screening v0.1978 HSD11B2 Zornitza Stark Marked gene: HSD11B2 as ready
BabyScreen+ newborn screening v0.1978 HSD11B2 Zornitza Stark Gene: hsd11b2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1978 HSD11B2 Zornitza Stark Classified gene: HSD11B2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1978 HSD11B2 Zornitza Stark Gene: hsd11b2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1977 HSD11B2 Zornitza Stark gene: HSD11B2 was added
gene: HSD11B2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: HSD11B2.
Mode of inheritance for gene: HSD11B2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HSD11B2 were set to Apparent mineralocorticoid excess, MIM# 218030; MONDO:0009025
Review for gene: HSD11B2 was set to GREEN
Added comment: Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type II (HSD11B2) activity, resulting in decreased conversion of biologically active cortisol to inactive cortisone; this defect allows cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. There is a favorable therapeutic response to spironolactone. More than 10 unrelated families reported.

Onset is usually in infancy or early childhood.

Non-genetic confirmatory testing: aldosterone, renin, potassium levels
Sources: Expert list
BabyScreen+ newborn screening v0.1976 HOGA1 Zornitza Stark Marked gene: HOGA1 as ready
BabyScreen+ newborn screening v0.1976 HOGA1 Zornitza Stark Gene: hoga1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1976 HOGA1 Zornitza Stark Classified gene: HOGA1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1976 HOGA1 Zornitza Stark Gene: hoga1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1975 HOGA1 Zornitza Stark gene: HOGA1 was added
gene: HOGA1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: HOGA1.
Mode of inheritance for gene: HOGA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HOGA1 were set to 20797690; 21896830; 22391140
Phenotypes for gene: HOGA1 were set to Hyperoxaluria, primary, type III MIM#613616
Review for gene: HOGA1 was set to GREEN
Added comment: Well-established association with primary hyperoxaluria type III. c.700+5G>T is a recurrent pathogenic variant in European populations (possibly founder) and has high frequency in gnomad (0.2-0.3%).

Onset in infancy, progressive multi-system disorder.

Treatment: pyridoxine, drinking large volumes, alkalinzation of urine, pyrophosphate-containing solutions, liver-kidney transplant

Non-genetic confirmatory testing: urinary oxalate
Sources: Expert list
Neurodegeneration with brain iron accumulation v0.15 GTPBP2 Shekeeb Mohammad gene: GTPBP2 was added
gene: GTPBP2 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: GTPBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTPBP2 were set to 26675814; 29449720
Phenotypes for gene: GTPBP2 were set to dystonia; ataxia; cognitive dysfunction; motor neuropathy; retinal abnormalities; sparse thin and brittle hair
Review for gene: GTPBP2 was set to GREEN
gene: GTPBP2 was marked as current diagnostic
Added comment: Sources: Literature
Neurodegeneration with brain iron accumulation v0.15 BCAS3 Shekeeb Mohammad gene: BCAS3 was added
gene: BCAS3 was added to Neuroferritinopathies. Sources: Expert Review,Literature
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to DOI:10.1002/mds.28915 Corpus ID: 245670502
Phenotypes for gene: BCAS3 were set to spasticity; intellectual disability; global developmental delay; microcephaly; short stature
Penetrance for gene: BCAS3 were set to unknown
Review for gene: BCAS3 was set to GREEN
gene: BCAS3 was marked as current diagnostic
Added comment: Sources: Expert Review, Literature
Neurodegeneration with brain iron accumulation v0.15 AFG3L2 Shekeeb Mohammad gene: AFG3L2 was added
gene: AFG3L2 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: AFG3L2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AFG3L2 were set to 32237276
Phenotypes for gene: AFG3L2 were set to ataxia; visual impairment; neuroregression
Review for gene: AFG3L2 was set to GREEN
gene: AFG3L2 was marked as current diagnostic
Added comment: Sources: Literature
Neurodegeneration with brain iron accumulation v0.15 SCP2 Shekeeb Mohammad edited their review of gene: SCP2: Changed rating: AMBER
Neurodegeneration with brain iron accumulation v0.15 SCP2 Shekeeb Mohammad reviewed gene: SCP2: Rating: RED; Mode of pathogenicity: None; Publications: 35996156; Phenotypes: progressive bulbar dysfunction, dementia, azoospermia, cardiac dysrhythmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
BabyScreen+ newborn screening v0.1974 UMPS Lilian Downie changed review comment from: megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).

Treat uridine
Very rare only 20 cases but treatable.
Sources: Expert list; to: megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).

Better check with John who wrote the paper!! PMID: 25030255

Treat uridine
Very rare only 20 cases but treatable.
Sources: Expert list
BabyScreen+ newborn screening v0.1974 UMPS Lilian Downie gene: UMPS was added
gene: UMPS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: UMPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UMPS were set to PMID: 9042911, PMID: 28205048, PMID: 25757096, PMID: 33489760
Phenotypes for gene: UMPS were set to Orotic aciduria MIM#258900
Review for gene: UMPS was set to GREEN
Added comment: megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).

Treat uridine
Very rare only 20 cases but treatable.
Sources: Expert list
BabyScreen+ newborn screening v0.1974 UNG Lilian Downie gene: UNG was added
gene: UNG was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: UNG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNG were set to PubMed: 12958596, PMID: 15967827, PMID: 19202054, PMID: 16860315
Phenotypes for gene: UNG were set to Immunodeficiency with hyper IgM, type 5 MIM#608106
Review for gene: UNG was set to RED
Added comment: normal or increased serum IgM concentrations associated with low or absent serum IgG, IgA, and IgE concentrations.
susceptibility to bacterial infections, lymphoid hyperplasia
only 3 patients reported in a single paper ?
Rx immunoglobulin replacement according to Rx genes but I can't find actual papers - i don't think there is enough evidence regarding age of onset or treatability.
Sources: Expert list
BabyScreen+ newborn screening v0.1974 HELLS Zornitza Stark Marked gene: HELLS as ready
BabyScreen+ newborn screening v0.1974 HELLS Zornitza Stark Gene: hells has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1974 HELLS Zornitza Stark Classified gene: HELLS as Green List (high evidence)
BabyScreen+ newborn screening v0.1974 HELLS Zornitza Stark Gene: hells has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1973 HELLS Zornitza Stark Tag treatable tag was added to gene: HELLS.
Tag immunological tag was added to gene: HELLS.
BabyScreen+ newborn screening v0.1973 HELLS Zornitza Stark gene: HELLS was added
gene: HELLS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: HELLS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HELLS were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 4, MIM# 616911
Review for gene: HELLS was set to GREEN
Added comment: Congenital onset.

Immunodeficiency-centromeric instability-facial anomalies syndrome-4 is characterized by recurrent infections in childhood and variable dysmorphic facial features. Laboratory studies show hypomethylation of certain chromosomal regions. Additional features, including delayed development, are variable. At least 4 unrelated families reported.

Treatment: bone marrow transplant.
Sources: Expert list
BabyScreen+ newborn screening v0.1972 USP18 Zornitza Stark Marked gene: USP18 as ready
BabyScreen+ newborn screening v0.1972 USP18 Zornitza Stark Gene: usp18 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1972 USP18 Zornitza Stark Classified gene: USP18 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1972 USP18 Zornitza Stark Gene: usp18 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1971 USP18 Zornitza Stark reviewed gene: USP18: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Pseudo-TORCH syndrome 2 MIM#617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1971 VKORC1 Zornitza Stark Marked gene: VKORC1 as ready
BabyScreen+ newborn screening v0.1971 VKORC1 Zornitza Stark Gene: vkorc1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1971 VKORC1 Zornitza Stark Mode of inheritance for gene: VKORC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1970 VKORC1 Zornitza Stark Classified gene: VKORC1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1970 VKORC1 Zornitza Stark Gene: vkorc1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1969 VKORC1 Zornitza Stark Tag treatable tag was added to gene: VKORC1.
Tag haematological tag was added to gene: VKORC1.
BabyScreen+ newborn screening v0.1969 VKORC1 Zornitza Stark reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2 MIM#607473; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1969 WDR1 Zornitza Stark Marked gene: WDR1 as ready
BabyScreen+ newborn screening v0.1969 WDR1 Zornitza Stark Gene: wdr1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1969 WDR1 Zornitza Stark Classified gene: WDR1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1969 WDR1 Zornitza Stark Gene: wdr1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1968 WDR1 Zornitza Stark Tag treatable tag was added to gene: WDR1.
Tag immunological tag was added to gene: WDR1.
Tag haematological tag was added to gene: WDR1.
Mendeliome v1.728 ACTA1 Zornitza Stark Phenotypes for gene: ACTA1 were changed from Myopathy, actin, congenital, with cores, MIM#161800; Myopathy, actin, congenital, with excess of thin myofilaments, MIM#161800; Myopathy, congenital, with fiber-type disproportion 1, MIM#255310; Nemaline myopathy 3, MIM#161800; ?Myopathy, scapulohumeroperoneal to Congenital myopathy 2C, severe infantile, autosomal dominant, MIM# 620278; Myopathy, actin, congenital, with cores, MIM#161800; Myopathy, actin, congenital, with excess of thin myofilaments, MIM#161800; Myopathy, congenital, with fiber-type disproportion 1, MIM#255310; Nemaline myopathy 3, MIM#161800; ?Myopathy, scapulohumeroperoneal
Mendeliome v1.727 ACTA1 Zornitza Stark reviewed gene: ACTA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 2C, severe infantile, autosomal dominant, MIM# 620278; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1968 GPIHBP1 Zornitza Stark Marked gene: GPIHBP1 as ready
BabyScreen+ newborn screening v0.1968 GPIHBP1 Zornitza Stark Gene: gpihbp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1968 GPIHBP1 Zornitza Stark Classified gene: GPIHBP1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1968 GPIHBP1 Zornitza Stark Gene: gpihbp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1967 GPIHBP1 Zornitza Stark Tag treatable tag was added to gene: GPIHBP1.
Tag metabolic tag was added to gene: GPIHBP1.
BabyScreen+ newborn screening v0.1967 GPIHBP1 Zornitza Stark gene: GPIHBP1 was added
gene: GPIHBP1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPIHBP1 were set to 31390500
Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D MIM#615947; familial chylomicronemia syndrome
Review for gene: GPIHBP1 was set to GREEN
Added comment: Well-established gene-disease association.

Usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly.

Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy.

Treatment: volanesorsen, dietary fat restriction

Non-genetic confirmatory testing: triglyceride level
Sources: Expert list
BabyScreen+ newborn screening v0.1966 GHRHR Zornitza Stark Marked gene: GHRHR as ready
BabyScreen+ newborn screening v0.1966 GHRHR Zornitza Stark Gene: ghrhr has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1966 GHRHR Zornitza Stark Classified gene: GHRHR as Green List (high evidence)
BabyScreen+ newborn screening v0.1966 GHRHR Zornitza Stark Gene: ghrhr has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1965 GHRHR Zornitza Stark Tag treatable tag was added to gene: GHRHR.
Tag endocrine tag was added to gene: GHRHR.
BabyScreen+ newborn screening v0.1965 GHRHR Zornitza Stark gene: GHRHR was added
gene: GHRHR was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GHRHR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GHRHR were set to 8528260; 10084571; 11232012
Phenotypes for gene: GHRHR were set to Growth hormone deficiency, isolated, type IV, MIM# 618157
Review for gene: GHRHR was set to GREEN
Added comment: IGHD type IV is characterized by early and severe growth failure (height SDS up to -7.4), a blunted growth hormone (GH) response to different provocation tests and low insulin-like growth factor-I and IGF-binding protein-3 concentrations, and a good response to growth hormone treatment. At least three unrelated families reported.

Non-genetic confirmatory testing: growth hormone stimulation test
Sources: Expert list
BabyScreen+ newborn screening v0.1964 GHR Zornitza Stark Marked gene: GHR as ready
BabyScreen+ newborn screening v0.1964 GHR Zornitza Stark Gene: ghr has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1964 GHR Zornitza Stark Classified gene: GHR as Green List (high evidence)
BabyScreen+ newborn screening v0.1964 GHR Zornitza Stark Gene: ghr has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1963 GHR Zornitza Stark Tag treatable tag was added to gene: GHR.
Tag endocrine tag was added to gene: GHR.
BabyScreen+ newborn screening v0.1963 GHR Zornitza Stark gene: GHR was added
gene: GHR was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GHR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: GHR were set to Growth hormone insensitivity, partial, MIM# 604271; Laron dwarfism, MIM# 262500
Review for gene: GHR was set to GREEN
Added comment: Well established gene-disease association.

Congenital onset.

Treatment: growth hormone.

Non-genetic confirmatory testing: growth hormone stimulation test
Sources: Expert list
BabyScreen+ newborn screening v0.1962 GH1 Zornitza Stark Marked gene: GH1 as ready
BabyScreen+ newborn screening v0.1962 GH1 Zornitza Stark Gene: gh1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1962 GH1 Zornitza Stark Classified gene: GH1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1962 GH1 Zornitza Stark Gene: gh1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1961 GH1 Zornitza Stark Tag treatable tag was added to gene: GH1.
Tag endocrine tag was added to gene: GH1.
BabyScreen+ newborn screening v0.1961 GH1 Zornitza Stark gene: GH1 was added
gene: GH1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: GH1 were set to Growth hormone deficiency, isolated, type IA, MIM# 262400; Growth hormone deficiency, isolated, type II, MIM# 173100; Kowarski syndrome, MIM# 262650
Review for gene: GH1 was set to GREEN
Added comment: Well established gene-disease association. Congenital onset.

Treatment: growth hormone.

Non-genetic confirmatory test: growth hormone stimulation test
Sources: Expert list
BabyScreen+ newborn screening v0.1960 GFI1 Zornitza Stark Marked gene: GFI1 as ready
BabyScreen+ newborn screening v0.1960 GFI1 Zornitza Stark Gene: gfi1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1960 GFI1 Zornitza Stark Classified gene: GFI1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1960 GFI1 Zornitza Stark Gene: gfi1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1959 GFI1 Zornitza Stark gene: GFI1 was added
gene: GFI1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GFI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GFI1 were set to 12778173; 20560965; 11810106; 22684987
Phenotypes for gene: GFI1 were set to Neutropenia, severe congenital 2, autosomal dominant, MIM# 613107
Review for gene: GFI1 was set to GREEN
Added comment: At least three unrelated families reported, and supportive functional data.

Severe congenital immunodeficiency.

Treatment: granulocyte colony-stimulating factor (G-CSF), Bone marrow transplant

Non-genetic confirmatory testing: FBE.
Sources: Expert list
Neurodegeneration with brain iron accumulation v0.15 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Neurodegeneration with brain iron accumulation v0.14 SCP2 Zornitza Stark Phenotypes for gene: SCP2 were changed from Neurodegeneration with brain iron accumulation; ataxia to Leukoencephalopathy with dystonia and motor neuropathy, MIM#613724; Neurodegeneration with brain iron accumulation; ataxia
Neurodegeneration with brain iron accumulation v0.13 SCP2 Zornitza Stark Publications for gene: SCP2 were set to 26497993
Neurodegeneration with brain iron accumulation v0.12 SCP2 Zornitza Stark Classified gene: SCP2 as Amber List (moderate evidence)
Neurodegeneration with brain iron accumulation v0.12 SCP2 Zornitza Stark Gene: scp2 has been classified as Amber List (Moderate Evidence).
Neurodegeneration with brain iron accumulation v0.11 SCP2 Zornitza Stark reviewed gene: SCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 26497993; Phenotypes: Leukoencephalopathy with dystonia and motor neuropathy, MIM#613724; Mode of inheritance: None
Mendeliome v1.727 REPS1 Zornitza Stark Marked gene: REPS1 as ready
Mendeliome v1.727 REPS1 Zornitza Stark Gene: reps1 has been classified as Red List (Low Evidence).
Mendeliome v1.727 REPS1 Zornitza Stark gene: REPS1 was added
gene: REPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: REPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REPS1 were set to 29395073
Phenotypes for gene: REPS1 were set to Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Review for gene: REPS1 was set to RED
Added comment: Two siblings reported with compound het missense variants in this gene and a neurodegenerative course in childhood.
Sources: Literature
Neurodegeneration with brain iron accumulation v0.11 REPS1 Zornitza Stark Marked gene: REPS1 as ready
Neurodegeneration with brain iron accumulation v0.11 REPS1 Zornitza Stark Gene: reps1 has been classified as Red List (Low Evidence).
Neurodegeneration with brain iron accumulation v0.11 REPS1 Zornitza Stark gene: REPS1 was added
gene: REPS1 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: REPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REPS1 were set to 29395073
Phenotypes for gene: REPS1 were set to Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Review for gene: REPS1 was set to RED
Added comment: Two siblings reported with compound het missense variants in this gene and a neurodegenerative course in childhood.
Sources: Literature
Hydrops fetalis v0.298 GLA Zornitza Stark Marked gene: GLA as ready
Hydrops fetalis v0.298 GLA Zornitza Stark Gene: gla has been classified as Red List (Low Evidence).
Hydrops fetalis v0.298 GLA Zornitza Stark Phenotypes for gene: GLA were changed from to Fabry disease, MIM# 301500
Hydrops fetalis v0.297 GLA Zornitza Stark Mode of inheritance for gene: GLA was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hydrops fetalis v0.296 GLA Zornitza Stark Classified gene: GLA as Red List (low evidence)
Hydrops fetalis v0.296 GLA Zornitza Stark Gene: gla has been classified as Red List (Low Evidence).
Hydrops fetalis v0.295 GLA Zornitza Stark reviewed gene: GLA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fabry disease, MIM# 301500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.726 MCF2L Zornitza Stark Mode of inheritance for gene: MCF2L was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Marked gene: MCF2L as ready
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Mode of inheritance for gene: MCF2L was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.275 MCF2L Zornitza Stark Classified gene: MCF2L as Red List (low evidence)
Congenital Heart Defect v0.275 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Mendeliome v1.725 FTH1 Zornitza Stark Phenotypes for gene: FTH1 were changed from Hemochromatosis, type 5, MIM# 615517 to Hemochromatosis, type 5, MIM# 615517; Neuroferritinopathy (MONDO:0011638)
Mendeliome v1.724 FTH1 Zornitza Stark Publications for gene: FTH1 were set to 11389486
Mendeliome v1.723 FTH1 Zornitza Stark Classified gene: FTH1 as Amber List (moderate evidence)
Mendeliome v1.723 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Regression v0.521 FTH1 Zornitza Stark Marked gene: FTH1 as ready
Regression v0.521 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Regression v0.521 FTH1 Zornitza Stark Classified gene: FTH1 as Amber List (moderate evidence)
Regression v0.521 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.722 TLN1 Zornitza Stark Phenotypes for gene: TLN1 were changed from idiopathic spontaneous coronary artery dissection MONDO:0007385 to idiopathic spontaneous coronary artery dissection MONDO:0007385; thrombocytopenia, MONDO:0002049, TLN1-related
Mendeliome v1.721 TLN1 Zornitza Stark Publications for gene: TLN1 were set to 30888838
Bleeding and Platelet Disorders v1.18 TLN1 Zornitza Stark Marked gene: TLN1 as ready
Bleeding and Platelet Disorders v1.18 TLN1 Zornitza Stark Gene: tln1 has been classified as Red List (Low Evidence).
Bleeding and Platelet Disorders v1.18 TLN1 Zornitza Stark Phenotypes for gene: TLN1 were changed from thrombocytopenia, MONDO:0002049 to thrombocytopenia, MONDO:0002049, TLN1-related
Bleeding and Platelet Disorders v1.17 TLN1 Zornitza Stark Classified gene: TLN1 as Red List (low evidence)
Bleeding and Platelet Disorders v1.17 TLN1 Zornitza Stark Gene: tln1 has been classified as Red List (Low Evidence).
Mendeliome v1.720 DPYSL2 Zornitza Stark Marked gene: DPYSL2 as ready
Mendeliome v1.720 DPYSL2 Zornitza Stark Gene: dpysl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.720 DPYSL2 Zornitza Stark Classified gene: DPYSL2 as Amber List (moderate evidence)
Mendeliome v1.720 DPYSL2 Zornitza Stark Gene: dpysl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.719 DPYSL2 Zornitza Stark gene: DPYSL2 was added
gene: DPYSL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL2 were set to 27249678; 35861646
Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071, DPYSL2-related
Review for gene: DPYSL2 was set to AMBER
Added comment: Two unrelated cases with monoallelic variants in DPYSL2/ CRMP2, supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5189 DPYSL2 Zornitza Stark Marked gene: DPYSL2 as ready
Intellectual disability syndromic and non-syndromic v0.5189 DPYSL2 Zornitza Stark Gene: dpysl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5189 DPYSL2 Zornitza Stark Phenotypes for gene: DPYSL2 were changed from intellectual disability, MONDO:0001071; Aplasia/Hypoplasia of the corpus callosum, HP:0007370 to intellectual disability, MONDO:0001071, DPYSL2-related
Intellectual disability syndromic and non-syndromic v0.5188 DPYSL2 Zornitza Stark Classified gene: DPYSL2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5188 DPYSL2 Zornitza Stark Gene: dpysl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5187 CTR9 Zornitza Stark Publications for gene: CTR9 were set to PMID: 35499524
Mendeliome v1.718 RBSN Zornitza Stark Marked gene: RBSN as ready
Mendeliome v1.718 RBSN Zornitza Stark Gene: rbsn has been classified as Green List (High Evidence).
Mendeliome v1.718 RBSN Zornitza Stark Classified gene: RBSN as Green List (high evidence)
Mendeliome v1.718 RBSN Zornitza Stark Gene: rbsn has been classified as Green List (High Evidence).
Mendeliome v1.717 RBSN Zornitza Stark gene: RBSN was added
gene: RBSN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBSN were set to 25233840; 29784638; 35652444
Phenotypes for gene: RBSN were set to intellectual disability, MONDO:0001071, RBSN-related
Review for gene: RBSN was set to GREEN
Added comment: Four unrelated families reported, consistent feature is ID.

PMID:25233840 reported a 6.5 year old female patient with a homozygous missense variant c.1273G > A (p.Gly425Arg) and her clinical presentation included intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis.

PMID:29784638 reported three siblings with homozygous variant c.289G>C (p.Gly97Arg) in RBSN. The proband presented global developmental delay, had complete 46,XY male-to-female sex reversal and died at age 20 months after multiple infections. The other 2 affected siblings underwent unrelated-donor bone marrow or stem cell transplantation at 8 and 6.5 months of age, respectively. Both have severe intellectual disability and are nonambulatory and nonverbal.

PMID:35652444 reported two unrelated families (three siblings from a family of Iranian descent identified with homozygous variant c.547G>A (p.Gly183Arg) and four members from a family of indigenous Cree descent identified with homozygous variant c.538C>G (p.Arg180Gly)) with overlapping phenotypes including developmental delay, intellectual disability, distal motor axonal neuropathy and facial dysmorphism.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5186 RBSN Zornitza Stark Marked gene: RBSN as ready
Intellectual disability syndromic and non-syndromic v0.5186 RBSN Zornitza Stark Gene: rbsn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5186 RBSN Zornitza Stark Classified gene: RBSN as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5186 RBSN Zornitza Stark Gene: rbsn has been classified as Green List (High Evidence).
Mendeliome v1.716 SRPRA Zornitza Stark Marked gene: SRPRA as ready
Mendeliome v1.716 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Mendeliome v1.716 SRPRA Zornitza Stark Classified gene: SRPRA as Amber List (moderate evidence)
Mendeliome v1.716 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Mendeliome v1.715 SRPRA Zornitza Stark gene: SRPRA was added
gene: SRPRA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRPRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRPRA were set to 36223592
Phenotypes for gene: SRPRA were set to Schwachman-Diamond syndrome MONDO:0009833, SRPA-related
Review for gene: SRPRA was set to AMBER
Added comment: De novo variant; zebrafish model. Schwachman-Diamond like.
Sources: Literature
Phagocyte Defects v1.14 SRPRA Zornitza Stark Marked gene: SRPRA as ready
Phagocyte Defects v1.14 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.14 SRPRA Zornitza Stark Phenotypes for gene: SRPRA were changed from neutropenia; myeloid maturation arrest; exocrine pancreatic insufficiency; growth deficiency to Schwachman-Diamond syndrome MONDO:0009833, SRPA-related
Phagocyte Defects v1.14 SRPRA Zornitza Stark Classified gene: SRPRA as Amber List (moderate evidence)
Phagocyte Defects v1.14 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.13 SRPRA Zornitza Stark Classified gene: SRPRA as Amber List (moderate evidence)
Phagocyte Defects v1.13 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.12 SRPRA Zornitza Stark reviewed gene: SRPRA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Schwachman-Diamond syndrome MONDO:0009833, SRPA-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bone Marrow Failure v1.32 SRPRA Zornitza Stark Marked gene: SRPRA as ready
Bone Marrow Failure v1.32 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.32 SRPRA Zornitza Stark Phenotypes for gene: SRPRA were changed from neutropenia; myeloid maturation arrest; exocrine pancreatic insufficiency; growth deficiency to Schwachman-Diamond syndrome MONDO:0009833, SRPA-related
Bone Marrow Failure v1.31 SRPRA Zornitza Stark Classified gene: SRPRA as Amber List (moderate evidence)
Bone Marrow Failure v1.31 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.30 SRPRA Zornitza Stark reviewed gene: SRPRA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Schwachman-Diamond syndrome MONDO:0009833, SRPA-relatted; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.714 SRP19 Zornitza Stark Marked gene: SRP19 as ready
Mendeliome v1.714 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.714 SRP19 Zornitza Stark Classified gene: SRP19 as Amber List (moderate evidence)
Mendeliome v1.714 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.713 SRP19 Zornitza Stark gene: SRP19 was added
gene: SRP19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP19 were set to 36223592
Phenotypes for gene: SRP19 were set to Neutropenia, MONDO:0001475, SRP19-related
Review for gene: SRP19 was set to AMBER
Added comment: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.
Sources: Literature
Bone Marrow Failure v1.30 SRP19 Zornitza Stark Classified gene: SRP19 as Amber List (moderate evidence)
Bone Marrow Failure v1.30 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.29 SRP19 Zornitza Stark edited their review of gene: SRP19: Added comment: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.; Changed rating: AMBER
Phagocyte Defects v1.12 SRP19 Zornitza Stark changed review comment from: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.; to: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.
Phagocyte Defects v1.12 SRP19 Zornitza Stark Marked gene: SRP19 as ready
Phagocyte Defects v1.12 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.12 SRP19 Zornitza Stark Phenotypes for gene: SRP19 were changed from neutropenia; myeloid maturation arrest; growth deficiency to Neutropenia, MONDO:0001475, SRP19-related
Phagocyte Defects v1.11 SRP19 Zornitza Stark Classified gene: SRP19 as Amber List (moderate evidence)
Phagocyte Defects v1.11 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.10 SRP19 Zornitza Stark edited their review of gene: SRP19: Added comment: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.; Changed rating: AMBER
Bone Marrow Failure v1.29 SRP19 Zornitza Stark Marked gene: SRP19 as ready
Bone Marrow Failure v1.29 SRP19 Zornitza Stark Gene: srp19 has been classified as Red List (Low Evidence).
Bone Marrow Failure v1.29 SRP19 Zornitza Stark Phenotypes for gene: SRP19 were changed from Neutropenia, MONDO:0001475, SRP19-related to Neutropenia, MONDO:0001475, SRP19-related
Bone Marrow Failure v1.29 SRP19 Zornitza Stark Phenotypes for gene: SRP19 were changed from neutropenia; myeloid maturation arrest; growth deficiency to Neutropenia, MONDO:0001475, SRP19-related
Phagocyte Defects v1.10 SRP19 Zornitza Stark reviewed gene: SRP19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neutropenia, MONDO:0001475, SRP19-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bone Marrow Failure v1.28 SRP19 Zornitza Stark Classified gene: SRP19 as Red List (low evidence)
Bone Marrow Failure v1.28 SRP19 Zornitza Stark Gene: srp19 has been classified as Red List (Low Evidence).
Bone Marrow Failure v1.27 SRP19 Zornitza Stark reviewed gene: SRP19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neutropenia, MONDO:0001475, SRP19-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.712 ATP5B Zornitza Stark Publications for gene: ATP5B were set to 36860166
Mendeliome v1.711 ATP5B Zornitza Stark changed review comment from: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature; to: PMID 36860166: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature
Mendeliome v1.711 ATP5B Zornitza Stark edited their review of gene: ATP5B: Changed publications: 36860166, 36239646
Mendeliome v1.711 ATP5B Zornitza Stark changed review comment from: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.
Sources: Literature; to: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature
Mitochondrial disease v0.859 ATP5B Zornitza Stark Marked gene: ATP5B as ready
Mitochondrial disease v0.859 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.859 ATP5B Zornitza Stark Classified gene: ATP5B as Amber List (moderate evidence)
Mitochondrial disease v0.859 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.858 ATP5B Zornitza Stark gene: ATP5B was added
gene: ATP5B was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: ATP5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5B were set to 36860166; 36239646
Phenotypes for gene: ATP5B were set to Inherited dystonia, MONDO:0044807, ATP5B-related
Review for gene: ATP5B was set to AMBER
Added comment: PMID 36860166: Two families, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram changed review comment from: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature; to: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. Particularly, Eph overexpressed flies had a poorer performance compared to controls in negative geotaxis assay. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 OXR1 Achchuthan Shanmugasundram changed review comment from: Comment on gene rating: This gene should be rated AMBER as there is one case and supportive functional data to associate OXR1 with hearing loss.

A four years old girl was identified with a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in OXR1 gene and was reported with sensorineural hearing loss.

Functional studies in zebrafish model showed that the ortholog orx1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL). In addition, knockdown of oxr1b resulted in a significant developmental defect of SAG and pLL and this phenotype was rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs.; to: Comment on gene rating: This gene should be rated AMBER as there is one case and supportive functional data to associate OXR1 with hearing loss.

A four years old girl was identified with a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in OXR1 gene and was reported with sensorineural hearing loss.

Functional studies in zebrafish model showed that the ortholog orx1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL). In addition, knockdown of oxr1b resulted in a significant developmental defect of SAG and pLL and this phenotype was rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs.

This gene has not yet been associated with hearing loss either in OMIM or in Gene2Phenotype.
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram changed review comment from: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature; to: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 OXR1 Achchuthan Shanmugasundram reviewed gene: OXR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36130215; Phenotypes: sensorineural hearing loss disorder, MONDO:0020678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram gene: EPHA10 was added
gene: EPHA10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EPHA10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPHA10 were set to 36048850
Phenotypes for gene: EPHA10 were set to postlingual non-syndromic genetic hearing loss, MONDO:0016298
Mode of pathogenicity for gene: EPHA10 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: EPHA10 was set to RED
Added comment: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
BabyScreen+ newborn screening v0.1958 USP18 Lilian Downie gene: USP18 was added
gene: USP18 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: USP18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP18 were set to PMID: 31940699, 27325888, 12833411
Phenotypes for gene: USP18 were set to Pseudo-TORCH syndrome 2 MIM#617397
Review for gene: USP18 was set to AMBER
Added comment: antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent. The disorder results from inappropriate activation of the interferon (IFN) immunologic pathway

Treatment Ruxolitinib (single patient only) - is a single patient with successful treatment enough?
Sources: Expert list
BabyScreen+ newborn screening v0.1958 VKORC1 Lilian Downie gene: VKORC1 was added
gene: VKORC1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: VKORC1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: VKORC1 were set to PMID:14765194, PMID: 26287237
Phenotypes for gene: VKORC1 were set to Vitamin K-dependent clotting factors, combined deficiency of, 2 MIM#607473
Review for gene: VKORC1 was set to AMBER
Added comment: Risk of intracranial haemmorhage in first weeks of life
Treatable with vitamin K
See below summary - feels like should be green for that homozygous mutation but not sure how to manage the gene overall? not report other variants?
Monoallelic - warfarin resistance

There is only one mutation known to result in the VKCFD2 phenotype. VKORC1:p.Arg98Trp causes diminished vitamin K epoxide reductase (VKOR) activity compared to that of the wild-type enzyme [15]. VKCFD2 patients exhibit severely diminished activities for the VKD coagulation factors and suffer spontaneous or surgery/injury induced bleeding episodes [16,17]. In addition to this haemorrhagic phenotype, abnormalities in epiphyseal growth have been reported in one case [18]. This phenotype is very rare. Worldwide, there are only four unrelated families known to be affected with VKCFD2 [16,17,18].
Sources: Expert list
BabyScreen+ newborn screening v0.1958 WDR1 Lilian Downie gene: WDR1 was added
gene: WDR1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: WDR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR1 were set to PMID: 32960541, 27994071, 27557945
Phenotypes for gene: WDR1 were set to Periodic fever, immunodeficiency, and thrombocytopenia syndrome MIM#150550
Review for gene: WDR1 was set to GREEN
Added comment: Strong gene disease association
Phenotype is early onset immunodeficiency with infections ++ and severe stomatitis
Treatable with bone marrow transplant.
Sources: Expert list
Mendeliome v1.711 ATP5B Zornitza Stark Marked gene: ATP5B as ready
Mendeliome v1.711 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.711 ATP5B Zornitza Stark Classified gene: ATP5B as Amber List (moderate evidence)
Mendeliome v1.711 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.710 ATP5B Zornitza Stark gene: ATP5B was added
gene: ATP5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5B were set to 36860166
Phenotypes for gene: ATP5B were set to Inherited dystonia, MONDO:0044807, ATP5B-related
Review for gene: ATP5B was set to AMBER
Added comment: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.
Sources: Literature
Dystonia - isolated/combined v1.32 ATP5B Zornitza Stark Marked gene: ATP5B as ready
Dystonia - isolated/combined v1.32 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Dystonia - isolated/combined v1.32 ATP5B Zornitza Stark Phenotypes for gene: ATP5B were changed from DYSTONIA; PROGRESSIVE DYSTONIA to Inherited dystonia, MONDO:0044807, ATP5B-related
Dystonia - isolated/combined v1.31 ATP5B Zornitza Stark Classified gene: ATP5B as Amber List (moderate evidence)
Dystonia - isolated/combined v1.31 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Dystonia - isolated/combined v1.30 ATP5B Zornitza Stark reviewed gene: ATP5B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Inherited dystonia, MONDO:0044807, ATP5B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paroxysmal Dyskinesia v0.109 SHQ1 Zornitza Stark Marked gene: SHQ1 as ready
Paroxysmal Dyskinesia v0.109 SHQ1 Zornitza Stark Gene: shq1 has been classified as Amber List (Moderate Evidence).
Paroxysmal Dyskinesia v0.109 SHQ1 Zornitza Stark Phenotypes for gene: SHQ1 were changed from PAROXYSMAL DYSTONIA; INTELLECTUAL DISABILITY; HYPOTONIA; CHOREOATHETOSIS; EPILEPSY to Neurodevelopmental disorder with dystonia and seizures, MIM# 619922
Mendeliome v1.709 SHQ1 Zornitza Stark Publications for gene: SHQ1 were set to 34542157; 29178645
Mendeliome v1.708 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Added comment: Fourth family reported in PMID 36847845 with hypotonia and paroxysmal dyskinesia.; Changed publications: 34542157, 29178645, 36847845
Paroxysmal Dyskinesia v0.108 SHQ1 Zornitza Stark Publications for gene: SHQ1 were set to
Paroxysmal Dyskinesia v0.107 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paroxysmal Dyskinesia v0.107 SHQ1 Zornitza Stark Classified gene: SHQ1 as Amber List (moderate evidence)
Paroxysmal Dyskinesia v0.107 SHQ1 Zornitza Stark Gene: shq1 has been classified as Amber List (Moderate Evidence).
Paroxysmal Dyskinesia v0.106 SHQ1 Zornitza Stark commented on gene: SHQ1: Four unrelated families reported. Family 1: isolated dystonia only; Family 2: dystonia, and neurodegeneration; Family 3: neurodegeneration; now Family 4: paroxysmal dyskinesia and hypotonia.

All likely represent a spectrum but caution warranted.
Paroxysmal Dyskinesia v0.106 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Changed rating: AMBER; Changed publications: 36847845
Paroxysmal Dyskinesia v0.106 SHQ1 Zornitza Stark reviewed gene: SHQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with dystonia and seizures, MIM# 619922; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.708 YWHAZ Zornitza Stark Marked gene: YWHAZ as ready
Mendeliome v1.708 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Red List (Low Evidence).
Mendeliome v1.708 YWHAZ Zornitza Stark gene: YWHAZ was added
gene: YWHAZ was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YWHAZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAZ were set to 36001342
Phenotypes for gene: YWHAZ were set to Intellectual disability, MONDO:0001071
Review for gene: YWHAZ was set to RED
Added comment: PMID:36001342 reported one large three-generation family with intellectual disability and global developmental delay, where all affected members were identified with a heterozygous missense variant (c.147A>T/ p.Lys49Asn) in YWHAZ gene. Although there were 10 other rare variants located in 10 genes (ARHGAP4, AGPS, APOL3, CES3, DACT2, ECH1, FAM71E2, KREMEN1, YWHAZ, ZFYVE26) that co-segregated with the ID/GDD phenotype were identified in the family, they were either not present in all affected members or present in unaffected members. In addition, computational modeling and knockdown/ knockin studies with Drosophila also confirmed the role of this YWHAZ variant in intellectual disability.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5185 YWHAZ Zornitza Stark Marked gene: YWHAZ as ready
Intellectual disability syndromic and non-syndromic v0.5185 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5185 YWHAZ Zornitza Stark Classified gene: YWHAZ as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.5185 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Red List (Low Evidence).
Mendeliome v1.707 KIF5B Zornitza Stark Publications for gene: KIF5B were set to PMID: 35342932
Fetal anomalies v1.91 PLXND1 Zornitza Stark Marked gene: PLXND1 as ready
Fetal anomalies v1.91 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Fetal anomalies v1.91 PLXND1 Zornitza Stark Classified gene: PLXND1 as Green List (high evidence)
Fetal anomalies v1.91 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Fetal anomalies v1.90 PLXND1 Zornitza Stark gene: PLXND1 was added
gene: PLXND1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLXND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXND1 were set to 35396997
Phenotypes for gene: PLXND1 were set to Congenital heart disease, MONDO:0005453, PLXND1-related
Review for gene: PLXND1 was set to GREEN
Added comment: 10 individuals including four fetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT)/truncus arteriosus.
Sources: Literature
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Marked gene: PLXND1 as ready
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Classified gene: PLXND1 as Green List (high evidence)
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.273 PLXND1 Zornitza Stark gene: PLXND1 was added
gene: PLXND1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: PLXND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXND1 were set to 35396997
Phenotypes for gene: PLXND1 were set to Congenital heart disease, MONDO:0005453, PLXND1-related
Review for gene: PLXND1 was set to GREEN
Added comment: 10 individuals including four fetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT)/truncus arteriosus.
Sources: Literature
Mendeliome v1.706 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Möbius syndrome to Möbius syndrome, MONDO:0008006; Congenital heart disease, MONDO:0005453, PLXND1-related
Mendeliome v1.705 PLXND1 Zornitza Stark Publications for gene: PLXND1 were set to 26068067
Mendeliome v1.704 PLXND1 Zornitza Stark Mode of inheritance for gene: PLXND1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.703 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Möbius syndrome, Congenital heart disease, MONDO:0005453, PLXND1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dystonia - complex v0.222 TRPM3 Zornitza Stark Marked gene: TRPM3 as ready
Dystonia - complex v0.222 TRPM3 Zornitza Stark Gene: trpm3 has been classified as Green List (High Evidence).
Dystonia - complex v0.222 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Intellectual disability; epilepsy; chorea; athetosis; hypotonia; dysmorphic features to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Dystonia - complex v0.221 TRPM3 Zornitza Stark Classified gene: TRPM3 as Green List (high evidence)
Dystonia - complex v0.221 TRPM3 Zornitza Stark Gene: trpm3 has been classified as Green List (High Evidence).
Dystonia - complex v0.220 TRPM3 Zornitza Stark reviewed gene: TRPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1958 WDR72 Zornitza Stark Marked gene: WDR72 as ready
BabyScreen+ newborn screening v0.1958 WDR72 Zornitza Stark Gene: wdr72 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1958 WDR72 Zornitza Stark Phenotypes for gene: WDR72 were changed from Distal renal tubular acidosis to Amelogenesis imperfecta, type IIA3, MIM# 613211; Distal RTA MONDO:0015827
BabyScreen+ newborn screening v0.1957 WDR72 Zornitza Stark Classified gene: WDR72 as Green List (high evidence)
BabyScreen+ newborn screening v0.1957 WDR72 Zornitza Stark Gene: wdr72 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1956 WDR72 Zornitza Stark Tag treatable tag was added to gene: WDR72.
Tag renal tag was added to gene: WDR72.
BabyScreen+ newborn screening v0.1956 WDR72 Zornitza Stark reviewed gene: WDR72: Rating: GREEN; Mode of pathogenicity: None; Publications: 30028003; Phenotypes: Amelogenesis imperfecta, type IIA3, MIM# 613211, Distal RTA MONDO:0015827; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1956 WIPF1 Zornitza Stark Marked gene: WIPF1 as ready
BabyScreen+ newborn screening v0.1956 WIPF1 Zornitza Stark Gene: wipf1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1956 WIPF1 Zornitza Stark Classified gene: WIPF1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1956 WIPF1 Zornitza Stark Gene: wipf1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1955 WIPF1 Zornitza Stark Tag treatable tag was added to gene: WIPF1.
Tag immunological tag was added to gene: WIPF1.
Tag haematological tag was added to gene: WIPF1.
Dystonia - complex v0.220 TRPM3 Shekeeb Mohammad gene: TRPM3 was added
gene: TRPM3 was added to Dystonia - complex. Sources: Literature
Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPM3 were set to 31278393; 35146895
Phenotypes for gene: TRPM3 were set to Intellectual disability; epilepsy; chorea; athetosis; hypotonia; dysmorphic features
Penetrance for gene: TRPM3 were set to Complete
Review for gene: TRPM3 was set to GREEN
gene: TRPM3 was marked as current diagnostic
Added comment: Sources: Literature
BabyScreen+ newborn screening v0.1955 WNK4 Zornitza Stark Marked gene: WNK4 as ready
BabyScreen+ newborn screening v0.1955 WNK4 Zornitza Stark Gene: wnk4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1955 WNK4 Zornitza Stark Classified gene: WNK4 as Green List (high evidence)
BabyScreen+ newborn screening v0.1955 WNK4 Zornitza Stark Gene: wnk4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1954 WNK4 Zornitza Stark Tag treatable tag was added to gene: WNK4.
Tag endocrine tag was added to gene: WNK4.
BabyScreen+ newborn screening v0.1954 ZBTB24 Zornitza Stark Marked gene: ZBTB24 as ready
BabyScreen+ newborn screening v0.1954 ZBTB24 Zornitza Stark Gene: zbtb24 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1954 ZBTB24 Zornitza Stark Classified gene: ZBTB24 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1954 ZBTB24 Zornitza Stark Gene: zbtb24 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1953 ZBTB24 Zornitza Stark Tag treatable tag was added to gene: ZBTB24.
Tag immunological tag was added to gene: ZBTB24.
BabyScreen+ newborn screening v0.1953 ZBTB24 Zornitza Stark reviewed gene: ZBTB24: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM#614069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Miscellaneous Metabolic Disorders v1.25 ZNF143 Zornitza Stark Marked gene: ZNF143 as ready
Miscellaneous Metabolic Disorders v1.25 ZNF143 Zornitza Stark Gene: znf143 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.25 ZNF143 Zornitza Stark gene: ZNF143 was added
gene: ZNF143 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF143 were set to 27349184
Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1, MONDO:0002012, ZNF143-related
Review for gene: ZNF143 was set to RED
Added comment: Single individual reported with compound heterozygous variants.
Sources: Expert Review
Mendeliome v1.703 ZNF143 Zornitza Stark Marked gene: ZNF143 as ready
Mendeliome v1.703 ZNF143 Zornitza Stark Gene: znf143 has been classified as Red List (Low Evidence).
Mendeliome v1.703 ZNF143 Zornitza Stark gene: ZNF143 was added
gene: ZNF143 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF143 were set to 27349184
Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1, MONDO:0002012, ZNF143-related
Review for gene: ZNF143 was set to RED
Added comment: Single individual reported with compound heterozygous variants.
Sources: Literature
BabyScreen+ newborn screening v0.1953 ZNF143 Zornitza Stark Marked gene: ZNF143 as ready
BabyScreen+ newborn screening v0.1953 ZNF143 Zornitza Stark Gene: znf143 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1953 ZNF143 Zornitza Stark Classified gene: ZNF143 as Red List (low evidence)
BabyScreen+ newborn screening v0.1953 ZNF143 Zornitza Stark Gene: znf143 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1952 ZNF143 Zornitza Stark reviewed gene: ZNF143: Rating: RED; Mode of pathogenicity: None; Publications: 27349184; Phenotypes: Combined methylmalonic acidemia and homocystinuria, cblX like 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1952 WDR72 Lilian Downie gene: WDR72 was added
gene: WDR72 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: WDR72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR72 were set to PMID: 30028003, PMID: 30779877, PMID:36836560, PMID: 33033857
Phenotypes for gene: WDR72 were set to Distal renal tubular acidosis
Review for gene: WDR72 was set to GREEN
Added comment: Amelogenesis imperecta - thickened and disoloured dental enamal with RTA
Reduced penetrance or variable expression? Some patients only have the tooth phenotype...
Presents with polyuria and growth restriction
Treat with oral alkali replacement therapy, potassium chloride
Sources: Expert list
BabyScreen+ newborn screening v0.1952 WIPF1 Lilian Downie gene: WIPF1 was added
gene: WIPF1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: WIPF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WIPF1 were set to PMID: 27742395, PMID: 30450104, PMID: 22231303
Phenotypes for gene: WIPF1 were set to Wiskott-Aldrich syndrome 2 MIM#614493
Review for gene: WIPF1 was set to GREEN
Added comment: Infant onset
recurrent infections, thrombycytopenia and eczema
Immunology testing to correlate
Treatment/cure with bone marrow transplant
Sources: Expert list
BabyScreen+ newborn screening v0.1952 WNK4 Lilian Downie gene: WNK4 was added
gene: WNK4 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: WNK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WNK4 were set to PMID: 22073419, PMID: 31795491, PMID: 10869238,
Phenotypes for gene: WNK4 were set to Pseudohypoaldosteronism, type IIB MIM#614491
Review for gene: WNK4 was set to GREEN
Added comment: Hyperkalaemia and hypertension
Hypercalciuria
Hypocalcaemia
Decreased bone mineral density
Renal calcium stones
Treatable with thiazide diuretics
Variable age of onset from infancy to adulthood but highly effective treatment so leaning toward include.
Sources: Expert list
BabyScreen+ newborn screening v0.1952 ZBTB24 Lilian Downie gene: ZBTB24 was added
gene: ZBTB24 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: ZBTB24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZBTB24 were set to PMID: 28128455, 21906047, 21596365, 23486536
Phenotypes for gene: ZBTB24 were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM#614069
Review for gene: ZBTB24 was set to AMBER
Added comment: INfant onset
Agammaglobulinemia, facial anomalies, and mental retardation. Facial anomalies included broad, flat nasal bridge, hypertelorism, and epicanthal folds.
Treat immunoglobulin and bone marrow transplant however, this only treats the immune deficiency
Consider exclusion due to untreatable ID phenotype?
Sources: Expert list
BabyScreen+ newborn screening v0.1952 ZNF143 Lilian Downie gene: ZNF143 was added
gene: ZNF143 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF143 were set to PMID: 20301503, PMID: 27349184
Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1
Review for gene: ZNF143 was set to RED
Added comment: Not in our mendeliome
Single case
Sources: Expert list
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram edited their review of gene: PLXND1: Changed phenotypes: Truncus arteriosus, HP:0001660
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram reviewed gene: PLXND1: Rating: ; Mode of pathogenicity: None; Publications: 35396997; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.702 KIF5B Achchuthan Shanmugasundram reviewed gene: KIF5B: Rating: ; Mode of pathogenicity: None; Publications: 36018820; Phenotypes: dilated cardiomyopathy, MONDO:0005021, ophthalmoplegia, MONDO:0003425, myopathy, MONDO:0005336, Hypotonia, HP:0001252, Seizure, HP:0001250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5184 YWHAZ Achchuthan Shanmugasundram gene: YWHAZ was added
gene: YWHAZ was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: YWHAZ was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: YWHAZ were set to 36001342
Phenotypes for gene: YWHAZ were set to Intellectual disability, MONDO:0001071
Review for gene: YWHAZ was set to RED
Added comment: PMID:36001342 reported one large three-generation family with intellectual disability and global developmental delay, where all affected members were identified with a heterozygous missense variant (c.147A>T/ p.Lys49Asn) in YWHAZ gene. Although there were 10 other rare variants located in 10 genes (ARHGAP4, AGPS, APOL3, CES3, DACT2, ECH1, FAM71E2, KREMEN1, YWHAZ, ZFYVE26) that co-segregated with the ID/GDD phenotype were identified in the family, they were either not present in all affected members or present in unaffected members.

In addition, computational modeling and knockdown/ knockin studies with Drosophila also confirmed the role of this YWHAZ variant in intellectual disability.
Sources: Literature
BabyScreen+ newborn screening v0.1952 FOLR1 Zornitza Stark Marked gene: FOLR1 as ready
BabyScreen+ newborn screening v0.1952 FOLR1 Zornitza Stark Gene: folr1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1952 FOLR1 Zornitza Stark Classified gene: FOLR1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1952 FOLR1 Zornitza Stark Gene: folr1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1951 FOLR1 Zornitza Stark gene: FOLR1 was added
gene: FOLR1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: FOLR1.
Mode of inheritance for gene: FOLR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOLR1 were set to 19732866; 30420205; 27743887
Phenotypes for gene: FOLR1 were set to Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068
Review for gene: FOLR1 was set to GREEN
Added comment: Folate is a neurotransmitter precursor. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Recognition and diagnosis of this disorder is critical because folinic acid therapy can reverse the clinical symptoms and improve brain abnormalities and function.

Treatment: folinic acid

Non-genetic confirmatory testing: cerebrospinal fluid 5-methyltetrahydrofolate level
Sources: Expert list
BabyScreen+ newborn screening v0.1950 FCHO1 Zornitza Stark Marked gene: FCHO1 as ready
BabyScreen+ newborn screening v0.1950 FCHO1 Zornitza Stark Gene: fcho1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1950 FCHO1 Zornitza Stark Classified gene: FCHO1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1950 FCHO1 Zornitza Stark Gene: fcho1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1949 FCHO1 Zornitza Stark edited their review of gene: FCHO1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1949 FCHO1 Zornitza Stark gene: FCHO1 was added
gene: FCHO1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: FCHO1.
Mode of inheritance for gene: FCHO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FCHO1 were set to 32098969; 30822429
Phenotypes for gene: FCHO1 were set to Immunodeficiency 76, MIM# 619164
Added comment: More than 10 affected individuals with bi-allelic variants in this gene reported. Functional data.

Immunodeficiency-76 (IMD76) is an autosomal recessive primary immunologic disorder characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show T-cell lymphopenia and may show variable B-cell or immunoglobulin abnormalities. More variable features found in some patients include lymphoma and neurologic features.

Treatment: bone marrow transplant.

Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, immunoglobulin levels
Sources: Expert list
BabyScreen+ newborn screening v0.1948 FAM111A Zornitza Stark Marked gene: FAM111A as ready
BabyScreen+ newborn screening v0.1948 FAM111A Zornitza Stark Gene: fam111a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1948 FAM111A Zornitza Stark Classified gene: FAM111A as Green List (high evidence)
BabyScreen+ newborn screening v0.1948 FAM111A Zornitza Stark Gene: fam111a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1947 FAM111A Zornitza Stark Tag treatable tag was added to gene: FAM111A.
Tag skeletal tag was added to gene: FAM111A.
BabyScreen+ newborn screening v0.1947 FAM111A Zornitza Stark gene: FAM111A was added
gene: FAM111A was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: FAM111A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FAM111A were set to Kenny-Caffey syndrome, type 2, MIM# 127000
Review for gene: FAM111A was set to GREEN
Added comment: Condition is characterised by impaired skeletal development with small and dense bones, short stature, ocular abnormalities, and primary hypoparathyroidism with hypocalcemia. At least 10 unrelated cases reported with de novo missense variants. Intellectual disability/developmental delay is a rare feature of the condition.

Treatment: magnesium, calcium and calcitriol or alfacalcidol

Non-genetic confirmatory testing: serum calcium, parathyroid hormone level, calcitonin level
Sources: Expert Review
BabyScreen+ newborn screening v0.1946 ERCC6L2 Zornitza Stark Marked gene: ERCC6L2 as ready
BabyScreen+ newborn screening v0.1946 ERCC6L2 Zornitza Stark Gene: ercc6l2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1946 ERCC6L2 Zornitza Stark Classified gene: ERCC6L2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1946 ERCC6L2 Zornitza Stark Gene: ercc6l2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1945 ERCC6L2 Zornitza Stark gene: ERCC6L2 was added
gene: ERCC6L2 was added to Baby Screen+ newborn screening. Sources: Expert Review
treatable, haematological tags were added to gene: ERCC6L2.
Mode of inheritance for gene: ERCC6L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC6L2 were set to 24507776; 27185855
Phenotypes for gene: ERCC6L2 were set to Bone marrow failure syndrome 2, MIM# 615715
Review for gene: ERCC6L2 was set to AMBER
Added comment: Trilineage bone marrow failure, learning disabilities, and microcephaly. Three consanguineous families reported, but two with the same truncating variant, founder effect likely.

Treatment: bone marrow transplant.

Amber rating due to limited number of families reported.
Sources: Expert Review
BabyScreen+ newborn screening v0.1944 DOCK2 Zornitza Stark Marked gene: DOCK2 as ready
BabyScreen+ newborn screening v0.1944 DOCK2 Zornitza Stark Gene: dock2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1944 DOCK2 Zornitza Stark Tag treatable tag was added to gene: DOCK2.
Tag immunological tag was added to gene: DOCK2.
BabyScreen+ newborn screening v0.1944 DOCK2 Zornitza Stark Classified gene: DOCK2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1944 DOCK2 Zornitza Stark Gene: dock2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1943 DOCK2 Zornitza Stark gene: DOCK2 was added
gene: DOCK2 was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: DOCK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOCK2 were set to 26083206; 29204803; 33928462; 30826364; 30838481; 11518968
Phenotypes for gene: DOCK2 were set to Immunodeficiency 40 MIM# 616433
Review for gene: DOCK2 was set to GREEN
Added comment: 13 unrelated individuals; two mouse models; 10 biallelic mutations found (6 led to premature termination of the protein & 4 missense mutations affecting conserved residues) All patients presented with combined immunodeficiency in infancy (defective IFN-mediated immunity), early onset of invasive bacterial and viral infections, functional defects in T/B/NK cells and elevated IgM (normal IgG/IgA).

Treatment: bone marrow transplant.

Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile
Sources: Expert Review
BabyScreen+ newborn screening v0.1942 DNASE2 Zornitza Stark Marked gene: DNASE2 as ready
BabyScreen+ newborn screening v0.1942 DNASE2 Zornitza Stark Gene: dnase2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1942 DNASE2 Zornitza Stark Classified gene: DNASE2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1942 DNASE2 Zornitza Stark Gene: dnase2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1941 DNASE2 Zornitza Stark Tag treatable tag was added to gene: DNASE2.
Tag immunological tag was added to gene: DNASE2.
BabyScreen+ newborn screening v0.1941 DNASE2 Zornitza Stark gene: DNASE2 was added
gene: DNASE2 was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: DNASE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNASE2 were set to 29259162; 31775019
Phenotypes for gene: DNASE2 were set to Autoinflammatory-pancytopenia syndrome, MIM# 619858
Review for gene: DNASE2 was set to GREEN
Added comment: Inflammatory disorder characterized by splenomegaly, glomerulonephritis, liver fibrosis, circulating anti-DNA autoantibodies, and progressive arthritis. Three families and functional data.

Treatment: baricitinib

Non-genetic confirmatory testing: Interferon signature
Sources: Expert Review
BabyScreen+ newborn screening v0.1940 DNAJC21 Zornitza Stark Marked gene: DNAJC21 as ready
BabyScreen+ newborn screening v0.1940 DNAJC21 Zornitza Stark Gene: dnajc21 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1940 DNAJC21 Zornitza Stark Tag treatable tag was added to gene: DNAJC21.
Tag haematological tag was added to gene: DNAJC21.
BabyScreen+ newborn screening v0.1940 DNAJC21 Zornitza Stark Classified gene: DNAJC21 as Green List (high evidence)
BabyScreen+ newborn screening v0.1940 DNAJC21 Zornitza Stark Gene: dnajc21 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1939 DNAJC21 Zornitza Stark gene: DNAJC21 was added
gene: DNAJC21 was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: DNAJC21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC21 were set to 29700810; 28062395; 27346687
Phenotypes for gene: DNAJC21 were set to Bone marrow failure syndrome 3, MIM# 617052
Review for gene: DNAJC21 was set to GREEN
Added comment: Onset of pancytopenia in early childhood; variable nonspecific somatic abnormalities, including poor growth, microcephaly, and skin anomalies.

Treatment: oral pancreatic enzymes, fat-soluble vitamins, blood and/or platelet transfusions, granulocyte-colony stimulation factor, bone marrow transplant

Confirmatory non-genetic testing: no; FBE as pancytopenia evolves.
Sources: Expert Review
BabyScreen+ newborn screening v0.1938 CYP2R1 Zornitza Stark Marked gene: CYP2R1 as ready
BabyScreen+ newborn screening v0.1938 CYP2R1 Zornitza Stark Gene: cyp2r1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1938 CYP2R1 Zornitza Stark Tag treatable tag was added to gene: CYP2R1.
Tag endocrine tag was added to gene: CYP2R1.
BabyScreen+ newborn screening v0.1938 CYP2R1 Zornitza Stark Classified gene: CYP2R1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1938 CYP2R1 Zornitza Stark Gene: cyp2r1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1937 CYP2R1 Zornitza Stark gene: CYP2R1 was added
gene: CYP2R1 was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: CYP2R1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP2R1 were set to 15128933; 28548312
Phenotypes for gene: CYP2R1 were set to Rickets due to defect in vitamin D 25-hydroxylation deficiency MIM#600081
Review for gene: CYP2R1 was set to GREEN
Added comment: At least 6 unrelated families reported.

Onset is generally in infancy.

Good response to vitamin D (calcifediol (25_OH_D3).

Confirmatory non-genetic testing: serum calcium, parathyroid hormone, 25-hydroxy vitamin D levels
Sources: Expert Review
BabyScreen+ newborn screening v0.1936 C17orf62 Zornitza Stark Marked gene: C17orf62 as ready
BabyScreen+ newborn screening v0.1936 C17orf62 Zornitza Stark Gene: c17orf62 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1936 C17orf62 Zornitza Stark Classified gene: C17orf62 as Green List (high evidence)
BabyScreen+ newborn screening v0.1936 C17orf62 Zornitza Stark Gene: c17orf62 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1935 C17orf62 Zornitza Stark gene: C17orf62 was added
gene: C17orf62 was added to Baby Screen+ newborn screening. Sources: Expert Review
new gene name, treatable, immunological tags were added to gene: C17orf62.
Mode of inheritance for gene: C17orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C17orf62 were set to 30361506; 30312704; 28351984
Phenotypes for gene: C17orf62 were set to Chronic granulomatous disease 5, autosomal recessive, MIM# 618935
Review for gene: C17orf62 was set to GREEN
Added comment: Seven Icelandic families reported with same homozygous variant, p.Tyr2Ter and an additional family from different ethnic background with different homozygous splice site variant. Functional data, including mouse model. Gene also known as EROS and CYBC1 (HGNC approved name)

Primary immunodeficiency characterized by onset of recurrent infections and severe colitis in the first decade of life. Patients often present with features of inflammatory bowel disease and may show granulomata on biopsy. Patients are particularly susceptible to catalase-positive organisms, including Burkholderia cepacia, Legionella, and Candida albicans. Some patients may develop autoinflammatory symptoms, including recurrent fever in the absence of infection, hemolytic anemia, and lymphopenia. Additional features may include short stature, viral infections, cutaneous abscesses, pulmonary infections, and lymphadenitis. Haematopoietic bone marrow transplant is curative.

Non-genetic confirmatory assay: dihydrorhodamine assay
Sources: Expert Review
Mendeliome v1.702 CYB561 Zornitza Stark Marked gene: CYB561 as ready
Mendeliome v1.702 CYB561 Zornitza Stark Gene: cyb561 has been classified as Green List (High Evidence).
Mendeliome v1.702 CYB561 Zornitza Stark Classified gene: CYB561 as Green List (high evidence)
Mendeliome v1.702 CYB561 Zornitza Stark Gene: cyb561 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1934 CYB561 Zornitza Stark Marked gene: CYB561 as ready
BabyScreen+ newborn screening v0.1934 CYB561 Zornitza Stark Gene: cyb561 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1934 CYB561 Zornitza Stark Classified gene: CYB561 as Green List (high evidence)
BabyScreen+ newborn screening v0.1934 CYB561 Zornitza Stark Gene: cyb561 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1933 CYB561 Zornitza Stark Tag treatable tag was added to gene: CYB561.
Tag endocrine tag was added to gene: CYB561.
Mendeliome v1.701 CYB561 Zornitza Stark gene: CYB561 was added
gene: CYB561 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CYB561 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYB561 were set to 29343526; 31822578
Phenotypes for gene: CYB561 were set to Orthostatic hypotension 2, MIM# 618182
Review for gene: CYB561 was set to GREEN
Added comment: Three families reported.

Severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood.

Treatment: L-threo-3,4-dihydroxyphenylserine (droxidopa)
Sources: Expert Review
BabyScreen+ newborn screening v0.1933 CYB561 Zornitza Stark gene: CYB561 was added
gene: CYB561 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CYB561 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYB561 were set to 29343526; 31822578
Phenotypes for gene: CYB561 were set to Orthostatic hypotension 2, MIM# 618182
Review for gene: CYB561 was set to GREEN
Added comment: Three families reported.

Severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood.

Treatment: L-threo-3,4-dihydroxyphenylserine (droxidopa)

Non-genetic confirmatory testing: plasma norepinephrine, epinephrine, dopamine
Sources: Expert list
BabyScreen+ newborn screening v0.1932 Zornitza Stark Panel name changed from gNBS to Baby Screen+ newborn screening
Panel status changed from internal to public
BabyScreen+ newborn screening v0.1931 CR2 Zornitza Stark Marked gene: CR2 as ready
BabyScreen+ newborn screening v0.1931 CR2 Zornitza Stark Gene: cr2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1931 CR2 Zornitza Stark Phenotypes for gene: CR2 were changed from Hypogammaglobulinaemia to Immunodeficiency, common variable, 7, MIM# 614699
BabyScreen+ newborn screening v0.1930 CR2 Zornitza Stark Tag treatable tag was added to gene: CR2.
Tag immunological tag was added to gene: CR2.
BabyScreen+ newborn screening v0.1930 CR2 Zornitza Stark reviewed gene: CR2: Rating: RED; Mode of pathogenicity: None; Publications: 22035880, 26325596; Phenotypes: Immunodeficiency, common variable, 7, MIM# 614699; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1930 CORO1A Zornitza Stark Marked gene: CORO1A as ready
BabyScreen+ newborn screening v0.1930 CORO1A Zornitza Stark Gene: coro1a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1930 CORO1A Zornitza Stark Classified gene: CORO1A as Green List (high evidence)
BabyScreen+ newborn screening v0.1930 CORO1A Zornitza Stark Gene: coro1a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1929 CORO1A Zornitza Stark gene: CORO1A was added
gene: CORO1A was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CORO1A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CORO1A were set to Immunodeficiency 8 MIM# 615401
Review for gene: CORO1A was set to GREEN
Added comment: 3 unrelated families and 1 unrelated individual reported with bi-allelic (deletion, missense, insertion) variants, resulting in premature stop codons and truncated protein/ alter a highly conserved residue in binding domain; one mouse model

All patients displayed T−B+NK+ SCID or CID presenting in early-onset recurrent infections and additional features that included EBV-associated lymphoproliferative disease and low immunoglobulin levels.

Congenital onset.

Treatment: bone marrow transplant

Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile
Sources: Expert list
BabyScreen+ newborn screening v0.1928 CDCA7 Zornitza Stark Marked gene: CDCA7 as ready
BabyScreen+ newborn screening v0.1928 CDCA7 Zornitza Stark Gene: cdca7 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1928 CDCA7 Zornitza Stark Classified gene: CDCA7 as Green List (high evidence)
BabyScreen+ newborn screening v0.1928 CDCA7 Zornitza Stark Gene: cdca7 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1927 CDCA7 Zornitza Stark Tag treatable tag was added to gene: CDCA7.
Tag immunological tag was added to gene: CDCA7.
BabyScreen+ newborn screening v0.1927 CDCA7 Zornitza Stark gene: CDCA7 was added
gene: CDCA7 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CDCA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDCA7 were set to 26216346
Phenotypes for gene: CDCA7 were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 3, MIM# 616910
Review for gene: CDCA7 was set to GREEN
Added comment: Congenital onset, severe disorder. At least 4 unrelated families reported.

Treatment: replacement immunoglobulins, bone marrow transplant

Non-genetic confirmatory testing: immunoglobulin levels, cytogenetic analysis for centromeric instability, DNA methylation studies
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.5184 RRAS2 Elena Savva Classified gene: RRAS2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5184 RRAS2 Elena Savva Gene: rras2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5183 RRAS2 Elena Savva Marked gene: RRAS2 as ready
Intellectual disability syndromic and non-syndromic v0.5183 RRAS2 Elena Savva Gene: rras2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5183 RRAS2 Elena Savva gene: RRAS2 was added
gene: RRAS2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RRAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RRAS2 were set to PMID: 31130282; 31130285
Phenotypes for gene: RRAS2 were set to Noonan syndrome 12 MIM#618624
Mode of pathogenicity for gene: RRAS2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RRAS2 was set to AMBER
Added comment: Gene has an established GOF mechanism

PMID: 31130282 - 3/9 individuals had mild learning difficulties or mild GDD

PMID: 31130285 - 1/3 individuals had mild ID, 1/3 had severe ID, 1/3 normal
Sources: Literature
BabyScreen+ newborn screening v0.1926 CD81 Zornitza Stark Marked gene: CD81 as ready
BabyScreen+ newborn screening v0.1926 CD81 Zornitza Stark Gene: cd81 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1926 CD81 Zornitza Stark Tag treatable tag was added to gene: CD81.
Tag immunological tag was added to gene: CD81.
BabyScreen+ newborn screening v0.1926 CD81 Zornitza Stark gene: CD81 was added
gene: CD81 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CD81 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD81 were set to 20237408
Phenotypes for gene: CD81 were set to Immunodeficiency, common variable, 6, MIM# 613496
Review for gene: CD81 was set to RED
Added comment: CVID, which would be congenital, severe and treatable with replacement immunoglobulins.

However, only a single individual reported.
Sources: Expert Review
BabyScreen+ newborn screening v0.1925 CD70 Zornitza Stark Marked gene: CD70 as ready
BabyScreen+ newborn screening v0.1925 CD70 Zornitza Stark Gene: cd70 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1925 CD70 Zornitza Stark Classified gene: CD70 as Green List (high evidence)
BabyScreen+ newborn screening v0.1925 CD70 Zornitza Stark Gene: cd70 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1924 CD70 Zornitza Stark gene: CD70 was added
gene: CD70 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CD70 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CD70 were set to Lymphoproliferative syndrome 3, MIM# 618261
Review for gene: CD70 was set to GREEN
Added comment: Severe lymphoproliferation following EBV infection.

Treatment: bone marrow transplant.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile
Sources: Expert Review
BabyScreen+ newborn screening v0.1923 CD55 Zornitza Stark Marked gene: CD55 as ready
BabyScreen+ newborn screening v0.1923 CD55 Zornitza Stark Gene: cd55 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1923 CD55 Zornitza Stark Classified gene: CD55 as Green List (high evidence)
BabyScreen+ newborn screening v0.1923 CD55 Zornitza Stark Gene: cd55 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1922 CD55 Zornitza Stark Tag treatable tag was added to gene: CD55.
Tag immunological tag was added to gene: CD55.
BabyScreen+ newborn screening v0.1922 CD55 Zornitza Stark gene: CD55 was added
gene: CD55 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CD55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD55 were set to 33398182
Phenotypes for gene: CD55 were set to Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy, MIM# 226300
Review for gene: CD55 was set to GREEN
Added comment: Severe congenital disorder, high mortality.

Treatment: Eculizumab

Non-genetic confirmatory testing: albumin level, immunoglobulin level
Sources: Expert Review
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Marked gene: CD40 as ready
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Gene: cd40 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Marked gene: CD40 as ready
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Gene: cd40 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Classified gene: CD40 as Green List (high evidence)
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Gene: cd40 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1920 CD40 Zornitza Stark gene: CD40 was added
gene: CD40 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CD40 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD40 were set to 29884852
Phenotypes for gene: CD40 were set to Immunodeficiency with hyper-IgM, type 3, MIM# 606843
Review for gene: CD40 was set to GREEN
Added comment: Severity can be variable but generally congenital onset, and predisposition to severe infections. Note CD40L already included.

Treatment: bone marrow transplantation.

Non-genetic confirmatory testing: immunoglobulin levels, flow cytometric analysis
Sources: Expert list
Paroxysmal Dyskinesia v0.106 SHQ1 Shekeeb Mohammad changed review comment from: Sources: Literature; to: Sources: Literature: PMID: 36847845
Paroxysmal Dyskinesia v0.106 SHQ1 Shekeeb Mohammad gene: SHQ1 was added
gene: SHQ1 was added to Paroxysmal Dyskinesia. Sources: Literature
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SHQ1 were set to PAROXYSMAL DYSTONIA; INTELLECTUAL DISABILITY; HYPOTONIA; CHOREOATHETOSIS; EPILEPSY
Review for gene: SHQ1 was set to GREEN
gene: SHQ1 was marked as current diagnostic
Added comment: Sources: Literature
Dystonia - isolated/combined v1.30 ATP5B Shekeeb Mohammad gene: ATP5B was added
gene: ATP5B was added to Dystonia - isolated/combined. Sources: Literature
Mode of inheritance for gene: ATP5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP5B were set to 36860166
Phenotypes for gene: ATP5B were set to DYSTONIA; PROGRESSIVE DYSTONIA
Penetrance for gene: ATP5B were set to Incomplete
Review for gene: ATP5B was set to GREEN
Added comment: Sources: Literature
Bone Marrow Failure v1.27 SRP19 Pasquale Barbaro gene: SRP19 was added
gene: SRP19 was added to Bone Marrow Failure. Sources: Literature
Mode of inheritance for gene: SRP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP19 were set to PMID: 36223592
Phenotypes for gene: SRP19 were set to neutropenia; myeloid maturation arrest; growth deficiency
Penetrance for gene: SRP19 were set to unknown
Review for gene: SRP19 was set to RED
Added comment: One kindred reported
Sources: Literature
Bone Marrow Failure v1.27 SRPRA Pasquale Barbaro gene: SRPRA was added
gene: SRPRA was added to Bone Marrow Failure. Sources: Literature
Mode of inheritance for gene: SRPRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRPRA were set to PMID: 36223592
Phenotypes for gene: SRPRA were set to neutropenia; myeloid maturation arrest; exocrine pancreatic insufficiency; growth deficiency
Penetrance for gene: SRPRA were set to unknown
Review for gene: SRPRA was set to RED
Added comment: One patient reported with functional data
Sources: Literature
Phagocyte Defects v1.10 SRPRA Pasquale Barbaro gene: SRPRA was added
gene: SRPRA was added to Phagocyte Defects. Sources: Literature
Mode of inheritance for gene: SRPRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRPRA were set to PMID: 36223592
Phenotypes for gene: SRPRA were set to neutropenia; myeloid maturation arrest; exocrine pancreatic insufficiency; growth deficiency
Penetrance for gene: SRPRA were set to unknown
Review for gene: SRPRA was set to RED
Added comment: One denovo variant identified in one patient
Sources: Literature
Phagocyte Defects v1.10 SRP19 Pasquale Barbaro gene: SRP19 was added
gene: SRP19 was added to Phagocyte Defects. Sources: Literature
Mode of inheritance for gene: SRP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP19 were set to PMID: 36223592
Phenotypes for gene: SRP19 were set to neutropenia; myeloid maturation arrest; growth deficiency
Penetrance for gene: SRP19 were set to unknown
Review for gene: SRP19 was set to RED
Added comment: Reported in 5 patients from one kindred
Sources: Literature
BabyScreen+ newborn screening v0.1919 CD3G Zornitza Stark Marked gene: CD3G as ready
BabyScreen+ newborn screening v0.1919 CD3G Zornitza Stark Gene: cd3g has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1919 CD3G Zornitza Stark Classified gene: CD3G as Green List (high evidence)
BabyScreen+ newborn screening v0.1919 CD3G Zornitza Stark Gene: cd3g has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1918 CD3G Zornitza Stark edited their review of gene: CD3G: Changed rating: GREEN
BabyScreen+ newborn screening v0.1918 CD3G Zornitza Stark Tag treatable tag was added to gene: CD3G.
Tag immunological tag was added to gene: CD3G.
BabyScreen+ newborn screening v0.1918 CD3G Zornitza Stark gene: CD3G was added
gene: CD3G was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CD3G was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD3G were set to 31921117
Phenotypes for gene: CD3G were set to Immunodeficiency 17; CD3 gamma deficient MIM# 615607
Added comment: 10 affected individuals from 5 unrelated families; homozygous and compound heterozygous variants (splicing, missense and small deletion variants) identified resulting in premature stop codons and truncated protein; multiple mouse models.

All individuals displayed immune deficiency and autoimmunity of variable severity. Some individuals presented at birth with failure to thrive due to lethal SCID features. The most common immunologic profile includes partial T lymphocytopenia and low CD3, with normal B cells, NK cells, and immunoglobulins.

Congenital onset.

Treatment: replacement immunoglobulin

Non-genetic confirmatory testing: immunoglobulin levels
Sources: Expert list
BabyScreen+ newborn screening v0.1917 CD27 Zornitza Stark Marked gene: CD27 as ready
BabyScreen+ newborn screening v0.1917 CD27 Zornitza Stark Gene: cd27 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1917 CD27 Zornitza Stark Classified gene: CD27 as Green List (high evidence)
BabyScreen+ newborn screening v0.1917 CD27 Zornitza Stark Gene: cd27 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1916 CD27 Zornitza Stark Tag treatable tag was added to gene: CD27.
Tag immunological tag was added to gene: CD27.
BabyScreen+ newborn screening v0.1916 CD27 Zornitza Stark gene: CD27 was added
gene: CD27 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CD27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD27 were set to 22197273; 22801960; 22365582; 25843314; 11062504
Phenotypes for gene: CD27 were set to CD27-deficiency MIM# 615122
Review for gene: CD27 was set to GREEN
Added comment: 17 affected individuals from 9 unrelated families; homozygous (missense) and compound heterozygous (missense/ nonsense) variants identified in CD27; one mouse model. Affected individuals present with varied phenotypes (even within the same families); most commonly with lymphadenopathy, fever, hepatosplenomegaly, EBV-related infections, and immunodeficiency associated with hypogammaglobulinaemia. However, some CD27-deficient individuals are asymptomatic or display borderline-low hypogammaglobulinaemia.

Treatment: replacement immunoglobulin treatment, rituximab, Bone marrow transplant.

Non-genetic confirmatory testing: immunoglobulin levels
Sources: Expert list
BabyScreen+ newborn screening v0.1915 CD247 Zornitza Stark Marked gene: CD247 as ready
BabyScreen+ newborn screening v0.1915 CD247 Zornitza Stark Gene: cd247 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1915 CD247 Zornitza Stark Classified gene: CD247 as Green List (high evidence)
BabyScreen+ newborn screening v0.1915 CD247 Zornitza Stark Gene: cd247 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1914 CD247 Zornitza Stark Tag treatable tag was added to gene: CD247.
Tag immunological tag was added to gene: CD247.
BabyScreen+ newborn screening v0.1914 CD247 Zornitza Stark gene: CD247 was added
gene: CD247 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CD247 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD247 were set to 16672702; 17170122
Phenotypes for gene: CD247 were set to Immunodeficiency 25, MIM# 610163
Review for gene: CD247 was set to GREEN
Added comment: Two reports in the literature, note additional two reports in ClinVar; functional data.

Congenital onset. Absent T cells, resulting in severe immunodeficiency.

Treatment: bone marrow transplant.

Non-genetic confirmatory testing: T, B and NK cell counts
Sources: Expert Review
BabyScreen+ newborn screening v0.1913 CD19 Zornitza Stark Marked gene: CD19 as ready
BabyScreen+ newborn screening v0.1913 CD19 Zornitza Stark Gene: cd19 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1913 CD19 Zornitza Stark Tag treatable tag was added to gene: CD19.
Tag immunological tag was added to gene: CD19.
BabyScreen+ newborn screening v0.1913 CD19 Zornitza Stark Classified gene: CD19 as Green List (high evidence)
BabyScreen+ newborn screening v0.1913 CD19 Zornitza Stark Gene: cd19 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1912 CD19 Zornitza Stark gene: CD19 was added
gene: CD19 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CD19 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CD19 were set to Immunodeficiency, common variable, 3, MIM# 613493
Review for gene: CD19 was set to GREEN
Added comment: More than 5 unrelated families reported. Clinical features include increased susceptibility to infection, hypogammaglobulinaemia, and normal numbers of mature B cells in blood, indicating a B-cell antibody-deficient immunodeficiency disorder.

Onset is congenital.

Treatment: IVIG

Non-genetic confirmatory testing: immunoglobulin levels
Sources: Expert list
BabyScreen+ newborn screening v0.1911 CAV1 Zornitza Stark Marked gene: CAV1 as ready
BabyScreen+ newborn screening v0.1911 CAV1 Zornitza Stark Gene: cav1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1911 CAV1 Zornitza Stark Classified gene: CAV1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1911 CAV1 Zornitza Stark Gene: cav1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1910 CAV1 Zornitza Stark Tag treatable tag was added to gene: CAV1.
Tag metabolic tag was added to gene: CAV1.
BabyScreen+ newborn screening v0.1910 CAV1 Zornitza Stark gene: CAV1 was added
gene: CAV1 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CAV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAV1 were set to 29704234
Phenotypes for gene: CAV1 were set to Lipodystrophy, congenital generalized, type 3, MIM# 612526
Review for gene: CAV1 was set to GREEN
Added comment: Established gene-disease association.

Bi-allelic disease is more severe. Onset is congenital.

Treatment: metreleptin

Non-genetic confirmatory testing: leptin levels
Sources: Expert list
BabyScreen+ newborn screening v0.1908 PRDX1 Zornitza Stark Marked gene: PRDX1 as ready
BabyScreen+ newborn screening v0.1908 PRDX1 Zornitza Stark Gene: prdx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1908 PRDX1 Zornitza Stark Classified gene: PRDX1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1908 PRDX1 Zornitza Stark Gene: prdx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1907 PRDX1 Zornitza Stark Tag for review tag was added to gene: PRDX1.
BabyScreen+ newborn screening v0.1907 PNP Zornitza Stark Marked gene: PNP as ready
BabyScreen+ newborn screening v0.1907 PNP Zornitza Stark Gene: pnp has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1907 PNP Zornitza Stark Tag treatable tag was added to gene: PNP.
Tag immunological tag was added to gene: PNP.
BabyScreen+ newborn screening v0.1907 PNP Zornitza Stark Classified gene: PNP as Green List (high evidence)
BabyScreen+ newborn screening v0.1907 PNP Zornitza Stark Gene: pnp has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1906 MTHFR Zornitza Stark Marked gene: MTHFR as ready
BabyScreen+ newborn screening v0.1906 MTHFR Zornitza Stark Gene: mthfr has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1906 MTHFR Zornitza Stark Phenotypes for gene: MTHFR were changed from Homocystinuria due to MTHFR deficiency to Homocystinuria due to MTHFR deficiency MIM#236250
BabyScreen+ newborn screening v0.1905 MTHFR Zornitza Stark Publications for gene: MTHFR were set to
BabyScreen+ newborn screening v0.1904 MTHFR Zornitza Stark Classified gene: MTHFR as Red List (low evidence)
BabyScreen+ newborn screening v0.1904 MTHFR Zornitza Stark Gene: mthfr has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1903 MCCC2 Zornitza Stark Marked gene: MCCC2 as ready
BabyScreen+ newborn screening v0.1903 MCCC2 Zornitza Stark Gene: mccc2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1903 MCCC2 Zornitza Stark Phenotypes for gene: MCCC2 were changed from 3-Methylcrotonyl-CoA carboxylase 2 deficiency; 3-Methylcrotonyl-CoA carboxylase 2 deficiency, MIM# 210210 to 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210
BabyScreen+ newborn screening v0.1902 MCCC2 Zornitza Stark Publications for gene: MCCC2 were set to
BabyScreen+ newborn screening v0.1901 MCCC2 Zornitza Stark reviewed gene: MCCC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1901 MCCC1 Zornitza Stark Marked gene: MCCC1 as ready
BabyScreen+ newborn screening v0.1901 MCCC1 Zornitza Stark Gene: mccc1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1901 MCCC1 Zornitza Stark Phenotypes for gene: MCCC1 were changed from 3-Methylcrotonyl-CoA carboxylase 1 deficiency; 3-Methylcrotonyl-CoA carboxylase 1 deficiency, MIM# 210200 to 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200
BabyScreen+ newborn screening v0.1900 MCCC1 Zornitza Stark Publications for gene: MCCC1 were set to
BabyScreen+ newborn screening v0.1899 MCCC1 Zornitza Stark Classified gene: MCCC1 as Red List (low evidence)
BabyScreen+ newborn screening v0.1899 MCCC1 Zornitza Stark Gene: mccc1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1898 MCCC1 Zornitza Stark reviewed gene: MCCC1: Rating: RED; Mode of pathogenicity: None; Publications: 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1898 MAT1A Zornitza Stark Marked gene: MAT1A as ready
BabyScreen+ newborn screening v0.1898 MAT1A Zornitza Stark Gene: mat1a has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1898 MAT1A Zornitza Stark Mode of inheritance for gene: MAT1A was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1897 MAT1A Zornitza Stark Phenotypes for gene: MAT1A were changed from Methionine adenosyltransferase deficiency to Methionine adenosyltransferase deficiency MIM#250850
BabyScreen+ newborn screening v0.1896 LIAS Zornitza Stark Marked gene: LIAS as ready
BabyScreen+ newborn screening v0.1896 LIAS Zornitza Stark Gene: lias has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1896 LIAS Zornitza Stark Publications for gene: LIAS were set to PMID: 24334290, 24777537,
BabyScreen+ newborn screening v0.1895 LIAS Zornitza Stark Source Expert list was removed from LIAS.
Source Expert Review was added to LIAS.
Rating Changed from No List (delete) to Red List (low evidence)
BabyScreen+ newborn screening v0.1894 LIAS Zornitza Stark All sources for gene: LIAS were removed
BabyScreen+ newborn screening v0.1893 LIAS Zornitza Stark All sources for gene: LIAS were removed
BabyScreen+ newborn screening v0.1892 LIAS Zornitza Stark Classified gene: LIAS as Red List (low evidence)
BabyScreen+ newborn screening v0.1892 LIAS Zornitza Stark Gene: lias has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1891 HPD Zornitza Stark Marked gene: HPD as ready
BabyScreen+ newborn screening v0.1891 HPD Zornitza Stark Gene: hpd has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1891 HPD Zornitza Stark Publications for gene: HPD were set to
BabyScreen+ newborn screening v0.1890 HPD Zornitza Stark reviewed gene: HPD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Tyrosinemia, type III MIM#276710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1890 HIBCH Zornitza Stark Tag for review tag was added to gene: HIBCH.
BabyScreen+ newborn screening v0.1890 HMGCS2 Zornitza Stark Marked gene: HMGCS2 as ready
BabyScreen+ newborn screening v0.1890 HMGCS2 Zornitza Stark Gene: hmgcs2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1890 HMGCS2 Zornitza Stark Classified gene: HMGCS2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1890 HMGCS2 Zornitza Stark Gene: hmgcs2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1889 HMGCS2 Zornitza Stark Tag for review tag was added to gene: HMGCS2.
Tag treatable tag was added to gene: HMGCS2.
Tag metabolic tag was added to gene: HMGCS2.
BabyScreen+ newborn screening v0.1889 HMGCS2 Zornitza Stark reviewed gene: HMGCS2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: HMG-CoA synthase-2 deficiency MIM#605911; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1889 HIBCH Zornitza Stark Marked gene: HIBCH as ready
BabyScreen+ newborn screening v0.1889 HIBCH Zornitza Stark Gene: hibch has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1889 HIBCH Zornitza Stark Phenotypes for gene: HIBCH were changed from Neurodegeneration, progressive infantile to 3-hydroxyisobutryl-CoA hydrolase deficiency MIM#250620
BabyScreen+ newborn screening v0.1888 HIBCH Zornitza Stark Publications for gene: HIBCH were set to
BabyScreen+ newborn screening v0.1887 HIBCH Zornitza Stark Tag treatable tag was added to gene: HIBCH.
Tag metabolic tag was added to gene: HIBCH.
BabyScreen+ newborn screening v0.1887 HIBCH Zornitza Stark Classified gene: HIBCH as Green List (high evidence)
BabyScreen+ newborn screening v0.1887 HIBCH Zornitza Stark Gene: hibch has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1886 GLIS3 Zornitza Stark Marked gene: GLIS3 as ready
BabyScreen+ newborn screening v0.1886 GLIS3 Zornitza Stark Gene: glis3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1886 GLIS3 Zornitza Stark Phenotypes for gene: GLIS3 were changed from Diabetes mellitus, neonatal, with congenital hypothyroidism; Diabetes mellitus, neonatal, with congenital hypothyroidism, MIM# 610199 to Diabetes mellitus, neonatal, with congenital hypothyroidism MIM#610199
BabyScreen+ newborn screening v0.1885 GLIS3 Zornitza Stark Publications for gene: GLIS3 were set to
BabyScreen+ newborn screening v0.1884 GLIS3 Zornitza Stark Classified gene: GLIS3 as Green List (high evidence)
BabyScreen+ newborn screening v0.1884 GLIS3 Zornitza Stark Gene: glis3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1883 GLIS3 Zornitza Stark Tag treatable tag was added to gene: GLIS3.
Tag endocrine tag was added to gene: GLIS3.
BabyScreen+ newborn screening v0.1883 GLIS3 Zornitza Stark reviewed gene: GLIS3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes mellitus, neonatal, with congenital hypothyroidism MIM#610199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1883 PRDX1 Lilian Downie gene: PRDX1 was added
gene: PRDX1 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: PRDX1 was set to Other
Publications for gene: PRDX1 were set to PMID: 20301503, PMID: 29396438, PMID: 34215320, PMID: 33982424
Phenotypes for gene: PRDX1 were set to Methylmalonic aciduria and homocystinuria, cblC type, digenic MIM#277400
Review for gene: PRDX1 was set to GREEN
Added comment: Digenic inheritance with mutation in other allele of MMACHC
On GUARDIAN and Rx genes list

Recently, three individuals who are double heterozygous for pathogenic variants in MMACHC and PRDX1 have been identified. PRDX1 is a neighboring gene on chromosome 1 transcribed from the reverse strand. Variants identified in PRDX1 located at the intron 5 splice acceptor site caused skipping of exon 6, transcription of antisense MMACHC, and hypermethylation of the MMACHC promoter/exon 1, resulting in no gene expression from that allele [Guéant et al 2018].

Treatable with cobalamin, carnitine & diet. NB MMACHC is green on our list, on newborn screening.
Sources: Expert list
BabyScreen+ newborn screening v0.1883 PNP Lilian Downie gene: PNP was added
gene: PNP was added to gNBS. Sources: Expert list
Mode of inheritance for gene: PNP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNP were set to PMID: 35968787, PMID: 35063692, PMID: 30885031, PMID: 1931007, PMID: 28674683
Phenotypes for gene: PNP were set to Immunodeficiency due to purine nucleoside phosphorylase deficiency MIM#613179
Review for gene: PNP was set to GREEN
Added comment: Decreased T cell function - SCID immunodeficiency
variable neurological phenotype
childhood onset
Treat bone marrow transplant
Sources: Expert list
BabyScreen+ newborn screening v0.1883 MTHFR Lilian Downie reviewed gene: MTHFR: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 34214447; Phenotypes: Homocystinuria due to MTHFR deficiency MIM#236250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1883 MCCC2 Lilian Downie reviewed gene: MCCC2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 22642865; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5182 RBSN Achchuthan Shanmugasundram gene: RBSN was added
gene: RBSN was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RBSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBSN were set to 25233840; 29784638; 35652444
Phenotypes for gene: RBSN were set to intellectual disability, MONDO:0001071
Review for gene: RBSN was set to GREEN
Added comment: This gene should be rated GREEN as bi-allelic variants in RBSN has been associated with a phenotype encompassing developmental delay and intellectual disability from four unrelated families.

PMID:25233840 reported a 6.5 year old female patient with a homozygous missense variant c.1273G > A (p.Gly425Arg) and her clinical presentation included intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis.

PMID:29784638 reported three siblings with homozygous variant c.289G>C (p.Gly97Arg) in RBSN. The proband presented global developmental delay, had complete 46,XY male-to-female sex reversal and died at age 20 months after multiple infections. The other 2 affected siblings underwent unrelated-donor bone marrow or stem cell transplantation at 8 and 6.5 months of age, respectively. Both have severe intellectual disability and are nonambulatory and nonverbal.

PMID:35652444 reported two unrelated families (three siblings from a family of Iranian descent identified with homozygous variant c.547G>A (p.Gly183Arg) and four members from a family of indigenous Cree descent identified with homozygous variant c.538C>G (p.Arg180Gly)) with overlapping phenotypes including developmental delay, intellectual disability, distal motor axonal neuropathy and facial dysmorphism.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5182 CTR9 Achchuthan Shanmugasundram changed review comment from: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).; to: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in zebrafish also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).
Intellectual disability syndromic and non-syndromic v0.5182 DPYSL2 Achchuthan Shanmugasundram gene: DPYSL2 was added
gene: DPYSL2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DPYSL2 were set to 27249678; 35861646
Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071; Aplasia/Hypoplasia of the corpus callosum, HP:0007370
Review for gene: DPYSL2 was set to AMBER
Added comment: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
BabyScreen+ newborn screening v0.1883 GATM Zornitza Stark Tag treatable tag was added to gene: GATM.
Tag metabolic tag was added to gene: GATM.
BabyScreen+ newborn screening v0.1883 GATM Zornitza Stark Marked gene: GATM as ready
BabyScreen+ newborn screening v0.1883 GATM Zornitza Stark Gene: gatm has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1883 GATM Zornitza Stark Classified gene: GATM as Green List (high evidence)
BabyScreen+ newborn screening v0.1883 GATM Zornitza Stark Gene: gatm has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1882 GATM Zornitza Stark reviewed gene: GATM: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301745; Phenotypes: Cerebral creatine deficiency syndrome 3, MIM#612718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1882 FOXE1 Zornitza Stark Marked gene: FOXE1 as ready
BabyScreen+ newborn screening v0.1882 FOXE1 Zornitza Stark Gene: foxe1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1882 FOXE1 Zornitza Stark Phenotypes for gene: FOXE1 were changed from Bamforth-Lazarus syndrome to Bamforth-Lazarus syndrome MIM# 241850
BabyScreen+ newborn screening v0.1881 FOXE1 Zornitza Stark Publications for gene: FOXE1 were set to
BabyScreen+ newborn screening v0.1880 FOXE1 Zornitza Stark Classified gene: FOXE1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1880 FOXE1 Zornitza Stark Gene: foxe1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1879 FOXE1 Zornitza Stark Tag treatable tag was added to gene: FOXE1.
Tag endocrine tag was added to gene: FOXE1.
Tag deafness tag was added to gene: FOXE1.
BabyScreen+ newborn screening v0.1879 ALDH4A1 Zornitza Stark Marked gene: ALDH4A1 as ready
BabyScreen+ newborn screening v0.1879 ALDH4A1 Zornitza Stark Gene: aldh4a1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1879 ALDH4A1 Zornitza Stark Phenotypes for gene: ALDH4A1 were changed from Hyperprolinemia, type II to Hyperprolinemia, type II MIM#239510
BabyScreen+ newborn screening v0.1878 ALDH4A1 Zornitza Stark Publications for gene: ALDH4A1 were set to
BabyScreen+ newborn screening v0.1877 ALDH4A1 Zornitza Stark Classified gene: ALDH4A1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1877 ALDH4A1 Zornitza Stark Gene: aldh4a1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1876 ALDH4A1 Zornitza Stark Tag treatable tag was added to gene: ALDH4A1.
Tag metabolic tag was added to gene: ALDH4A1.
BabyScreen+ newborn screening v0.1876 ALDH4A1 Zornitza Stark reviewed gene: ALDH4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperprolinemia, type II MIM#239510; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1876 ACADSB Zornitza Stark Marked gene: ACADSB as ready
BabyScreen+ newborn screening v0.1876 ACADSB Zornitza Stark Gene: acadsb has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1876 ACADSB Zornitza Stark Phenotypes for gene: ACADSB were changed from 2-Methylbutyryl-CoA dehydrogenase deficiency to 2-methylbutyrylglycinuria MIM#610006
BabyScreen+ newborn screening v0.1875 ACADS Zornitza Stark Marked gene: ACADS as ready
BabyScreen+ newborn screening v0.1875 ACADS Zornitza Stark Gene: acads has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1875 ABCD4 Zornitza Stark Marked gene: ABCD4 as ready
BabyScreen+ newborn screening v0.1875 ABCD4 Zornitza Stark Gene: abcd4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1875 ABCD4 Zornitza Stark Phenotypes for gene: ABCD4 were changed from MAHCJ, MIM#614857; Methylmalonic aciduria and homocystinuria, cblJ TYPE; Methylmalonic aciduria and homocystinuria, cblJ type to Methylmalonic aciduria and homocystinuria, cblJ type MIM#614857
BabyScreen+ newborn screening v0.1874 ABCD4 Zornitza Stark Publications for gene: ABCD4 were set to
BabyScreen+ newborn screening v0.1873 ABCD4 Zornitza Stark Classified gene: ABCD4 as Green List (high evidence)
BabyScreen+ newborn screening v0.1873 ABCD4 Zornitza Stark Gene: abcd4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1872 ABCD4 Zornitza Stark reviewed gene: ABCD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22922874, 30651581, 28572511, 31113616; Phenotypes: Methylmalonic aciduria and homocystinuria, cblJ type MIM#614857; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.700 TLN1 Achchuthan Shanmugasundram reviewed gene: TLN1: Rating: RED; Mode of pathogenicity: None; Publications: 35861643; Phenotypes: thrombocytopenia, MONDO:0002049, lymphopenia, MONDO:0003783; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Bleeding and Platelet Disorders v1.16 TLN1 Achchuthan Shanmugasundram gene: TLN1 was added
gene: TLN1 was added to Bleeding and Platelet Disorders. Sources: Literature
Mode of inheritance for gene: TLN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TLN1 were set to 35861643
Phenotypes for gene: TLN1 were set to thrombocytopenia, MONDO:0002049
Review for gene: TLN1 was set to RED
Added comment: PMID:35861643 reported a 20-year old man of Mexican ancestry with a complex phenotype including thrombocytopenia, T lymphopenia, and low IgG levels. The patient generally had a platelet count of <20 000/mcL, but without significant bleeding. He was identified with a de novo heterozygous variant c.685C > T (p.Pro 229 Ser) that was not present in his parents.
Sources: Literature
Hereditary Neuropathy_CMT - isolated v1.28 PCK2 Bryony Thompson Marked gene: PCK2 as ready
Hereditary Neuropathy_CMT - isolated v1.28 PCK2 Bryony Thompson Gene: pck2 has been classified as Amber List (Moderate Evidence).
Hereditary Neuropathy_CMT - isolated v1.28 PCK2 Bryony Thompson Classified gene: PCK2 as Amber List (moderate evidence)
Hereditary Neuropathy_CMT - isolated v1.28 PCK2 Bryony Thompson Gene: pck2 has been classified as Amber List (Moderate Evidence).
Hereditary Neuropathy_CMT - isolated v1.26 PCK2 Bryony Thompson gene: PCK2 was added
gene: PCK2 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature
Mode of inheritance for gene: PCK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCK2 were set to 36845668
Phenotypes for gene: PCK2 were set to Peripheral neuropathy (MONDO#0005244), PCK2-related
Mendeliome v1.700 PCK2 Bryony Thompson Classified gene: PCK2 as Amber List (moderate evidence)
Mendeliome v1.700 PCK2 Bryony Thompson Gene: pck2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.699 PCK2 Bryony Thompson reviewed gene: PCK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36845668; Phenotypes: Peripheral neuropathy (MONDO#0005244), PCK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 MCCC1 Lilian Downie reviewed gene: MCCC1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 22642865; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5182 CTR9 Achchuthan Shanmugasundram reviewed gene: CTR9: Rating: ; Mode of pathogenicity: None; Publications: 35717577; Phenotypes: ; Mode of inheritance: None
Regression v0.520 FTH1 Paul De Fazio gene: FTH1 was added
gene: FTH1 was added to Regression. Sources: Literature
Mode of inheritance for gene: FTH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FTH1 were set to 36778397
Phenotypes for gene: FTH1 were set to Neuroferritinopathy (MONDO:0011638)
Mode of pathogenicity for gene: FTH1 was set to Other
Review for gene: FTH1 was set to AMBER
gene: FTH1 was marked as current diagnostic
Added comment: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature
Cerebellar and Pontocerebellar Hypoplasia v1.60 FTH1 Paul De Fazio changed review comment from: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature; to: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. All patients had pontocerebellar hypoplasia during infancy. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature
Cerebellar and Pontocerebellar Hypoplasia v1.60 FTH1 Seb Lunke Marked gene: FTH1 as ready
Cerebellar and Pontocerebellar Hypoplasia v1.60 FTH1 Seb Lunke Gene: fth1 has been classified as Amber List (Moderate Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.60 FTH1 Seb Lunke Classified gene: FTH1 as Amber List (moderate evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.60 FTH1 Seb Lunke Gene: fth1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.699 FTH1 Paul De Fazio reviewed gene: FTH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36778397; Phenotypes: Neuroferritinopathy (MONDO:0011638); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Cerebellar and Pontocerebellar Hypoplasia v1.59 FTH1 Paul De Fazio gene: FTH1 was added
gene: FTH1 was added to Cerebellar and Pontocerebellar Hypoplasia. Sources: Literature
Mode of inheritance for gene: FTH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FTH1 were set to 36778397
Phenotypes for gene: FTH1 were set to Neuroferritinopathy (MONDO:0011638)
Mode of pathogenicity for gene: FTH1 was set to Other
Review for gene: FTH1 was set to AMBER
gene: FTH1 was marked as current diagnostic
Added comment: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature
Congenital Heart Defect v0.272 MCF2L Michelle Torres gene: MCF2L was added
gene: MCF2L was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: MCF2L was set to Unknown
Publications for gene: MCF2L were set to 36760094
Phenotypes for gene: MCF2L were set to vascular malformation MONDO:0024291, MCF2L-related
Review for gene: MCF2L was set to RED
Added comment: Three families with Systemic malformation (resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT) had missense variants in the MCF2L gene (families 1, 2 and 7).
Family 1 (Val875Met: v2 & v3: 113 hets) did no present PA (pulmonary artery).
Family 2 (Cys199Gly : v2 & v3: 260 hets, 1 hom) did no present PA (pulmonary artery).
Family 7: Leu130Pro (1 het, 0 hom), segregated in family 7 with SA-PA (systemic artery to the pulmonary artery), with 5x affected tested (Sanger or WES). Unaffected and other 6x individuals affected were not tested.
Sources: Literature
Neurodegeneration with brain iron accumulation v0.10 FTH1 Zornitza Stark Classified gene: FTH1 as Amber List (moderate evidence)
Neurodegeneration with brain iron accumulation v0.10 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.272 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Congenital Heart Defect v0.272 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Mendeliome v1.699 MCF2L Zornitza Stark Marked gene: MCF2L as ready
Mendeliome v1.699 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.272 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Congenital Heart Defect v0.272 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Mendeliome v1.699 MCF2L Zornitza Stark Classified gene: MCF2L as Red List (low evidence)
Mendeliome v1.699 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.271 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Congenital Heart Defect v0.271 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.270 SMPD4 Elena Savva Marked gene: SMPD4 as ready
Congenital Heart Defect v0.270 SMPD4 Elena Savva Gene: smpd4 has been classified as Red List (Low Evidence).
Mendeliome v1.698 MCF2L Michelle Torres gene: MCF2L was added
gene: MCF2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCF2L was set to Unknown
Publications for gene: MCF2L were set to 36760094
Phenotypes for gene: MCF2L were set to vascular malformation MONDO:0024291, MCF2L-related
Review for gene: MCF2L was set to RED
Added comment: Three families with Systemic malformation (resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT) had missense variants in the MCF2L gene (families 1, 2 and 7).
Family 1 (Val875Met: v2 & v3: 113 hets) did no present PA (pulmonary artery).
Family 2 (Cys199Gly : v2 & v3: 260 hets, 1 hom) did no present PA (pulmonary artery).
Family 7: Leu130Pro (1 het, 0 hom), segregated in family 7 with SA-PA (systemic artery to the pulmonary artery), with 5x affected tested (Sanger or WES). Unaffected and other 6x individuals affected were not tested.
Sources: Literature
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Marked gene: AMOTL1 as ready
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.90 PMM2 Zornitza Stark Marked gene: PMM2 as ready
Inflammatory bowel disease v0.90 PMM2 Zornitza Stark Gene: pmm2 has been classified as Red List (Low Evidence).
Inflammatory bowel disease v0.90 PMM2 Zornitza Stark Phenotypes for gene: PMM2 were changed from Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease to Congenital disorder of glycosylation, type Ia, MIM# 212065; Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease
Congenital Heart Defect v0.270 SMPD4 Elena Savva gene: SMPD4 was added
gene: SMPD4 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SMPD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPD4 were set to PMID: 36732302
Phenotypes for gene: SMPD4 were set to Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies MIM#618622
Review for gene: SMPD4 was set to GREEN
Added comment: PMID: 36732302 - 44% of patients have a type of congenital heart defect including ASD (16%), persistent ductus arteriosus (20%), long QT (4%), DCM (4%), VSD (8%) and transposition of the great arteries (4%)
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5182 AMOTL1 Seb Lunke Marked gene: AMOTL1 as ready
Intellectual disability syndromic and non-syndromic v0.5182 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Mendeliome v1.698 TRPV1 Krithika Murali reviewed gene: TRPV1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 36454632, PMID: 36472910; Phenotypes: Channelopathy-associated congenital insensitivity to pain, autosomal recessive - MONDO:0009459; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Classified gene: AMOTL1 as Green List (high evidence)
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5182 AMOTL1 Seb Lunke Classified gene: AMOTL1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5182 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.89 PMM2 Zornitza Stark Classified gene: PMM2 as Red List (low evidence)
Inflammatory bowel disease v0.89 PMM2 Zornitza Stark Gene: pmm2 has been classified as Red List (Low Evidence).
Mendeliome v1.698 TEFM Zornitza Stark Marked gene: TEFM as ready
Mendeliome v1.698 TEFM Zornitza Stark Gene: tefm has been classified as Green List (High Evidence).
Clefting disorders v0.194 AMOTL1 Seb Lunke Publications for gene: AMOTL1 were set to 33026150; 33026150
Intellectual disability syndromic and non-syndromic v0.5181 AMOTL1 Lucy Spencer gene: AMOTL1 was added
gene: AMOTL1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMOTL1 were set to 36751037
Phenotypes for gene: AMOTL1 were set to Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related
Review for gene: AMOTL1 was set to GREEN
Added comment: PMID: 36751037- 16 individuals from 12 families with orofacial clefting syndrome and het variants in AMOTL1. Many in 1 hotspot: 5 individuals from 3 families have R157C, 6 individuals from another 4 families have R157H, 1 has P160L, and another has Q161R. Out of this hostpaot- 1 with P368A, 1 with E507K, 1 with E579K. 7 are de novo. All but 2 have clefting, 7 are dysmorphic, 5 have hearing loss, 9 have CHD, 7 have tall stature, 6 have dev delay. Other features include liver disease, myopia, scoliosis and immune involvement.

Another 2 families have been previously reported (described in the panelapp review in mendeliome) with variants in this hotspot 1 has 2 individuals with R157C, the other has 1 individual with P160L. All hotspot are absent from gnomad v2.
Sources: Literature
Monogenic Diabetes v0.37 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Monogenic Diabetes v0.37 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Mendeliome v1.698 TEFM Zornitza Stark Classified gene: TEFM as Green List (high evidence)
Mendeliome v1.698 TEFM Zornitza Stark Gene: tefm has been classified as Green List (High Evidence).
Monogenic Diabetes v0.36 SMPD4 Elena Savva Marked gene: SMPD4 as ready
Monogenic Diabetes v0.36 SMPD4 Elena Savva Gene: smpd4 has been classified as Red List (Low Evidence).
Mitochondrial disease v0.857 TEFM Zornitza Stark Marked gene: TEFM as ready
Mitochondrial disease v0.857 TEFM Zornitza Stark Gene: tefm has been classified as Green List (High Evidence).
Clefting disorders v0.193 AMOTL1 Seb Lunke Publications for gene: AMOTL1 were set to 33026150
Clefting disorders v0.192 AMOTL1 Seb Lunke Phenotypes for gene: AMOTL1 were changed from Cleft lip and palate; imperforate anus; dysmorphism to Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related
Clefting disorders v0.191 AMOTL1 Seb Lunke Classified gene: AMOTL1 as Green List (high evidence)
Clefting disorders v0.191 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.269 AMOTL1 Lucy Spencer gene: AMOTL1 was added
gene: AMOTL1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMOTL1 were set to 36751037
Phenotypes for gene: AMOTL1 were set to Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related
Review for gene: AMOTL1 was set to GREEN
Added comment: PMID: 36751037- 16 individuals from 12 families with orofacial clefting syndrome and het variants in AMOTL1. Many in 1 hotspot: 5 individuals from 3 families have R157C, 6 individuals from another 4 families have R157H, 1 has P160L, and another has Q161R. Out of this hostpaot- 1 with P368A, 1 with E507K, 1 with E579K. 7 are de novo. All but 2 have clefting, 7 are dysmorphic, 5 have hearing loss, 9 have CHD, 7 have tall stature, 6 have dev delay. Other features include liver disease, myopia, scoliosis and immune involvement.

Another 2 families have been previously reported (described in the panelapp review below) with variants in this hotspot 1 has 2 individuals with R157C, the other has 1 individual with P160L. All hotspot are absent from gnomad v2.
Sources: Literature
Mendeliome v1.697 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Mitochondrial disease v0.857 TEFM Zornitza Stark Classified gene: TEFM as Green List (high evidence)
Mitochondrial disease v0.857 TEFM Zornitza Stark Gene: tefm has been classified as Green List (High Evidence).
Mendeliome v1.697 AMOTL1 Seb Lunke Phenotypes for gene: AMOTL1 were changed from Cleft lip and palate; imperforate anus; dysmorphism to Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related
Monogenic Diabetes v0.36 SMPD4 Elena Savva gene: SMPD4 was added
gene: SMPD4 was added to Monogenic Diabetes. Sources: Literature
Mode of inheritance for gene: SMPD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPD4 were set to PMID: 36732302
Phenotypes for gene: SMPD4 were set to Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies MIM#618622
Review for gene: SMPD4 was set to GREEN
Added comment: PMID: 36732302 - five individuals with microcephaly, brain anomalies and insulin-dependent diabetes in childhood. Reviews past reports, notes 27% of patients have insulin-dependent diabetes.
Sources: Literature
Mitochondrial disease v0.856 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Inflammatory bowel disease v0.88 PMM2 Sarah Pantaleo gene: PMM2 was added
gene: PMM2 was added to Inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMM2 were set to 36773065
Phenotypes for gene: PMM2 were set to Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease
Penetrance for gene: PMM2 were set to Incomplete
Review for gene: PMM2 was set to RED
Added comment: “A specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology.”

Cohort of patients affected by hyperinsulinaemic hypoglycaemia and ARPKD with a specific underlying variant in the PMM2 promoter. Three of these patients additionally developed IBD in childhood and manifest a distinctive pattern of gastric antral disease involvement.

The authors describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6 and 10 years of age. IBD was of variable severity at onset. The organ level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A).

All three patients have the same genotype, two pathogenic variants (ClinVar): A promoter variant, c.-167G>T, in trans with c.422G>A; p.(Arg141His). The promoter region is not covered in gnomAD. c.422G>A is in gnomAD v2 891 hets, v3 557 hets.

Functional studies: Protein expression of PMM2 and HNF4A assessed by immunohistochemistry for two patients. Patient 1 there appeared to be reduced protein expression compared to the control, especially in the gastric antrum and colon, but for patient 2, the expression profile closely matched the control.

Observation of intestinal inflammation and gastric antral foveolar hyperplasia in three patients with identical pathogenic genetic variants in the PMM2 locus, from independent kindreds, extends the previously reported spectrum of PMM2-related HI/ARPKD disease. It identifies PMM2 as a potential novel Mendelian association of early-onset IBD. Estimate low penetrance of IBD of 10% based on 30 patients in the literature.
Sources: Literature
Mendeliome v1.696 AMOTL1 Seb Lunke Publications for gene: AMOTL1 were set to 33026150
Hyperammonaemia v0.10 SLC25A36 Zornitza Stark Marked gene: SLC25A36 as ready
Hyperammonaemia v0.10 SLC25A36 Zornitza Stark Gene: slc25a36 has been classified as Green List (High Evidence).
Hyperammonaemia v0.10 SLC25A36 Zornitza Stark Classified gene: SLC25A36 as Green List (high evidence)
Hyperammonaemia v0.10 SLC25A36 Zornitza Stark Gene: slc25a36 has been classified as Green List (High Evidence).
Hyperinsulinism v1.8 SLC25A36 Zornitza Stark Marked gene: SLC25A36 as ready
Hyperinsulinism v1.8 SLC25A36 Zornitza Stark Gene: slc25a36 has been classified as Green List (High Evidence).
Hyperinsulinism v1.8 SLC25A36 Zornitza Stark Classified gene: SLC25A36 as Green List (high evidence)
Hyperinsulinism v1.8 SLC25A36 Zornitza Stark Gene: slc25a36 has been classified as Green List (High Evidence).
Mendeliome v1.695 TEFM Ee Ming Wong gene: TEFM was added
gene: TEFM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Mitochondrial disease (MONDO#0044970), TEFM-related
Review for gene: TEFM was set to GREEN
gene: TEFM was marked as current diagnostic
Added comment: - Seven TEFM variants (4 missense, 2 fs, 1 in-frame del) in seven individuals across five unrelated families
- Muscle and primary fibroblast from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts
- TEFM knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function
Sources: Literature
Mendeliome v1.695 AMOTL1 Seb Lunke Classified gene: AMOTL1 as Green List (high evidence)
Mendeliome v1.695 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v0.142 COQ7 Zornitza Stark Publications for gene: COQ7 were set to PMID: 36454683
Hyperammonaemia v0.9 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Hyperammonaemia. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Hereditary Neuropathy - complex v0.141 COQ7 Zornitza Stark Classified gene: COQ7 as Green List (high evidence)
Hereditary Neuropathy - complex v0.141 COQ7 Zornitza Stark Gene: coq7 has been classified as Green List (High Evidence).
Clefting disorders v0.190 AMOTL1 Lucy Spencer reviewed gene: AMOTL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33026150; Phenotypes: Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disease v0.856 TEFM Ee Ming Wong gene: TEFM was added
gene: TEFM was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Mitochondrial disease (MONDO#0044970), TEFM-related
Review for gene: TEFM was set to GREEN
gene: TEFM was marked as current diagnostic
Added comment: - Seven TEFM variants (4 missense, 2 fs, 1 in-frame del) in seven individuals across five unrelated families
- Muscle and primary fibroblast from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts
- TEFM knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function
Sources: Literature
Hyperinsulinism v1.7 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Hereditary Neuropathy - complex v0.140 COQ7 Chern Lim reviewed gene: COQ7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:36758993, 36759155; Phenotypes: Distal hereditary motor neuropathy (MONDO#0018894), COQ7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.694 AMOTL1 Lucy Spencer reviewed gene: AMOTL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36751037; Phenotypes: Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Polydactyly v0.266 HMGB1 Ain Roesley Phenotypes for gene: HMGB1 were changed from brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905 to brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905
Polydactyly v0.265 HMGB1 Ain Roesley Phenotypes for gene: HMGB1 were changed from Mirror image foot polydactyly to brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905
Polydactyly v0.265 HMGB1 Ain Roesley Publications for gene: HMGB1 were set to 34159400
Fetal anomalies v1.89 HMGB1 Ain Roesley Phenotypes for gene: HMGB1 were changed from Neurodevelopmental disorder MONDO:0700092, HMGB1-related; microcephaly; intellectual disability to Neurodevelopmental disorder MONDO:0700092, HMGB1-related; microcephaly; intellectual disability; brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905
Fetal anomalies v1.89 HMGB1 Ain Roesley Publications for gene: HMGB1 were set to 34164801
Mendeliome v1.694 HMGB1 Ain Roesley Phenotypes for gene: HMGB1 were changed from Mirror image foot polydactyly; Neurodevelopmental disorder MONDO:0700092, HMGB1-related to brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Neurodevelopmental disorder MONDO:0700092, HMGB1-related
Mendeliome v1.694 HMGB1 Ain Roesley Publications for gene: HMGB1 were set to 34159400; 34164801
Mendeliome v1.693 LGR4 Elena Savva Phenotypes for gene: LGR4 were changed from {Bone mineral density, low, susceptibility to} MIM#615311; Delayed puberty, self-limited MIM#619613; Syndromic disease, LGR4-related (MONDO#0002254) to {Bone mineral density, low, susceptibility to} MIM#615311; Delayed puberty, self-limited MIM#619613; Syndromic disease, LGR4-related (MONDO#0002254)
Polydactyly v0.265 HMGB1 Ain Roesley Classified gene: HMGB1 as Green List (high evidence)
Polydactyly v0.265 HMGB1 Ain Roesley Gene: hmgb1 has been classified as Green List (High Evidence).
Mendeliome v1.692 LGR4 Elena Savva Phenotypes for gene: LGR4 were changed from Delayed puberty to {Bone mineral density, low, susceptibility to} MIM#615311; Delayed puberty, self-limited MIM#619613; Syndromic disease, LGR4-related (MONDO#0002254)
Mendeliome v1.691 HMGB1 Ain Roesley edited their review of gene: HMGB1: Added comment: PMID:36755093
4 new families with de novo protein truncating variants.

In addition with PMID 34159400 ( all de novos)

c.556_559delGAAG;p.(Glu186Argfs*42) - 1 family
c.551_554delAGAA;p.(Lys184Argfs*44) - 4 families; Changed rating: GREEN; Changed publications: 34159400, 36755093; Changed phenotypes: brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Set current diagnostic: yes
Fetal anomalies v1.88 HMGB1 Ain Roesley reviewed gene: HMGB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36755093, 34159400; Phenotypes: brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v1.691 LGR4 Elena Savva Publications for gene: LGR4 were set to 32493844
Mendeliome v1.690 LGR4 Elena Savva Mode of inheritance for gene: LGR4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Polydactyly v0.264 HMGB1 Ain Roesley edited their review of gene: HMGB1: Added comment: PMID:36755093
4 new families with de novo protein truncating variants.

In addition with PMID 34159400,

c.556_559delGAAG;p.(Glu186Argfs*42) - 1 family
c.551_554delAGAA;p.(Lys184Argfs*44) - 4 families; Changed rating: GREEN; Changed publications: 34159400, 36755093; Changed phenotypes: brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905
Neurodegeneration with brain iron accumulation v0.9 FTH1 Paul De Fazio gene: FTH1 was added
gene: FTH1 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: FTH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FTH1 were set to 36778397
Phenotypes for gene: FTH1 were set to Neuroferritinopathy (MONDO:0011638)
Mode of pathogenicity for gene: FTH1 was set to Other
Review for gene: FTH1 was set to AMBER
gene: FTH1 was marked as current diagnostic
Added comment: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature
Pain syndromes v0.34 TRPV1 Zornitza Stark Marked gene: TRPV1 as ready
Pain syndromes v0.34 TRPV1 Zornitza Stark Gene: trpv1 has been classified as Red List (Low Evidence).
Pain syndromes v0.34 TRPV1 Zornitza Stark Classified gene: TRPV1 as Red List (low evidence)
Pain syndromes v0.34 TRPV1 Zornitza Stark Gene: trpv1 has been classified as Red List (Low Evidence).
Mendeliome v1.689 LGR4 Elena Savva changed review comment from: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; to: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).
Mendeliome v1.689 LGR4 Elena Savva edited their review of gene: LGR4: Added comment: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; Changed publications: PMID: 32493844, 36538378; Changed phenotypes: {Bone mineral density, low, susceptibility to} MIM#615311; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Pain syndromes v0.33 TRPV1 Krithika Murali changed review comment from: PMID: 36454632 Katz et al 2023 describe two individuals from a consanguineous Palestinian Arab family with elevated heat pain and cold pain threshold with insensitivity to application of capsaicin to mouth and skin. No obvious associated health issues reported in this 11 year old and 1 year old individual secondary to this. Homozygous TPRV1 c.993C>G; p.N331K variant identified in both individuals (absent from gnomAD, highly conserved). Variant cell lines demonstrated loss of channel function with normal expression. In addition, homozygous PROKR1 variant identified in both affected individuals with potential for contribution to phenotype.

PMID: 36472910 - knockin mouse models with missense TRPV1 variant (K710N) also showed reduced capsaicin-induced calcium influx in dorsal root ganglion neurons.
Sources: Literature; to: PMID: 36454632 Katz et al 2023 describe two individuals from a consanguineous Palestinian Arab family with elevated heat pain and cold pain threshold with insensitivity to application of capsaicin to mouth and skin. No obvious associated health issues reported in this 11 year old and 1 year old individual secondary to this. Homozygous TPRV1 c.993C>G; p.N331K variant identified in both individuals (absent from gnomAD, highly conserved). Variant cell lines demonstrated loss of channel function with normal expression. In addition, homozygous PROKR1 gene variant identified in both affected individuals with potential for contribution to phenotype.

PMID: 36472910 - knockin mouse models with missense TRPV1 variant (K710N) also showed reduced capsaicin-induced calcium influx in dorsal root ganglion neurons.
Sources: Literature
Pain syndromes v0.33 TRPV1 Krithika Murali gene: TRPV1 was added
gene: TRPV1 was added to Pain syndromes. Sources: Literature
Mode of inheritance for gene: TRPV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRPV1 were set to PMID: 36454632; PMID: 36472910
Phenotypes for gene: TRPV1 were set to Channelopathy-associated congenital insensitivity to pain, autosomal recessive - MONDO:0009459
Review for gene: TRPV1 was set to RED
Added comment: PMID: 36454632 Katz et al 2023 describe two individuals from a consanguineous Palestinian Arab family with elevated heat pain and cold pain threshold with insensitivity to application of capsaicin to mouth and skin. No obvious associated health issues reported in this 11 year old and 1 year old individual secondary to this. Homozygous TPRV1 c.993C>G; p.N331K variant identified in both individuals (absent from gnomAD, highly conserved). Variant cell lines demonstrated loss of channel function with normal expression. In addition, homozygous PROKR1 variant identified in both affected individuals with potential for contribution to phenotype.

PMID: 36472910 - knockin mouse models with missense TRPV1 variant (K710N) also showed reduced capsaicin-induced calcium influx in dorsal root ganglion neurons.
Sources: Literature
Mendeliome v1.689 USMG5 Bryony Thompson Marked gene: USMG5 as ready
Mendeliome v1.689 USMG5 Bryony Thompson Gene: usmg5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.689 USMG5 Bryony Thompson Classified gene: USMG5 as Amber List (moderate evidence)
Mendeliome v1.689 USMG5 Bryony Thompson Gene: usmg5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.688 USMG5 Bryony Thompson gene: USMG5 was added
gene: USMG5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USMG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USMG5 were set to 29917077; 30240627
Phenotypes for gene: USMG5 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6 MIM#618683
Review for gene: USMG5 was set to AMBER
Added comment: A homozygous splice site mutation in 4 patients from 3 unrelated families of Ashkenazi Jewish descent. Experimental analyses demonstrated that the splice variant leads to loss of protein expression and haplotype analysis suggested a founder effect. In situ cryo-ET analysis of the mitochondria of a homozygous affected case showed profound disturbances of mitochondrial crista ultrastructure.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5181 SLC35B2 Zornitza Stark Marked gene: SLC35B2 as ready
Intellectual disability syndromic and non-syndromic v0.5181 SLC35B2 Zornitza Stark Gene: slc35b2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5181 SLC35B2 Zornitza Stark Classified gene: SLC35B2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5181 SLC35B2 Zornitza Stark Gene: slc35b2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5180 SLC35B2 Zornitza Stark gene: SLC35B2 was added
gene: SLC35B2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35B2 were set to 35325049
Phenotypes for gene: SLC35B2 were set to Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269
Review for gene: SLC35B2 was set to AMBER
Added comment: 2 x individuals with homozygous variants (c.1218_1220del and c.1224_1225del) in SLC35B2. Phenotypes included pre- and postnatal growth retardation, scoliosis, severe motor and intellectual disabilities and hypomyelinating leukodystrophy. Functional analysis on patient cells showed that the variants result in a decreased expression of mRNA and affect protein subcellular localization leading to functional impairment of the protein.
Sources: Literature
Leukodystrophy - paediatric v0.282 SLC35B2 Zornitza Stark edited their review of gene: SLC35B2: Changed phenotypes: Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269
Mendeliome v1.687 SLC35B2 Zornitza Stark Phenotypes for gene: SLC35B2 were changed from Leukodystrophy, MONDO:0019046, SLC35B2-related to Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269
Mendeliome v1.686 SLC35B2 Zornitza Stark reviewed gene: SLC35B2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5179 EMC1 Achchuthan Shanmugasundram reviewed gene: EMC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35234901; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5179 ATG4D Zornitza Stark Marked gene: ATG4D as ready
Intellectual disability syndromic and non-syndromic v0.5179 ATG4D Zornitza Stark Gene: atg4d has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5179 ATG4D Zornitza Stark Phenotypes for gene: ATG4D were changed from neurodevelopmental disorder; Abnormal facial shape to Neurodevelopmental disorder, MONDO:0700092, ATG4D-related
Intellectual disability syndromic and non-syndromic v0.5178 ATG4D Zornitza Stark Classified gene: ATG4D as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5178 ATG4D Zornitza Stark Gene: atg4d has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5177 ATG4D Zornitza Stark reviewed gene: ATG4D: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, ATG4D-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.686 ATG4D Zornitza Stark Marked gene: ATG4D as ready
Mendeliome v1.686 ATG4D Zornitza Stark Gene: atg4d has been classified as Green List (High Evidence).
Mendeliome v1.686 ATG4D Zornitza Stark Phenotypes for gene: ATG4D were changed from neurodevelopmental disorder; Abnormal facial shape to Neurodevelopmental disorder, MONDO:0700092, ATG4D-related
Mendeliome v1.685 ATG4D Zornitza Stark Classified gene: ATG4D as Green List (high evidence)
Mendeliome v1.685 ATG4D Zornitza Stark Gene: atg4d has been classified as Green List (High Evidence).
Mendeliome v1.684 ATG4D Zornitza Stark reviewed gene: ATG4D: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, ATG4D-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.684 NLGN4X Elena Savva reviewed gene: NLGN4X: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36747195; Phenotypes: Intellectual developmental disorder, X-linked MIM#300495; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Proteinuria v0.215 GLA Ain Roesley Phenotypes for gene: GLA were changed from Fairy disease, MIM# 301500 to Fabry disease, MIM# 301500
Disorders of immune dysregulation v0.166 DOCK2 Peter McNaughton gene: DOCK2 was added
gene: DOCK2 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: DOCK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DOCK2 were set to PMID: 36836791
Phenotypes for gene: DOCK2 were set to HLH
Review for gene: DOCK2 was set to AMBER
Added comment: Patient with recurrent HLH. Heterozygous c.1334A>G (p.Asn445Ser) variant. Functional studies showing lower CD107a expression and diminished NK degranulation and cytotoxicity. ? partial dominant negative.
Sources: Literature
Hyperammonaemia v0.9 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
BabyScreen+ newborn screening v0.1872 MAT1A Lilian Downie reviewed gene: MAT1A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Methionine adenosyltransferase deficiency MIM#250850; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 LIAS Lilian Downie gene: LIAS was added
gene: LIAS was added to gNBS. Sources: Expert list
Mode of inheritance for gene: LIAS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIAS were set to PMID: 24334290, 24777537,
Phenotypes for gene: LIAS were set to Hyperglycinemia, lactic acidosis, and seizures MIM#614462
Review for gene: LIAS was set to RED
Added comment: pyruvate dehydrogenase lipoic acid synthetase deficiency (PDHLD)
increased serum glycine and lactate in the first days of life, hypotonia, seizures, early death
No treatment
Sources: Expert list
BabyScreen+ newborn screening v0.1872 HPD Lilian Downie reviewed gene: HPD: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 9343288, PMID: 11916315, PMID: 32520295; Phenotypes: Tyrosinemia, type III MIM#276710; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 HMGCS2 Lilian Downie gene: HMGCS2 was added
gene: HMGCS2 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: HMGCS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMGCS2 were set to PMID: 32259399, 32470406
Phenotypes for gene: HMGCS2 were set to HMG-CoA synthase-2 deficiency MIM#605911
Penetrance for gene: HMGCS2 were set to Incomplete
Review for gene: HMGCS2 was set to AMBER
Added comment: Metabolic disorder; patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting. Recover completely between illnesses, do develop fatty liver.
?incomplete penetrance or variable age of onset
On GUARDIAN and Rx Genes
Rx IV glucose during acute episodes, avoid prolonged fasting
Metabolic parameters are normal in between episodes, so no ability to do a confirmatory biochemical test.
Pros: readily treatable if child has an episode Cons: unncessary worry as child may never have episode
Super rare ?30 cases
Discuss with JC?
Sources: Expert list
BabyScreen+ newborn screening v0.1872 HIBCH Lilian Downie reviewed gene: HIBCH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32642440, PMID: 17160907, PMID: 27400804; Phenotypes: 3-hydroxyisobutryl-CoA hydrolase deficiency MIM#250620; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v0.229 DDRGK1 Achchuthan Shanmugasundram gene: DDRGK1 was added
gene: DDRGK1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: DDRGK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDRGK1 were set to 28263186; 35377455; 35670300; 36243336
Phenotypes for gene: DDRGK1 were set to Spondyloepimetaphyseal dysplasia, Shohat type, OMIM:602557
Review for gene: DDRGK1 was set to GREEN
Added comment: Comment on gene classification: This gene should be rated GREEN as it has been associated with Spondyloepimetaphyseal dysplasia, Shohat type from seven unrelated cases from multiple ethnicities and supported by functional studies.

PMID:28263186 reported six individuals from three different families of Iraqi Jewish descent (three patients from family 1 and one individual each from families 2-4) identified with homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK1 and presented with Shohat-type spondyloepimetaphyseal dysplasia (SEMD). It is a skeletal dysplasia that affects cartilage development.

PMID: 35670300 reported two unrelated cases of Moroccan descent identified with homozygous missense variant c.406G>A and presented with SEMD. PMID:36243336 reported an Omani female patient identified with the same homozygous variant as the Iraqi cases and was reported with SEMD.

In addition, studies on both zebrafish and mouse models confirms the physiological role of DDRGK1 in the development and maintenance of the growth plate cartilage and deficiency of DDRGK1 recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD (PMID:28263186; PMID:35377455).

This gene has been associated with relevant phenotype in OMIM (MIM #602557), but not in Gene2Phenotype.
Sources: Literature
BabyScreen+ newborn screening v0.1872 GLIS3 Lilian Downie reviewed gene: GLIS3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 29406006, 29992946, 27899417, PMID: 26259131; Phenotypes: Diabetes mellitus, neonatal, with congenital hypothyroidism MIM#610199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 GATM Lilian Downie gene: GATM was added
gene: GATM was added to gNBS. Sources: Expert list
Mode of inheritance for gene: GATM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GATM were set to PMID: 20301745, 34972654
Phenotypes for gene: GATM were set to Cerebral creatine deficiency syndrome 3 MIM#612718
Review for gene: GATM was set to GREEN
Added comment: GUARDIAN gene list (not on babyseq or rxgenes)
ID and myopathy, early onset
Rx creatine
Seems like a good fit? I'm not clear from the literature how effective the treatment is. check with JC
Sources: Expert list
BabyScreen+ newborn screening v0.1872 FOXE1 Lilian Downie reviewed gene: FOXE1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33272083, 2918525, 20453517, 35963604; Phenotypes: Bamforth-Lazarus syndrome MIM# 241850; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 ALDH4A1 Lilian Downie reviewed gene: ALDH4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31884946, 34037900, 30930802, 34302426; Phenotypes: Hyperprolinemia, type II MIM#239510; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 ACADSB Lilian Downie reviewed gene: ACADSB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 2-methylbutyrylglycinuria MIM#610006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia - isolated/combined v1.30 CACNA1B Bryony Thompson Marked gene: CACNA1B as ready
Dystonia - isolated/combined v1.30 CACNA1B Bryony Thompson Gene: cacna1b has been classified as Red List (Low Evidence).
Dystonia - isolated/combined v1.30 CACNA1B Bryony Thompson gene: CACNA1B was added
gene: CACNA1B was added to Dystonia - isolated/combined. Sources: Other
Mode of inheritance for gene: CACNA1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1B were set to 25296916; 26157024; 35698023; 33051750; 35041927
Phenotypes for gene: CACNA1B were set to Myoclonus-dystonia syndrome MONDO:0000903
Review for gene: CACNA1B was set to RED
Added comment: The original report of the association of the gene with dystonia was a variant with a higher allele frequency than expected for a variant. There have been no compelling reports since.
PMID: 25296916 - c.4166G>A:p.R1389H was identified segregating in a family with myoclonus dystonia (M-D) and in vitro assays of the variant demonstrated an effect on protein function. However, the variant is present in 122 hets in gnomAD v2.1 (AF 0.04%) which is higher than expected for a dominant disease.
PMID: 26157024 - study with a case-control analysis that does not support a causal association for c.4166G>A:p.R1389H with M-D
PMID: 35698023 - c.2681A > T; p.K894M was identified in 2 siblings with generalised dystonia. Both parents were unaffected and did not undergo testing for the variant. However, this variant is present in 25 hets in gnomAD v3.1 (AF 0.02%) which is higher than expected for a dominant disease.
PMID: 33051750 - reports 2 CACNA1B variants in an isolated focal dystonia cohort, but the quality of the study is questionable. They report a supposed 2 bp deletion, but the screenshot of the reads is an apparent 1 bp deletion and the frequency in the cohort is questionable. They also report a missense c.6834T>G pLeu2215Arg, which is actually a common benign synonymous variant NM_000718.4(CACNA1B):c.6831T>G (p.Thr2277=)
PMID: 35041927 - Taiwanese dystonia cohort - c.6506A>T(p.N2169I - 1 het in gnomAD v3.1) was identified in case with childhood-onset of segmental dystonia involving the face, neck, and shoulder, associated with myoclonus. FH present, but segregation not possible. c.6694C>G (p.L2232V - absent in gnomAD) and c.6928G>A (p.V2310M - 3 hets in gnomAD v3.1) were identified each in a case with sporadic cervical dystonia. All VUS.
Sources: Other
Dystonia - isolated/combined v1.29 RELN Bryony Thompson Marked gene: RELN as ready
Dystonia - isolated/combined v1.29 RELN Bryony Thompson Gene: reln has been classified as Red List (Low Evidence).
Dystonia - isolated/combined v1.29 RELN Bryony Thompson gene: RELN was added
gene: RELN was added to Dystonia - isolated/combined. Sources: Other
Mode of inheritance for gene: RELN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RELN were set to 32334381; 25648840
Phenotypes for gene: RELN were set to Myoclonus-dystonia syndrome MONDO:0000903
Review for gene: RELN was set to RED
Added comment: Only identified a single proband with a rare de novo variant with a complex myoclonus-dystonia syndrome phenotype. Other study with segregation evidence, were missense variants that are too common in gnomAD v2.1
PMID: 32334381 - de novo c.6259T > C; W2087R. Male proband age of onset 26 yrs, with non progressive right upper limb dystonia, myoclonus, epilepsy, pyramidal syndrome, mild ID
PMID: 25648840 - 2 myoclonus-dystonia (MD) families segregating p.Thr1904Met (fam 1: 5 affected carriers & 5 unaffected non-carriers; fam 2: 5 affected carriers including obligates, 3 unaffected carriers, & 4 unaffected non-carriers). But, variant has 82 hets in gnomAD v2.1 (AF 0.03%) which is a bit high for a dominant condition. Another family segregating p.Ile1217Met with MD (3 affected carriers & 3 unaffected non carriers). However, there are 713 alleles in gnomAD v2.1 including 2 homozygotes (0.25% AF) which is too high for a dominant condition. 2 other missense reported in 2 MD probands, but both present in gnomAD v2.1 at frequencies not consistent with dominant disease.
Sources: Other
Mendeliome v1.684 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: Short stature with microcephaly and distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.88 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: Short stature with microcephaly and distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v1.59 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: ; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: Short stature with microcephaly and distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephalic Primordial Dwarfism and Slender bone dysplasias v0.24 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: Short stature with microcephaly and distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.194 CRIPT Suliman Khan changed review comment from: PMID: 36630262 reported a patient with profound prenatal/postnatal growth restriction, developmental delay, dysmorphic facial features, and skin lesions along with the findings of bicytopenia and extensive retinal pigmentation defect. A novel truncating homozygous variant c.7_8delTG; p.(Cys3Argfs*4) was detected in CRIPT gene.; to: PMID: 36630262 reported a patient with profound prenatal/postnatal growth restriction, developmental delay, dysmorphic facial features, and skin lesions along with the findings of bicytopenia and extensive retinal pigmentation defect. A novel truncating homozygous variant was detected in CRIPT gene.
Microcephaly v1.194 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: short stature, microcephaly, distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 ACADS Lilian Downie reviewed gene: ACADS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Acyl-CoA dehydrogenase, short-chain, deficiency of MIM#201470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 ABCD4 Lilian Downie reviewed gene: ABCD4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22922874, PMID: 33729671; Phenotypes: Methylmalonic aciduria and homocystinuria, cblJ type MIM#614857; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital nystagmus v1.17 ROBO1 Achchuthan Shanmugasundram gene: ROBO1 was added
gene: ROBO1 was added to Congenital nystagmus. Sources: Literature
Mode of inheritance for gene: ROBO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ROBO1 were set to 35348658
Phenotypes for gene: ROBO1 were set to nystagmus, congenital, autosomal recessive, MONDO:0009762
Review for gene: ROBO1 was set to RED
Added comment: Comment on classification of gene: This gene should be rated RED as this gene has been associated with nystagmus from only one family.

PMID:35348658 reported three male siblings from the same family with nystagmus and they were identified with a homozygous missense variant p.Ser1522Leu.

This gene has not yet been associated with any phenotypes either in OMIM or Gene2Phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5177 ROBO1 Achchuthan Shanmugasundram gene: ROBO1 was added
gene: ROBO1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ROBO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ROBO1 were set to 28286008; 30692597; 35227688; 35348658
Phenotypes for gene: ROBO1 were set to intellectual disability, MONDO:0001071
Review for gene: ROBO1 was set to GREEN
Added comment: Comment on gene classification: This gene should be rated green as this gene has been associated with intellectual disability from six unrelated cases. However, the MOI should be set as "BIALLELIC, autosomal or pseudoautosomal" as five of these cases were reported with biallelic variants and only one case was reported with monoallelic variant.

PMID:28286008 reported a boy with compound heterozygous variants that was presented with developmental delay in 13 months and had severe intellectual disability and hyperactivity at nine years of age. He was nonverbal and wheelchair dependent because of spastic diplegia and ataxia.

PMID:30692597 reported a five year old boy identified with a homozygous ROBO1 variant who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus and characteristic facial features.

PMID:35227688 reported eight patients including the boy reported in PMID:30692597. Of the other seven patients, three were presented with intellectual disability. Of these three patients, two harboured compound heterozygous and one harboured homozygous variants.

PMID:35348658 reported a patient identified with monoallelic de novo variant (p.D422G) who presented with early-onset epileptic encephalopathy and had severe developmental delay.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.684 ELOC Achchuthan Shanmugasundram gene: ELOC was added
gene: ELOC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ELOC was set to Unknown
Publications for gene: ELOC were set to 35323939
Phenotypes for gene: ELOC were set to von Hippel-Lindau disease, MONDO:0008667; renal cell carcinoma, MONDO:0005086; retinal hemangioblastoma, MONDO:0003343
Review for gene: ELOC was set to RED
Added comment: Comment on gene classification: This gene should be rated red as there is only one case with germline variant found so far.

A female patient was identified with a germline de novo missense variant in ELOC gene (c.236A>G/ p.Tyr79Cys) and satisfied the clinical diagnostic criteria for von Hippel-Lindau (VHL) disease. The patient had left retinal haemangioblastomas, renal cell carcinomas, cyst of the right kidney, spinal haemangioblastoma, a haemangioblastoma at the cervicomedullary junction and Henoch-Schonlein purpura (PMID:35323939).

This is the only germline variant detected in ELOC gene and was associated with VHL so far. However, ~20 somatic ELOC variants have been reported to be associated with renal cell carcinomas so far.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Ectodermal Dysplasia v0.80 RIPK4 Achchuthan Shanmugasundram gene: RIPK4 was added
gene: RIPK4 was added to Ectodermal Dysplasia. Sources: Literature
Mode of inheritance for gene: RIPK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIPK4 were set to 26129644; 28940926; 33713555; 35220430
Phenotypes for gene: RIPK4 were set to CHAND syndrome, OMIM:214350; Popliteal pterygium syndrome, Bartsocas-Papas type 1, OMIM:263650; ectodermal dysplasia syndrome, MONDO:0019287
Review for gene: RIPK4 was set to GREEN
Added comment: Comment on classification of gene: RIPK4 should be rated green as biallelic variants in this gene has been implicated in ectodermal dysplasias (ED) of varying severity in multiple (>3) unrelated patients and supported by functional studies.

This gene has already been associated with relevant phenotypes in both OMIM and Gene2Phenotype.

The clinically distinct ED syndromes reported with RIPK4 variants include early lethal BPS (MIM #263650) and milder forms such as PPS and CHAND syndrome (MIM #214350). BPS1 is characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly and CHAND is characterized by ankyloblepharon, sparse, curly, and woolly hair, nail dysplasia, and oral frenula.

PMID:35220430 reported two siblings with novel biallelic (compound heterozygous) variants presented with cutaneous syndactyly associated to hair defects, alopecia, nail dysplasia and hyperkeratosis. This phenotype expands the clinical spectrum of the disorder further and is intermediary between BPS and CHAND syndrome.
Sources: Literature
Mendeliome v1.684 ATG4D Suliman Khan gene: ATG4D was added
gene: ATG4D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG4D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG4D were set to PMID: 36765070
Phenotypes for gene: ATG4D were set to neurodevelopmental disorder; Abnormal facial shape
Penetrance for gene: ATG4D were set to unknown
Review for gene: ATG4D was set to GREEN
Added comment: PMID: 36765070 reported three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment with a similar facial gestalt comprising almond-shaped eyes, depressed nasal bridge, and a prominent Cupid’s bow with variable disease severity and progression. NGS analysis revealed bi-allelic loss-of-function variants in ATG4D gene. Based on the clinical, bioinformatic, and functional data, the author concluded that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of syndromic neurodevelopmental disorder.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5177 ATG4D Suliman Khan gene: ATG4D was added
gene: ATG4D was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATG4D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG4D were set to PMID: 36765070
Phenotypes for gene: ATG4D were set to neurodevelopmental disorder; Abnormal facial shape
Penetrance for gene: ATG4D were set to unknown
Review for gene: ATG4D was set to GREEN
Added comment: PMID: 36765070 reported three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment with a similar facial gestalt comprising almond-shaped eyes, depressed nasal bridge, and a prominent Cupid’s bow with variable disease severity and progression. NGS analysis revealed bi-allelic loss-of-function variants in ATG4D gene. Based on the clinical, bioinformatic, and functional data, the author concluded that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of syndromic neurodevelopmental disorder.
Sources: Literature
Mendeliome v1.684 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224 to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224; Cataract 50 with or without glaucoma, MIM#620253
Mendeliome v1.683 TRPM3 Zornitza Stark Publications for gene: TRPM3 were set to 31278393
Mendeliome v1.682 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Added comment: Publications 25090642; 33484482: Single multi-generational family reported with a missense variant in this gene and cataract. Mouse model of same variant supports association. Amber for this association.; Changed publications: 31278393, 25090642, 33484482; Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224, Cataract 50 with or without glaucoma, MIM#620253
Cataract v0.350 TRPM3 Zornitza Stark Marked gene: TRPM3 as ready
Cataract v0.350 TRPM3 Zornitza Stark Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Cataract v0.350 TRPM3 Zornitza Stark Classified gene: TRPM3 as Amber List (moderate evidence)
Cataract v0.350 TRPM3 Zornitza Stark Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Cataract v0.349 TRPM3 Zornitza Stark gene: TRPM3 was added
gene: TRPM3 was added to Cataract. Sources: Expert list
Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPM3 were set to 25090642; 33484482
Phenotypes for gene: TRPM3 were set to Cataract 50 with or without glaucoma, MIM#620253
Review for gene: TRPM3 was set to AMBER
Added comment: Single multi-generational family reported with a missense variant in this gene and cataract. Mouse model of same variant.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.5177 PPM1K Zornitza Stark Publications for gene: PPM1K were set to 23086801
Intellectual disability syndromic and non-syndromic v0.5176 PPM1K Zornitza Stark Classified gene: PPM1K as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5176 PPM1K Zornitza Stark Gene: ppm1k has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5175 PPM1K Zornitza Stark edited their review of gene: PPM1K: Added comment: PMID: 36706222 reported a patient with MSUD with mild findings and elevated BCAA levels carrying a novel homozygous start-loss variant in PPM1K.; Changed rating: AMBER; Changed publications: 23086801, 36706222
Mendeliome v1.682 PPM1K Zornitza Stark Publications for gene: PPM1K were set to 23086801
Mendeliome v1.681 PPM1K Zornitza Stark Classified gene: PPM1K as Amber List (moderate evidence)
Mendeliome v1.681 PPM1K Zornitza Stark Gene: ppm1k has been classified as Amber List (Moderate Evidence).
Mendeliome v1.680 PPM1K Zornitza Stark edited their review of gene: PPM1K: Added comment: PMID: 36706222 reported a patient with MSUD with mild findings and elevated BCAA levels carrying a novel homozygous start-loss variant in PPM1K; Changed rating: AMBER; Changed publications: 23086801, 36706222
Aminoacidopathy v1.4 PPM1K Zornitza Stark Phenotypes for gene: PPM1K were changed from maple syrup urine disease, mild variant MONDO:0014057 to Maple syrup urine disease, mild variant MONDO:0014057
Aminoacidopathy v1.3 PPM1K Zornitza Stark Publications for gene: PPM1K were set to 29152456; 23086801
Aminoacidopathy v1.2 PPM1K Zornitza Stark Classified gene: PPM1K as Amber List (moderate evidence)
Aminoacidopathy v1.2 PPM1K Zornitza Stark Gene: ppm1k has been classified as Amber List (Moderate Evidence).
Arrhythmogenic Cardiomyopathy v0.68 KBTBD13 Zornitza Stark Marked gene: KBTBD13 as ready
Arrhythmogenic Cardiomyopathy v0.68 KBTBD13 Zornitza Stark Gene: kbtbd13 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.680 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related to Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related
Mendeliome v1.679 ARHGAP35 Zornitza Stark Publications for gene: ARHGAP35 were set to 33057194; 36450800
Mendeliome v1.678 ARHGAP35 Zornitza Stark reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: 36178483; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.88 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Fetal anomalies v1.88 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Differences of Sex Development v0.272 ARHGAP35 Zornitza Stark Marked gene: ARHGAP35 as ready
Differences of Sex Development v0.272 ARHGAP35 Zornitza Stark Gene: arhgap35 has been classified as Green List (High Evidence).
Differences of Sex Development v0.272 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from Idiopathic hypogonadotropic hypogonadism, no OMIM # to Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related
Differences of Sex Development v0.271 ARHGAP35 Zornitza Stark reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.88 EFCAB1 Zornitza Stark Classified gene: EFCAB1 as Green List (high evidence)
Fetal anomalies v1.88 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Fetal anomalies v1.87 EFCAB1 Zornitza Stark gene: EFCAB1 was added
gene: EFCAB1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Heterotaxy v1.29 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Heterotaxy v1.29 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Heterotaxy v1.29 EFCAB1 Zornitza Stark Phenotypes for gene: EFCAB1 were changed from Primary ciliary dyskinesia and heterotaxy, no OMIM # to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Ciliary Dyskinesia v1.28 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Ciliary Dyskinesia v1.28 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Ciliary Dyskinesia v1.28 EFCAB1 Zornitza Stark Phenotypes for gene: EFCAB1 were changed from Primary ciliary dyskinesia and heterotaxy, no OMIM # to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Mendeliome v1.678 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Mendeliome v1.678 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Mendeliome v1.678 EFCAB1 Zornitza Stark Phenotypes for gene: EFCAB1 were changed from Primary ciliary dyskinesia and heterotaxy, no OMIM # to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Mendeliome v1.677 EFCAB1 Zornitza Stark reviewed gene: EFCAB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.677 CST6 Zornitza Stark Marked gene: CST6 as ready
Mendeliome v1.677 CST6 Zornitza Stark Gene: cst6 has been classified as Green List (High Evidence).
Mendeliome v1.677 CST6 Zornitza Stark Classified gene: CST6 as Green List (high evidence)
Mendeliome v1.677 CST6 Zornitza Stark Gene: cst6 has been classified as Green List (High Evidence).
Mendeliome v1.676 CST6 Zornitza Stark gene: CST6 was added
gene: CST6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CST6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CST6 were set to 30425301; 36371786
Phenotypes for gene: CST6 were set to Ectodermal dysplasia 15, hypohidrotic/hair type MIM#618535
Review for gene: CST6 was set to GREEN
Added comment: Two families reported and functional data.
Sources: Literature
Hair disorders v0.68 CST6 Zornitza Stark Publications for gene: CST6 were set to 30425301; 12393798
Hair disorders v0.67 CST6 Zornitza Stark reviewed gene: CST6: Rating: AMBER; Mode of pathogenicity: None; Publications: 36371786; Phenotypes: Ectodermal dysplasia 15, hypohidrotic/hair type, 618535; Mode of inheritance: None
Ectodermal Dysplasia v0.80 CST6 Zornitza Stark Marked gene: CST6 as ready
Ectodermal Dysplasia v0.80 CST6 Zornitza Stark Gene: cst6 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.80 CST6 Zornitza Stark Phenotypes for gene: CST6 were changed from ?Ectodermal dysplasia 15, hypohidrotic/hair type, 618535 to Ectodermal dysplasia 15, hypohidrotic/hair type, 618535
Ectodermal Dysplasia v0.79 CST6 Zornitza Stark Publications for gene: CST6 were set to 30425301
Cone-rod Dystrophy v0.49 KCNV2 Zornitza Stark Publications for gene: KCNV2 were set to 30679166; 16909397; 18235024; 21882291
Palmoplantar Keratoderma and Erythrokeratoderma v0.128 KDSR Zornitza Stark Publications for gene: KDSR were set to 28774589; 30467204; 28575652
Intellectual disability syndromic and non-syndromic v0.5175 RAB39B Zornitza Stark Marked gene: RAB39B as ready
Intellectual disability syndromic and non-syndromic v0.5175 RAB39B Zornitza Stark Gene: rab39b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5175 RAB39B Zornitza Stark Phenotypes for gene: RAB39B were changed from to Intellectual developmental disorder, X-linked 72, OMIM:300271; Waisman syndrome, OMIM:311510
Intellectual disability syndromic and non-syndromic v0.5174 RAB39B Zornitza Stark Publications for gene: RAB39B were set to
Intellectual disability syndromic and non-syndromic v0.5173 RAB39B Zornitza Stark Mode of inheritance for gene: RAB39B was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.5172 JPH3 Zornitza Stark Phenotypes for gene: JPH3 were changed from Intellectual disability; dystonia to Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Intellectual disability; dystonia
Intellectual disability syndromic and non-syndromic v0.5171 JPH3 Zornitza Stark Publications for gene: JPH3 were set to 33824468
Intellectual disability syndromic and non-syndromic v0.5170 JPH3 Zornitza Stark Mode of inheritance for gene: JPH3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5169 JPH3 Zornitza Stark Classified gene: JPH3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5169 JPH3 Zornitza Stark Gene: jph3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5168 JPH3 Zornitza Stark reviewed gene: JPH3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36273396; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.675 JPH3 Zornitza Stark Phenotypes for gene: JPH3 were changed from Intellectual disability; dystonia to Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Intellectual disability; dystonia
Mendeliome v1.674 JPH3 Zornitza Stark Publications for gene: JPH3 were set to 33824468
Mendeliome v1.673 JPH3 Zornitza Stark Mode of inheritance for gene: JPH3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.672 JPH3 Zornitza Stark Classified gene: JPH3 as Amber List (moderate evidence)
Mendeliome v1.672 JPH3 Zornitza Stark Gene: jph3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.671 JPH3 Zornitza Stark reviewed gene: JPH3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36273396; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paroxysmal Dyskinesia v0.106 JPH3 Zornitza Stark Marked gene: JPH3 as ready
Paroxysmal Dyskinesia v0.106 JPH3 Zornitza Stark Gene: jph3 has been classified as Amber List (Moderate Evidence).
Paroxysmal Dyskinesia v0.106 JPH3 Zornitza Stark Mode of pathogenicity for gene: JPH3 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Paroxysmal Dyskinesia v0.105 JPH3 Zornitza Stark Classified gene: JPH3 as Amber List (moderate evidence)
Paroxysmal Dyskinesia v0.105 JPH3 Zornitza Stark Gene: jph3 has been classified as Amber List (Moderate Evidence).
Paroxysmal Dyskinesia v0.104 JPH3 Zornitza Stark changed review comment from: Two families reported with bi-allelic variants and neurodevelopmental disorder involving paroxysmal dystonia. One family with mono-allelic variant, milder.; to: Two families reported with bi-allelic variants and neurodevelopmental disorder involving paroxysmal dystonia. One family with mono-allelic variant, milder.

Note STRs in this gene cause a separate disorder.
Paroxysmal Dyskinesia v0.104 JPH3 Zornitza Stark reviewed gene: JPH3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36273396; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.90 WNT11 Zornitza Stark Marked gene: WNT11 as ready
Osteogenesis Imperfecta and Osteoporosis v0.90 WNT11 Zornitza Stark Gene: wnt11 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.90 WNT11 Zornitza Stark Classified gene: WNT11 as Green List (high evidence)
Osteogenesis Imperfecta and Osteoporosis v0.90 WNT11 Zornitza Stark Gene: wnt11 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.89 WNT11 Zornitza Stark gene: WNT11 was added
gene: WNT11 was added to Osteogenesis Imperfecta. Sources: Literature
Mode of inheritance for gene: WNT11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WNT11 were set to 34875064
Phenotypes for gene: WNT11 were set to Osteoporosis, MONDO:0005298, WNT11-related
Review for gene: WNT11 was set to GREEN
Added comment: This gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene.

Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures.

A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures.

A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met).

This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells.
Sources: Literature
Mendeliome v1.671 WNT11 Zornitza Stark Marked gene: WNT11 as ready
Mendeliome v1.671 WNT11 Zornitza Stark Gene: wnt11 has been classified as Green List (High Evidence).
Mendeliome v1.671 WNT11 Zornitza Stark Classified gene: WNT11 as Green List (high evidence)
Mendeliome v1.671 WNT11 Zornitza Stark Gene: wnt11 has been classified as Green List (High Evidence).
Mendeliome v1.670 MRPS7 Zornitza Stark Publications for gene: MRPS7 were set to 25556185
Mendeliome v1.669 MRPS7 Zornitza Stark Classified gene: MRPS7 as Amber List (moderate evidence)
Mendeliome v1.669 MRPS7 Zornitza Stark Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.668 MRPS7 Zornitza Stark edited their review of gene: MRPS7: Added comment: Now second publication (PMID: 36421788) describes sisters with an overlapping phenotype including sensorineural deafness and premature ovarian insufficiency. They both had compound heterozygous (one missense, one nonsense) MRPS7 variants.; Changed rating: AMBER; Changed publications: 25556185, 36421788
Mitochondrial disease v0.856 MRPS7 Zornitza Stark Publications for gene: MRPS7 were set to 25556185
Mitochondrial disease v0.855 MRPS7 Zornitza Stark Classified gene: MRPS7 as Amber List (moderate evidence)
Mitochondrial disease v0.855 MRPS7 Zornitza Stark Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.309 MRPS7 Zornitza Stark Marked gene: MRPS7 as ready
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.309 MRPS7 Zornitza Stark Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.309 MRPS7 Zornitza Stark Phenotypes for gene: MRPS7 were changed from sensorineural deafness; renal failure; liver failure; primary ovarian insufficiency to Combined oxidative phosphorylation deficiency 34, MIM# 617872; sensorineural deafness; renal failure; liver failure; primary ovarian insufficiency
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.308 MRPS7 Zornitza Stark Classified gene: MRPS7 as Amber List (moderate evidence)
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.308 MRPS7 Zornitza Stark Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.668 STAT6 Zornitza Stark Marked gene: STAT6 as ready
Mendeliome v1.668 STAT6 Zornitza Stark Gene: stat6 has been classified as Green List (High Evidence).
Mendeliome v1.668 STAT6 Zornitza Stark Classified gene: STAT6 as Green List (high evidence)
Mendeliome v1.668 STAT6 Zornitza Stark Gene: stat6 has been classified as Green List (High Evidence).
Mendeliome v1.667 STAT6 Zornitza Stark gene: STAT6 was added
gene: STAT6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STAT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STAT6 were set to 36216080; 36758835
Phenotypes for gene: STAT6 were set to Allergic disease, MONDO:0005271, STAT6-related; early-onset multiorgan allergies
Review for gene: STAT6 was set to GREEN
Added comment: Two families reported with GoF variants and extensive functional data.
Sources: Literature
Disorders of immune dysregulation v0.166 STAT6 Zornitza Stark Marked gene: STAT6 as ready
Disorders of immune dysregulation v0.166 STAT6 Zornitza Stark Gene: stat6 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.166 STAT6 Zornitza Stark Phenotypes for gene: STAT6 were changed from early-onset multiorgan allergies to Allergic disease, MONDO:0005271, STAT6-related; early-onset multiorgan allergies
Disorders of immune dysregulation v0.165 STAT6 Zornitza Stark Classified gene: STAT6 as Green List (high evidence)
Disorders of immune dysregulation v0.165 STAT6 Zornitza Stark Gene: stat6 has been classified as Green List (High Evidence).
Mendeliome v1.666 LTV1 Zornitza Stark Marked gene: LTV1 as ready
Mendeliome v1.666 LTV1 Zornitza Stark Gene: ltv1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.666 LTV1 Zornitza Stark Classified gene: LTV1 as Amber List (moderate evidence)
Mendeliome v1.666 LTV1 Zornitza Stark Gene: ltv1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1872 TANGO2 Zornitza Stark Marked gene: TANGO2 as ready
BabyScreen+ newborn screening v0.1872 TANGO2 Zornitza Stark Gene: tango2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1872 TANGO2 Zornitza Stark Phenotypes for gene: TANGO2 were changed from Cardiomyopathy; Metabolic Crises; Arrhythmia; Neurodevelopmental to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM# 616878
BabyScreen+ newborn screening v0.1871 TANGO2 Zornitza Stark Classified gene: TANGO2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1871 TANGO2 Zornitza Stark Gene: tango2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1870 TANGO2 Zornitza Stark Tag treatable tag was added to gene: TANGO2.
Tag metabolic tag was added to gene: TANGO2.
BabyScreen+ newborn screening v0.1870 LAMP2 Zornitza Stark Phenotypes for gene: LAMP2 were changed from Danon disease, MIM# 300257 to Danon disease, MIM# 300257
BabyScreen+ newborn screening v0.1869 LAMP2 Zornitza Stark Classified gene: LAMP2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1869 LAMP2 Zornitza Stark Gene: lamp2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1868 NKX2-5 Zornitza Stark Marked gene: NKX2-5 as ready
BabyScreen+ newborn screening v0.1868 NKX2-5 Zornitza Stark Gene: nkx2-5 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1868 NKX2-5 Zornitza Stark Phenotypes for gene: NKX2-5 were changed from Congenital heart disease to Atrial septal defect 7, with or without AV conduction defects, MIM# 108900
BabyScreen+ newborn screening v0.1867 NKX2-5 Zornitza Stark Tag cardiac tag was added to gene: NKX2-5.
BabyScreen+ newborn screening v0.1867 NKX2-5 Zornitza Stark Classified gene: NKX2-5 as Green List (high evidence)
BabyScreen+ newborn screening v0.1867 NKX2-5 Zornitza Stark Gene: nkx2-5 has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.8 AVP Zornitza Stark Marked gene: AVP as ready
Renal Tubulopathies and related disorders v1.8 AVP Zornitza Stark Gene: avp has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.8 AVP Zornitza Stark Phenotypes for gene: AVP were changed from Diabetes insipidus, neurohypophyseal to Diabetes insipidus, neurohypophyseal MIM#125700
Renal Tubulopathies and related disorders v1.7 AVP Zornitza Stark Classified gene: AVP as Green List (high evidence)
Renal Tubulopathies and related disorders v1.7 AVP Zornitza Stark Gene: avp has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.6 AVP Ella Wilkins gene: AVP was added
gene: AVP was added to Renal Tubulopathies and related disorders. Sources: Expert list
Mode of inheritance for gene: AVP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: AVP were set to Diabetes insipidus, neurohypophyseal
Review for gene: AVP was set to GREEN
Added comment: Included due to phenotypic overlap with nephrogenic DI.
Sources: Expert list
Mendeliome v1.665 LTV1 Achchuthan Shanmugasundram gene: LTV1 was added
gene: LTV1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LTV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTV1 were set to 34999892
Phenotypes for gene: LTV1 were set to Inflammatory poikiloderma with hair abnormalities and acral keratoses, OMIM:620199
Review for gene: LTV1 was set to AMBER
Added comment: Comment on classification of gene: This gene should be rated amber as it has been implicated in inflammatory poikiloderma with hair abnormalities and acral keratoses as identified from two unrelated families harbouring the same biallelic variant and supported by functional studies.

PMID:34999892 reported four UK women of South Asian origin (three Pakistani sisters and an unrelated Indian woman) identified with homozygous variant c.503A>G, (p.Asn168Ser) and presented with poikiloderma, hair abnormalities, and acral keratoses, which the authors named as inflammatory poikiloderma with hair abnormalities and acral keratoses (IPHAK).

Both in silico modelling and splicing assays from a patient sample showed that this variant is responsible for splicing defects and defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm in yeast.

This gene has already been associated with relevant phenotype (MIM #620199) in OMIM, but not in Gene2Phenotype.
Sources: Literature
Disorders of immune dysregulation v0.164 STAT6 Peter McNaughton edited their review of gene: STAT6: Added comment: Report of another child with severe atopic dermatitis, eosinophilia and elevated IgE with extensive functional data.; Changed rating: GREEN; Changed publications: PMID: 36216080, PMID: 36758835
Disorders of immune dysregulation v0.164 STAT6 Peter McNaughton changed review comment from: STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with
3 affected members, extensive functional data to support mechanism of allergic disease.
Sources: Literature; to: STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with
3 affected members, extensive functional data to support mechanism of allergic disease.
Sources: Literature
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.307 MRPS7 Elena Tucker gene: MRPS7 was added
gene: MRPS7 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature
Mode of inheritance for gene: MRPS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS7 were set to PMID: 25556185; 36421788
Phenotypes for gene: MRPS7 were set to sensorineural deafness; renal failure; liver failure; primary ovarian insufficiency
Review for gene: MRPS7 was set to AMBER
Added comment: The initial report (PMID: 25556185) describes a homozygous missense variant in two sisters with sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. One sister died in early adolescence but the other survived beyond puberty and had primary ovarian insufficiency. Experimental evidence supported causation of the MRPS7 variant.

The second publication (PMID: 36421788) describes sisters with an overlapping phenotype including sensorineural deafness and premature ovarian insufficiency. They both had compound heterozygous (one missense, one nonsense) MRPS7 variants.
Sources: Literature
Mitochondrial disease v0.854 MRPS7 Elena Tucker reviewed gene: MRPS7: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36421788, 25556185; Phenotypes: sensorineural deafness, renal failure, liver failure, primary ovarian insufficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.665 WNT11 Achchuthan Shanmugasundram gene: WNT11 was added
gene: WNT11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WNT11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WNT11 were set to 34875064
Phenotypes for gene: WNT11 were set to osteoporosis, MONDO:0005298; osteoarthritis, MONDO:0005178; recurrent fractures
Review for gene: WNT11 was set to GREEN
Added comment: Comment on gene classification: The rating of this gene can be added as green as this gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene.

Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures.

A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures.

A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met).

This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells.

This gene has not yet been reported with any phenotypes either in OMIM or in G2P.
Sources: Literature
BabyScreen+ newborn screening v0.1866 ACTA2 Zornitza Stark Mode of inheritance for gene: ACTA2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1865 HADHA Ari Horton reviewed gene: HADHA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31575911; Phenotypes: Cardiomyopathy, Metabolic Disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1865 TANGO2 Ari Horton changed review comment from: Folate may assist with TANGO2
DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1

While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD

Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY

Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias

Specific diet and fasting plans are recommended for all patients from the neonatal period
Sources: Expert Review; to: Folate may assist with TANGO2
DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1

PMID: 35568137

While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD

Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY

Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias

Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4–9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all (median 547 ms; IQR 504–600 ms) and a type I Brugada pattern in 8 (26%). Arrhythmias included VT in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. There were 10 deaths (37%), 6 related to arrhythmias. In 5 patients, recalcitrant VT occurred despite use of antiarrhythmic drugs. In 6 patients, arrhythmias were controlled after extracorporeal membrane oxygenation (ECMO) support; 5 of these patients survived. Among 10 patients who survived VT without ECMO, successful treatment included intravenous magnesium, isoproterenol, and atrial pacing in multiple cases and verapamil in 1 patient. Initiation of feeds seemed to decrease VT events.

Specific diet and fasting plans are recommended for all patients from the neonatal period
Sources: Expert Review
BabyScreen+ newborn screening v0.1865 TANGO2 Ari Horton gene: TANGO2 was added
gene: TANGO2 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TANGO2 were set to Cardiomyopathy; Metabolic Crises; Arrhythmia; Neurodevelopmental
Penetrance for gene: TANGO2 were set to Complete
Review for gene: TANGO2 was set to GREEN
Added comment: Folate may assist with TANGO2
DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1

While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD

Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY

Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias

Specific diet and fasting plans are recommended for all patients from the neonatal period
Sources: Expert Review
BabyScreen+ newborn screening v0.1865 LAMP2 Ari Horton reviewed gene: LAMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Childhood onset cardiomyopathy (Severe), Neuordevelopmental phenotype; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
BabyScreen+ newborn screening v0.1865 NKX2-5 Ari Horton reviewed gene: NKX2-5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neonatal onset cardiomyopathy, Congenital Heart Disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
BabyScreen+ newborn screening v0.1865 GATA4 Ari Horton reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, Congenital Heart Disease, Arrhythmia, Extra-cardiac Manifestations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
BabyScreen+ newborn screening v0.1865 ACTA2 Ari Horton reviewed gene: ACTA2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.665 DEPDC5 Zornitza Stark Mode of inheritance for gene: DEPDC5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.86 ATP9A Zornitza Stark Phenotypes for gene: ATP9A were changed from neurodevelopmental disorder, ATP9A-related MONDO#0700092 to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Intellectual disability syndromic and non-syndromic v0.5168 ATP9A Zornitza Stark Phenotypes for gene: ATP9A were changed from Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Intellectual disability syndromic and non-syndromic v0.5167 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Microcephaly v1.194 ATP9A Zornitza Stark Phenotypes for gene: ATP9A were changed from Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Microcephaly v1.193 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Mendeliome v1.664 ATP9A Zornitza Stark Phenotypes for gene: ATP9A were changed from Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Mendeliome v1.663 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Mendeliome v1.663 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: NeurodevNeurodevelopmental disorder with poor growth and behavioral abnormalities, MIM# 620242
Paroxysmal Dyskinesia v0.104 JPH3 SHEKEEB MOHAMMAD gene: JPH3 was added
gene: JPH3 was added to Paroxysmal Dyskinesia. Sources: Literature
Mode of inheritance for gene: JPH3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: JPH3 were set to PMID: 36273396
Phenotypes for gene: JPH3 were set to paroxysmal dystonia, intellectual disability
Penetrance for gene: JPH3 were set to unknown
Mode of pathogenicity for gene: JPH3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: JPH3 was set to GREEN
Added comment: Sources: Literature
Fetal anomalies v1.85 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from neuromuscular disease, GOLGA2-related MONDO#0019056 to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Fetal anomalies v1.84 GOLGA2 Zornitza Stark edited their review of gene: GOLGA2: Added comment: Third family reported but again hypoplasia of CC which may be difficult to detect. Onset of microcephaly uncertain.; Changed publications: 34424553; Changed phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Intellectual disability syndromic and non-syndromic v0.5167 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Intellectual disability syndromic and non-syndromic v0.5166 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Intellectual disability syndromic and non-syndromic v0.5165 GOLGA2 Zornitza Stark edited their review of gene: GOLGA2: Added comment: Third family reported.; Changed publications: 34424553; Changed phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Muscular dystrophy and myopathy_Paediatric v0.126 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Muscular dystrophy and myopathy_Paediatric v0.125 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Muscular dystrophy and myopathy_Paediatric v0.124 GOLGA2 Zornitza Stark edited their review of gene: GOLGA2: Added comment: Third family reported.; Changed publications: 34424553
Muscular dystrophy and myopathy_Paediatric v0.124 GOLGA2 Zornitza Stark edited their review of gene: GOLGA2: Changed phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.193 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Microcephaly v1.192 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Microcephaly v1.191 GOLGA2 Zornitza Stark reviewed gene: GOLGA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34424553; Phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.663 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Mendeliome v1.662 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Mendeliome v1.661 GOLGA2 Zornitza Stark reviewed gene: GOLGA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34424553; Phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.661 THSD1 Zornitza Stark Phenotypes for gene: THSD1 were changed from Aneurysm, intracranial berry, 12 , MIM# 618734; Hydrops fetalis MONDO:0015193, THSD1-related to Aneurysm, intracranial berry, 12 , MIM# 618734; Lymphatic malformation 13, MIM# 620244
Mendeliome v1.660 THSD1 Zornitza Stark Mode of inheritance for gene: THSD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hydrops fetalis v0.295 THSD1 Zornitza Stark Phenotypes for gene: THSD1 were changed from Hydrops fetalis MONDO:0015193, THSD1-related to Lymphatic malformation 13, MIM# 620244
Hydrops fetalis v0.294 THSD1 Zornitza Stark reviewed gene: THSD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lymphatic malformation 13, MIM# 620244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5165 RAB39B Achchuthan Shanmugasundram reviewed gene: RAB39B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20159109, 25434005, 11050621, 29152164, 32873259, 34761259; Phenotypes: Intellectual developmental disorder, X-linked 72, OMIM:300271, Waisman syndrome, OMIM:311510; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Palmoplantar Keratoderma and Erythrokeratoderma v0.127 KDSR Achchuthan Shanmugasundram reviewed gene: KDSR: Rating: GREEN; Mode of pathogenicity: None; Publications: 34686882; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1865 MCFD2 Zornitza Stark Classified gene: MCFD2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1865 MCFD2 Zornitza Stark Gene: mcfd2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1864 MCFD2 Zornitza Stark changed review comment from: Reviewed with Meg Wall, haematologist.
Treatable, including with prophylactic DDAVP, include.; to: Reviewed with Meg Wall, haematologist.
Treatable, including with prophylactic DDAVP; however, generally mild, therefore exclude.
BabyScreen+ newborn screening v0.1864 MCFD2 Zornitza Stark edited their review of gene: MCFD2: Changed rating: AMBER
BabyScreen+ newborn screening v0.1864 HBB Zornitza Stark Phenotypes for gene: HBB were changed from Sickle cell anaemia, MIM# 603903; Thalassaemia, beta, MIM# 613985 to Sickle cell anaemia, MIM# 603903
BabyScreen+ newborn screening v0.1863 HBB Zornitza Stark edited their review of gene: HBB: Changed phenotypes: Sickle cell anaemia, MIM# 603903
Intellectual disability syndromic and non-syndromic v0.5165 WDR11 Zornitza Stark reviewed gene: WDR11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.191 WDR11 Zornitza Stark Phenotypes for gene: WDR11 were changed from Intellectual disability; Microcephaly; Short stature to Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Intellectual disability; Microcephaly; Short stature
Microcephaly v1.190 WDR11 Zornitza Stark edited their review of gene: WDR11: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 78, MIM# 620237, Intellectual disability, Microcephaly, Short stature
Mendeliome v1.659 WDR11 Zornitza Stark Phenotypes for gene: WDR11 were changed from Intellectual disability; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858 to Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
Mendeliome v1.658 WDR11 Zornitza Stark edited their review of gene: WDR11: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 78, MIM# 620237, Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
Cone-rod Dystrophy v0.48 KCNV2 Achchuthan Shanmugasundram changed review comment from: Seven cases are identified with homozygous variants in KCNV2 gene and reported with cone dystrophy with supernormal rod responses (CDSRR) in PMID:23221069. Similarly, 15 unrelated patients were identified with three different homozygous KCNV2 variants and reported with CDSRR in PMID:31960170. PMID:34535971 reports a Chinese family with compound heterozygous variants and implicated in CDSRR. KCNV2 knockout mouse exhibits aberrant retinal activities that phenocopies CDSRR patients (PMID:34652420).; to: Additional cases: Seven cases are identified with homozygous variants in KCNV2 gene and reported with cone dystrophy with supernormal rod responses (CDSRR) in PMID:23221069. Similarly, 15 unrelated patients were identified with three different homozygous KCNV2 variants and reported with CDSRR in PMID:31960170. PMID:34535971 reports a Chinese family with compound heterozygous variants and implicated in CDSRR.

Functional studies: KCNV2 knockout mouse exhibits aberrant retinal activities that phenocopies CDSRR patients (PMID:34652420).
Cone-rod Dystrophy v0.48 KCNV2 Achchuthan Shanmugasundram reviewed gene: KCNV2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23221069, 31960170, 34535971, 34652420; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1863 RUNX1 Zornitza Stark Classified gene: RUNX1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1863 RUNX1 Zornitza Stark Gene: runx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1862 RUNX1 Zornitza Stark edited their review of gene: RUNX1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1862 MCFD2 Zornitza Stark Marked gene: MCFD2 as ready
BabyScreen+ newborn screening v0.1862 MCFD2 Zornitza Stark Gene: mcfd2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1862 MCFD2 Zornitza Stark Tag for review was removed from gene: MCFD2.
Tag treatable tag was added to gene: MCFD2.
BabyScreen+ newborn screening v0.1862 MCFD2 Zornitza Stark reviewed gene: MCFD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Factor V and factor VIII, combined deficiency of, MIM# 613625; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1862 HBB Zornitza Stark Tag for review was removed from gene: HBB.
BabyScreen+ newborn screening v0.1862 HBB Zornitza Stark changed review comment from: Well established gene-disease associations.

Congenital onset.

Both sickle cell anaemia and beta thalassaemia are treatable disorders.

Beta thal: gene therapy (betibeglogene autotemcel - clinical trial), red cell transfusions, bone marrow transplantation (Hematopoietic Stem Cell Transplantation (HSCT)), Luspatercept

Sickle cell: glutamine, voxelotor, crizanlizumab, hydroxyurea, ,red cell transfusions, bone marrow transplantation (Hematopoietic Stem Cell Transplantation (HSCT)), gene therapy (BCH-BB694 BCL11A shmiR lentiviral vector - clinical trial and autologous CRISPR-Cas9-edited CD34+ hematopoietic stem and progenitor cells) - clinical trial)

Some of the beta-that variants are structural -- ability to detect reliably? For review.; to: Well established gene-disease associations.

Congenital onset.

Both sickle cell anaemia and beta thalassaemia are treatable disorders.

Beta thal: gene therapy (betibeglogene autotemcel - clinical trial), red cell transfusions, bone marrow transplantation (Hematopoietic Stem Cell Transplantation (HSCT)), Luspatercept

Sickle cell: glutamine, voxelotor, crizanlizumab, hydroxyurea, ,red cell transfusions, bone marrow transplantation (Hematopoietic Stem Cell Transplantation (HSCT)), gene therapy (BCH-BB694 BCL11A shmiR lentiviral vector - clinical trial and autologous CRISPR-Cas9-edited CD34+ hematopoietic stem and progenitor cells) - clinical trial)

Some of the beta-that variants are structural -- ability to detect reliably? For review.

We are only able to reliably screen for the HbS association.
BabyScreen+ newborn screening v0.1862 HBA2 Zornitza Stark Classified gene: HBA2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1862 HBA2 Zornitza Stark Gene: hba2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1861 HBA2 Zornitza Stark edited their review of gene: HBA2: Changed rating: AMBER
BabyScreen+ newborn screening v0.1861 HBA1 Zornitza Stark Classified gene: HBA1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1861 HBA1 Zornitza Stark Gene: hba1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1860 HBA1 Zornitza Stark changed review comment from: Well established gene-disease association.

Congenital onset.

Treatable: transfusions, bone marrow transplant.

However, there is widespread screening in pregnancy. Also note mutational spectrum includes SVs/CNVs: can we reliably diagnose? For review.; to: Well established gene-disease association.

Congenital onset.

Treatable: transfusions, bone marrow transplant.

However, there is widespread screening in pregnancy. Also note mutational spectrum includes SVs/CNVs: can we reliably diagnose?

Exclude for now due to technical concerns.
BabyScreen+ newborn screening v0.1860 HBA1 Zornitza Stark edited their review of gene: HBA1: Changed rating: AMBER
BabyScreen+ newborn screening v0.1860 F8 Zornitza Stark Classified gene: F8 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1860 F8 Zornitza Stark Gene: f8 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1859 F8 Zornitza Stark changed review comment from: Well established gene-disease association.

Variable severity.

Treatment: recombinant factor VIII. Gene therapy trial.

Non-genetic confirmatory testing: factor VIII levels.

Note: excluded from other screening tests due to concerns regarding ability to detect the intron 22 inversion (Inv22) mutation of F8 which causes about 45% of severe HA cases. For review.; to: Well established gene-disease association.

Variable severity.

Treatment: recombinant factor VIII. Gene therapy trial.

Non-genetic confirmatory testing: factor VIII levels.

Note: excluded from other screening tests due to concerns regarding ability to detect the intron 22 inversion (Inv22) mutation of F8 which causes about 45% of severe HA cases. Intron 1 inversion also common.

Excluded for now until we can confirm we can detect inversion.
BabyScreen+ newborn screening v0.1859 F8 Zornitza Stark edited their review of gene: F8: Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v0.5165 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder, MONDO:0700092, TRPM3-related to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Intellectual disability syndromic and non-syndromic v0.5164 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Genetic Epilepsy v0.1833 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder, MONDO:0700092, TRPM3-related to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Genetic Epilepsy v0.1832 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Mendeliome v1.658 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder, MONDO:0700092, TRPM3-related to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Mendeliome v1.657 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Disorders of immune dysregulation v0.164 STAT6 Peter McNaughton gene: STAT6 was added
gene: STAT6 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: STAT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STAT6 were set to PMID: 36216080
Phenotypes for gene: STAT6 were set to early-onset multiorgan allergies
Mode of pathogenicity for gene: STAT6 was set to Other
Review for gene: STAT6 was set to AMBER
Added comment: STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with
3 affected members, extensive functional data to support mechanism of allergic disease.
Sources: Literature
Ectodermal Dysplasia v0.78 CST6 Chirag Patel Classified gene: CST6 as Green List (high evidence)
Ectodermal Dysplasia v0.78 CST6 Chirag Patel Gene: cst6 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.77 CST6 Chirag Patel reviewed gene: CST6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36371786; Phenotypes: dry skin, desquamation and abnormal keratosis without hypotrichosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.657 EFCAB1 Chirag Patel Classified gene: EFCAB1 as Green List (high evidence)
Mendeliome v1.657 EFCAB1 Chirag Patel Gene: efcab1 has been classified as Green List (High Evidence).
Heterotaxy v1.28 EFCAB1 Chirag Patel Classified gene: EFCAB1 as Green List (high evidence)
Heterotaxy v1.28 EFCAB1 Chirag Patel Gene: efcab1 has been classified as Green List (High Evidence).
Mendeliome v1.656 EFCAB1 Chirag Patel gene: EFCAB1 was added
gene: EFCAB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to PMID: 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia and heterotaxy, no OMIM #
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Ciliary Dyskinesia v1.27 EFCAB1 Chirag Patel Classified gene: EFCAB1 as Green List (high evidence)
Ciliary Dyskinesia v1.27 EFCAB1 Chirag Patel Gene: efcab1 has been classified as Green List (High Evidence).
Heterotaxy v1.27 EFCAB1 Chirag Patel gene: EFCAB1 was added
gene: EFCAB1 was added to Heterotaxy. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to PMID: 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia and heterotaxy, no OMIM #
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Ciliary Dyskinesia v1.27 EFCAB1 Chirag Patel Classified gene: EFCAB1 as Green List (high evidence)
Ciliary Dyskinesia v1.27 EFCAB1 Chirag Patel Gene: efcab1 has been classified as Green List (High Evidence).
Ciliary Dyskinesia v1.26 EFCAB1 Chirag Patel gene: EFCAB1 was added
gene: EFCAB1 was added to Ciliary Dyskinesia. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to PMID: 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia and heterotaxy, no OMIM #
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Differences of Sex Development v0.271 ARHGAP35 Chirag Patel Classified gene: ARHGAP35 as Green List (high evidence)
Differences of Sex Development v0.271 ARHGAP35 Chirag Patel Gene: arhgap35 has been classified as Green List (High Evidence).
Differences of Sex Development v0.270 ARHGAP35 Chirag Patel gene: ARHGAP35 was added
gene: ARHGAP35 was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to PMID: 36178483
Phenotypes for gene: ARHGAP35 were set to Idiopathic hypogonadotropic hypogonadism, no OMIM #
Review for gene: ARHGAP35 was set to GREEN
Added comment: 12 patients with idiopathic hypogonadotropic hypogonadism. Rare protein-truncating variants (n = 5) and missense variants (n = 7) found in the RhoGAP domain of ARHGAP35 gene. Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a (predominant ARHGAP35 paralog in zebrafish brain), displayed decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant (Arg1284Trp) had decreased GAP activity.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5164 WDR5 Bryony Thompson Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Intellectual disability syndromic and non-syndromic v0.5163 WDR5 Bryony Thompson edited their review of gene: WDR5: Changed publications: 36408368
Mendeliome v1.655 WDR5 Bryony Thompson Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Mendeliome v1.654 WDR5 Bryony Thompson edited their review of gene: WDR5: Changed publications: 36408368
Arrhythmogenic Cardiomyopathy v0.68 KBTBD13 Bryony Thompson Classified gene: KBTBD13 as Amber List (moderate evidence)
Arrhythmogenic Cardiomyopathy v0.68 KBTBD13 Bryony Thompson Gene: kbtbd13 has been classified as Amber List (Moderate Evidence).
Arrhythmogenic Cardiomyopathy v0.67 KBTBD13 Bryony Thompson gene: KBTBD13 was added
gene: KBTBD13 was added to Arrhythmogenic Cardiomyopathy. Sources: Literature
Mode of inheritance for gene: KBTBD13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KBTBD13 were set to 36335629
Phenotypes for gene: KBTBD13 were set to Intrinsic cardiomyopathy MONDO:0000591
Review for gene: KBTBD13 was set to AMBER
gene: KBTBD13 was marked as current diagnostic
Added comment: In 3 families with the Nemaline myopathy type 6 (NEM6) Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C), a cardiac phenotype was found to co-segregate with the variant (LOD score 6.02). In total, 65 NEM6 patients were evaluated of whom 12% presented with LV dilatation, 29% with LVEF < 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Although some patients meet criteria for dilated cardiomyopathy, others have normal LV dimensions and meet criteria for arrhythmogenic cardiomyopathy, or display arrhythmia in the absence of cardiomyopathy. Mouse studies demonstrated that mice harbouring the Kbtbd13 p.R408C variant displayed mild diastolic dysfunction and Kbtbd13-deficient mice have systolic dysfunction. Currently, a cardiac phenotype has not been identified in individuals with any other pathogenic variants in KBTBD13.
Sources: Literature
Mendeliome v1.654 KBTBD13 Bryony Thompson reviewed gene: KBTBD13: Rating: AMBER; Mode of pathogenicity: None; Publications: 36335629; Phenotypes: Cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.654 KLHL24 Zornitza Stark Phenotypes for gene: KLHL24 were changed from Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy; Hypertrophic cardiomyopathy to Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MIM# 620236
Hypertrophic cardiomyopathy_HCM v0.172 KLHL24 Zornitza Stark Phenotypes for gene: KLHL24 were changed from Hypertrophic cardiomyopathy to Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MIM# 620236
Mendeliome v1.653 ASNA1 Zornitza Stark Marked gene: ASNA1 as ready
Mendeliome v1.653 ASNA1 Zornitza Stark Gene: asna1 has been classified as Red List (Low Evidence).
Mendeliome v1.653 ASNA1 Zornitza Stark Classified gene: ASNA1 as Red List (low evidence)
Mendeliome v1.653 ASNA1 Zornitza Stark Gene: asna1 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.157 ASNA1 Zornitza Stark Marked gene: ASNA1 as ready
Cardiomyopathy_Paediatric v0.157 ASNA1 Zornitza Stark Gene: asna1 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.157 ASNA1 Zornitza Stark Classified gene: ASNA1 as Red List (low evidence)
Cardiomyopathy_Paediatric v0.157 ASNA1 Zornitza Stark Gene: asna1 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.156 RRAGD Zornitza Stark Marked gene: RRAGD as ready
Cardiomyopathy_Paediatric v0.156 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.156 RRAGD Zornitza Stark Classified gene: RRAGD as Green List (high evidence)
Cardiomyopathy_Paediatric v0.156 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.155 RRAGD Zornitza Stark gene: RRAGD was added
gene: RRAGD was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to 34607910
Phenotypes for gene: RRAGD were set to Inherited renal tubular disease, MONDO:0015962, RRAGD-related; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Review for gene: RRAGD was set to GREEN
Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Renal Tubulopathies and related disorders v1.6 RRAGD Zornitza Stark Marked gene: RRAGD as ready
Renal Tubulopathies and related disorders v1.6 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.6 RRAGD Zornitza Stark Classified gene: RRAGD as Green List (high evidence)
Renal Tubulopathies and related disorders v1.6 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.5 RRAGD Zornitza Stark gene: RRAGD was added
gene: RRAGD was added to Renal Tubulopathies and related disorders. Sources: Literature
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to 34607910
Phenotypes for gene: RRAGD were set to Inherited renal tubular disease, MONDO:0015962, RRAGD-related; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Review for gene: RRAGD was set to GREEN
Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Mendeliome v1.652 RRAGD Zornitza Stark Classified gene: RRAGD as Green List (high evidence)
Mendeliome v1.652 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Mendeliome v1.651 RRAGD Zornitza Stark Marked gene: RRAGD as ready
Mendeliome v1.651 RRAGD Zornitza Stark Gene: rragd has been removed from the panel.
Mendeliome v1.651 RRAGD Zornitza Stark Phenotypes for gene: RRAGD were changed from Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis to Inherited renal tubular disease, MONDO:0015962, RRAGD-related; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Mendeliome v1.650 PMEL Zornitza Stark Marked gene: PMEL as ready
Mendeliome v1.650 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Mendeliome v1.650 PMEL Zornitza Stark Classified gene: PMEL as Red List (low evidence)
Mendeliome v1.650 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Hirschsprung disease v0.24 PMEL Zornitza Stark Marked gene: PMEL as ready
Hirschsprung disease v0.24 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Hirschsprung disease v0.24 PMEL Zornitza Stark Classified gene: PMEL as Red List (low evidence)
Hirschsprung disease v0.24 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Ocular and Oculocutaneous Albinism v1.9 PMEL Zornitza Stark Marked gene: PMEL as ready
Ocular and Oculocutaneous Albinism v1.9 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Ocular and Oculocutaneous Albinism v1.9 PMEL Zornitza Stark Classified gene: PMEL as Red List (low evidence)
Ocular and Oculocutaneous Albinism v1.9 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Mendeliome v1.649 ASNA1 Naomi Baker gene: ASNA1 was added
gene: ASNA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASNA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASNA1 were set to 31461301; 16797549
Phenotypes for gene: ASNA1 were set to Dilated cardiomyopathy, MONDO:0001644, ASNA1-related
Review for gene: ASNA1 was set to RED
Added comment: Two siblings reported with biallelic variants - there were two variants on the paternal allele (c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*)) and one variant on the maternal allele (c.488T>C p.(Val163Ala)). Unaffected sibling was heterozygous for maternal allele. Western blotting demonstrated reduced protein expression. Knockout of asna1 in zebrafish mode resulted in cardiac defects and early lethality. The Asna1 knockout mice displayed early embryonic lethality, consistent with a role of Asna1 in early embryonic development.
Sources: Literature
Cardiomyopathy_Paediatric v0.154 ASNA1 Naomi Baker gene: ASNA1 was added
gene: ASNA1 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: ASNA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASNA1 were set to 31461301; 16797549
Phenotypes for gene: ASNA1 were set to Dilated cardiomyopathy, MONDO:0001644, ASNA1-related
Review for gene: ASNA1 was set to RED
Added comment: Two siblings reported with biallelic variants - there were two variants on the paternal allele (c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*)) and one variant on the maternal allele (c.488T>C p.(Val163Ala)). Unaffected sibling was heterozygous for maternal allele. Western blotting demonstrated reduced protein expression. Knockout of asna1 in zebrafish mode resulted in cardiac defects and early lethality. The Asna1 knockout mice displayed early embryonic lethality, consistent with a role of Asna1 in early embryonic development.
Sources: Literature
Mendeliome v1.649 RRAGD Hazel Phillimore changed review comment from: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature; to: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Mendeliome v1.649 RRAGD Hazel Phillimore gene: RRAGD was added
gene: RRAGD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to PMID: 34607910
Phenotypes for gene: RRAGD were set to Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Review for gene: RRAGD was set to GREEN
Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Ocular and Oculocutaneous Albinism v1.8 PMEL Paul De Fazio edited their review of gene: PMEL: Changed phenotypes: Oculocutaneous albinism, PMEL-related MONDO:0018910
Hirschsprung disease v0.23 PMEL Paul De Fazio edited their review of gene: PMEL: Changed phenotypes: Oculocutaneous albinism, PMEL-related MONDO:0018910
Mendeliome v1.649 PMEL Paul De Fazio gene: PMEL was added
gene: PMEL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PMEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMEL were set to 36166100; 36207673
Phenotypes for gene: PMEL were set to Oculocutaneous albinism, PMEL-related MONDO:0018910
Review for gene: PMEL was set to RED
gene: PMEL was marked as current diagnostic
Added comment: A consanguineous family with oculocutaneous albinism and Hirschsprung disease was found to have a biallelic LoF variant in PMEL, which although NMD-predicted was found not to result in NMD by RT-PCR.

Some evidence that polymorphisms in this gene influence pigmentation in cattle.
Sources: Literature
Hirschsprung disease v0.23 PMEL Paul De Fazio gene: PMEL was added
gene: PMEL was added to Hirschsprung disease. Sources: Literature
Mode of inheritance for gene: PMEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMEL were set to 36166100
Phenotypes for gene: PMEL were set to Cculocutaneous albinism, PMEL-related MONDO:0018910
Review for gene: PMEL was set to RED
gene: PMEL was marked as current diagnostic
Added comment: A consanguineous family with oculocutaneous albinism and Hirschsprung disease was found to have a biallelic LoF variant in PMEL, which although NMD-predicted was found not to result in NMD by RT-PCR.
Sources: Literature
Gastrointestinal neuromuscular disease v1.20 MIR145 Zornitza Stark Marked gene: MIR145 as ready
Gastrointestinal neuromuscular disease v1.20 MIR145 Zornitza Stark Gene: mir145 has been classified as Red List (Low Evidence).
Mendeliome v1.649 SPTSSA Seb Lunke Marked gene: SPTSSA as ready
Mendeliome v1.649 SPTSSA Seb Lunke Gene: sptssa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.649 SPTSSA Seb Lunke Classified gene: SPTSSA as Amber List (moderate evidence)
Mendeliome v1.649 SPTSSA Seb Lunke Added comment: Comment on list classification: Three individuals but only two variants with different inheritance. Amber despite functional data.
Mendeliome v1.649 SPTSSA Seb Lunke Gene: sptssa has been classified as Amber List (Moderate Evidence).
Ocular and Oculocutaneous Albinism v1.8 PMEL Paul De Fazio gene: PMEL was added
gene: PMEL was added to Ocular and Oculocutaneous Albinism. Sources: Literature
Mode of inheritance for gene: PMEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMEL were set to 36166100; 36207673
Phenotypes for gene: PMEL were set to Cculocutaneous albinism, PMEL-related MONDO:0018910
Review for gene: PMEL was set to RED
gene: PMEL was marked as current diagnostic
Added comment: A consanguineous family with oculocutaneous albinism and Hirschsprung disease was found to have a biallelic LoF variant in PMEL, which although NMD-predicted was found not to result in NMD by RT-PCR.

Some evidence that polymorphisms in this gene influence pigmentation in cattle.
Sources: Literature
Gastrointestinal neuromuscular disease v1.20 MIR145 Zornitza Stark Classified gene: MIR145 as Red List (low evidence)
Gastrointestinal neuromuscular disease v1.20 MIR145 Zornitza Stark Gene: mir145 has been classified as Red List (Low Evidence).
Mendeliome v1.648 SPTSSA Seb Lunke gene: SPTSSA was added
gene: SPTSSA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTSSA was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SPTSSA were set to 36718090
Phenotypes for gene: SPTSSA were set to complex hereditary spastic paraplegia, MONDO:0015150
Review for gene: SPTSSA was set to AMBER
Added comment: Three unrelated individuals with common neurological features of developmental delay, progressive motor impairment, progressive lower extremity spasticity, and epileptiform activity or seizures. Other additional features varied.

Two of the individuals had the same de-novo missense, Thr51Ile, while the third was homozygous for a late truncating variant, Gln58AlafsTer10. The patient with the hom variant was described as less severe.

Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in flies, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA.

The de-novo missense were shown to impact regulation more than the hom truncation, while the truncated region was shown to previously to be important for ORMDL regulation.

Mice with a hom KO of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration.
Sources: Literature
Mendeliome v1.647 MIR145 Zornitza Stark Marked gene: MIR145 as ready
Mendeliome v1.647 MIR145 Zornitza Stark Gene: mir145 has been classified as Red List (Low Evidence).
Mendeliome v1.647 MIR145 Zornitza Stark Classified gene: MIR145 as Red List (low evidence)
Mendeliome v1.647 MIR145 Zornitza Stark Gene: mir145 has been classified as Red List (Low Evidence).
Ocular and Oculocutaneous Albinism v1.8 TPCN2 Seb Lunke Marked gene: TPCN2 as ready
Ocular and Oculocutaneous Albinism v1.8 TPCN2 Seb Lunke Gene: tpcn2 has been classified as Amber List (Moderate Evidence).
Ocular and Oculocutaneous Albinism v1.8 TPCN2 Seb Lunke Classified gene: TPCN2 as Amber List (moderate evidence)
Ocular and Oculocutaneous Albinism v1.8 TPCN2 Seb Lunke Gene: tpcn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.646 TRU-TCA1-1 Zornitza Stark Marked gene: TRU-TCA1-1 as ready
Mendeliome v1.646 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.646 TRU-TCA1-1 Zornitza Stark Phenotypes for gene: TRU-TCA1-1 were changed from Hyperthyroidism MONDO:0004425 to Inherited thyroid metabolism disease, MONDO:0045046, TRU-TCA1-1 related
Genetic Epilepsy v0.1832 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Genetic Epilepsy v0.1832 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Mendeliome v1.645 TRU-TCA1-1 Zornitza Stark Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Mendeliome v1.645 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Congenital Disorders of Glycosylation v1.33 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Congenital Disorders of Glycosylation v1.33 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Mendeliome v1.644 TRU-TCA1-1 Zornitza Stark Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Mendeliome v1.644 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.644 C1GALT1C1 Ain Roesley Phenotypes for gene: C1GALT1C1 were changed from Tn polyagglutination syndrome, somatic MIM#300622 to Tn polyagglutination syndrome, somatic MIM#300622; atypical haemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Genetic Epilepsy v0.1831 CAMLG Seb Lunke Marked gene: CAMLG as ready
Genetic Epilepsy v0.1831 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Congenital Disorders of Glycosylation v1.32 CAMLG Seb Lunke Marked gene: CAMLG as ready
Congenital Disorders of Glycosylation v1.32 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Mendeliome v1.643 C1GALT1C1 Ain Roesley Publications for gene: C1GALT1C1 were set to 18537974; 16251947
Genetic Epilepsy v0.1831 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Genetic Epilepsy v0.1831 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Congenital Disorders of Glycosylation v1.32 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Congenital Disorders of Glycosylation v1.32 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Arthrogryposis v0.359 CAMLG Seb Lunke Marked gene: CAMLG as ready
Arthrogryposis v0.359 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Hyperthyroidism v0.23 TRU-TCA1-1 Zornitza Stark Marked gene: TRU-TCA1-1 as ready
Hyperthyroidism v0.23 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Hyperthyroidism v0.23 TRU-TCA1-1 Zornitza Stark Phenotypes for gene: TRU-TCA1-1 were changed from Hyperthyroidism MONDO:0004425 to Inherited thyroid metabolism disease, MONDO:0045046, TRU-TCA1-1 related
Mendeliome v1.642 CAMLG Seb Lunke Marked gene: CAMLG as ready
Mendeliome v1.642 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Mendeliome v1.642 C1GALT1C1 Ain Roesley edited their review of gene: C1GALT1C1: Added comment: Red association for aHUS

1x male with de novo p.(Thr89Ile) which is absent in gnomAD v2 and v3 and has very high conservation; Changed publications: 18537974, 16251947, 36599939; Changed phenotypes: Tn polyagglutination syndrome, somatic MIM#300622, atypical haemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Mendeliome v1.642 CAMLG Seb Lunke Phenotypes for gene: CAMLG were changed from Congenital disorder of glycosylation type IIz, 620201 to Congenital disorder of glycosylation type IIz, OMIM# 620201
Arthrogryposis v0.359 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Arthrogryposis v0.359 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Atypical Haemolytic Uraemic Syndrome_MPGN v0.49 C1GALT1C1 Ain Roesley edited their review of gene: C1GALT1C1: Changed phenotypes: atypical haemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Atypical Haemolytic Uraemic Syndrome_MPGN v0.49 C1GALT1C1 Ain Roesley Marked gene: C1GALT1C1 as ready
Atypical Haemolytic Uraemic Syndrome_MPGN v0.49 C1GALT1C1 Ain Roesley Gene: c1galt1c1 has been classified as Red List (Low Evidence).
Mendeliome v1.641 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Mendeliome v1.641 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Hyperthyroidism v0.22 TRU-TCA1-1 Zornitza Stark Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Hyperthyroidism v0.22 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.641 SPRY1 Elena Savva Phenotypes for gene: SPRY1 were changed from to Craniosynostosis, SPRY1-related, MONDO:0015469
Craniosynostosis v1.47 SPRY1 Elena Savva Phenotypes for gene: SPRY1 were changed from Craniosynostosis, SPRY1-related, MONDO:0015469 to Craniosynostosis, SPRY1-related, MONDO:0015469
Atypical Haemolytic Uraemic Syndrome_MPGN v0.49 C1GALT1C1 Ain Roesley gene: C1GALT1C1 was added
gene: C1GALT1C1 was added to Atypical Haemolytic Uraemic Syndrome_MPGN. Sources: Literature
Mode of inheritance for gene: C1GALT1C1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: C1GALT1C1 were set to 36599939
Phenotypes for gene: C1GALT1C1 were set to atypical hemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Review for gene: C1GALT1C1 was set to RED
gene: C1GALT1C1 was marked as current diagnostic
Added comment: 1x male with de novo p.(Thr89Ile) which is absent in gnomAD v2 and v3 and has very high conservation
Sources: Literature
Mendeliome v1.640 SPRY1 Elena Savva Publications for gene: SPRY1 were set to
Gastrointestinal neuromuscular disease v1.19 MIR145 Lucy Spencer gene: MIR145 was added
gene: MIR145 was added to Gastrointestinal neuromuscular disease. Sources: Literature
Mode of inheritance for gene: MIR145 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MIR145 were set to 36649075
Phenotypes for gene: MIR145 were set to multisystemic smooth muscle dysfunction syndrome (MONDO:0013452)
Review for gene: MIR145 was set to RED
Added comment: PMID: 36649075- a patient whose fetal ultrasound revealed polyhydramnios, enlarged abdomenand bladder, and prune belly syndrome. During infancy/childhood profound gastrointestinal dysmotility, cerebrovascular disease, and multiple strokes. Described as a multisystemic smooth muscle dysfunction syndrome. Patient was found to have a de novo SNP in MIR145 NR_029686.1:n.18C>A. The MIR145transcript is processed into two microRNAs, with the variant position at nucleotide 3 of miR-145-5p.

Transfection of an siRNA against mutant miR145-5p induced a notable decrease in the expression of several cytoskeletal proteins including transgelin, calponin, and importantly, smooth muscle actin. Hybridization analysis and miR RNA-seq demonstrated a decrease in expression of miR145-5p in the presence of mutant miR145-5p. RNA-seq showed that the differentially expressed genes were substantially different between patient and control fibroblasts.
Sources: Literature
Mendeliome v1.639 SPRY1 Elena Savva Mode of inheritance for gene: SPRY1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.638 SPRY1 Elena Savva Classified gene: SPRY1 as Amber List (moderate evidence)
Mendeliome v1.638 SPRY1 Elena Savva Gene: spry1 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.47 SPRY1 Elena Savva Classified gene: SPRY1 as Amber List (moderate evidence)
Craniosynostosis v1.47 SPRY1 Elena Savva Gene: spry1 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.190 CCDC84 Zornitza Stark Marked gene: CCDC84 as ready
Microcephaly v1.190 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.190 CCDC84 Zornitza Stark Classified gene: CCDC84 as Amber List (moderate evidence)
Microcephaly v1.190 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.47 SPRY1 Elena Savva Phenotypes for gene: SPRY1 were changed from raniosynostosis MONDO:0015469 to Craniosynostosis, SPRY1-related, MONDO:0015469
Mendeliome v1.637 SPRY1 Elena Savva Classified gene: SPRY1 as Amber List (moderate evidence)
Mendeliome v1.637 SPRY1 Elena Savva Gene: spry1 has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia - paediatric v1.57 SPTSSA Seb Lunke Marked gene: SPTSSA as ready
Hereditary Spastic Paraplegia - paediatric v1.57 SPTSSA Seb Lunke Gene: sptssa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.636 CCDC84 Zornitza Stark Marked gene: CCDC84 as ready
Mendeliome v1.636 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.47 SPRY1 Elena Savva Classified gene: SPRY1 as Amber List (moderate evidence)
Craniosynostosis v1.47 SPRY1 Elena Savva Gene: spry1 has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia - paediatric v1.57 SPTSSA Seb Lunke Classified gene: SPTSSA as Amber List (moderate evidence)
Hereditary Spastic Paraplegia - paediatric v1.57 SPTSSA Seb Lunke Gene: sptssa has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.46 SPRY1 Elena Savva Marked gene: SPRY1 as ready
Craniosynostosis v1.46 SPRY1 Elena Savva Gene: spry1 has been classified as Red List (Low Evidence).
Mendeliome v1.636 CCDC84 Zornitza Stark Classified gene: CCDC84 as Amber List (moderate evidence)
Mendeliome v1.636 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.635 SPRY1 Elena Savva reviewed gene: SPRY1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36543535; Phenotypes: Craniosynostosis, SPRY1-related, MONDO:0015469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Marked gene: CCDC84 as ready
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Classified gene: CCDC84 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.46 SPRY1 Elena Savva gene: SPRY1 was added
gene: SPRY1 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: SPRY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRY1 were set to 36543535
Phenotypes for gene: SPRY1 were set to raniosynostosis MONDO:0015469
Review for gene: SPRY1 was set to AMBER
Added comment: no homozygous PTCs in gnomAD

PMID: 36543535:
- Hom null mutant mice display kidney/urinary tract abnormalities and altered size of the skull, het mice were normal
- 1 hom proband (3' NMD escape PTC) with sagittal craniosynostosis
- Functional studies proved NMD escape, but loss of full length protein
Sources: Literature
Mendeliome v1.635 TPCN2 Paul De Fazio reviewed gene: TPCN2: Rating: AMBER; Mode of pathogenicity: Other; Publications: 36641477; Phenotypes: Hypopigmentation of the skin, TPCN2-related MONDO:0019290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.635 MIR145 Lucy Spencer gene: MIR145 was added
gene: MIR145 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIR145 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MIR145 were set to 36649075
Phenotypes for gene: MIR145 were set to multisystemic smooth muscle dysfunction syndrome (MONDO:0013452), MIR145-related
Review for gene: MIR145 was set to RED
Added comment: PMID: 36649075- a patient whose fetal ultrasound revealed polyhydramnios, enlarged abdomenand bladder, and prune belly syndrome. During infancy/childhood profound gastrointestinal dysmotility, cerebrovascular disease, and multiple strokes. Described as a multisystemic smooth muscle dysfunction syndrome. Patient was found to have a de novo SNP in MIR145 NR_029686.1:n.18C>A. The MIR145transcript is processed into two microRNAs, with the variant position at nucleotide 3 of miR-145-5p.

Transfection of an siRNA against mutant miR145-5p induced a notable decrease in the expression of several cytoskeletal proteins including transgelin, calponin, and importantly, smooth muscle actin. Hybridization analysis and miR RNA-seq demonstrated a decrease in expression of miR145-5p in the presence of mutant miR145-5p. RNA-seq showed that the differentially expressed genes were substantially different between patient and control fibroblasts.
Sources: Literature
Ataxia - paediatric v1.6 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Hereditary Spastic Paraplegia - paediatric v1.56 SPTSSA Seb Lunke gene: SPTSSA was added
gene: SPTSSA was added to Hereditary Spastic Paraplegia - paediatric. Sources: Literature
Mode of inheritance for gene: SPTSSA was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SPTSSA were set to 36718090
Phenotypes for gene: SPTSSA were set to complex hereditary spastic paraplegia, MONDO:0015150
Review for gene: SPTSSA was set to GREEN
Added comment: Three unrelated individuals with common neurological features of developmental delay, progressive motor impairment, progressive lower extremity spasticity, and epileptiform activity or seizures. Other additional features varied.

Two of the individuals had the same de-novo missense, Thr51Ile, while the third was homozygous for a late truncating variant, Gln58AlafsTer10. The patient with the hom variant was described as less severe.

Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in flies, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA.

The de-novo missense were shown to impact regulation more than the hom truncation, while the truncated region was shown to previously to be important for ORMDL regulation.

Mice with a hom KO of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration.
Sources: Literature
Ataxia - paediatric v1.5 TTI1 Zornitza Stark Mode of inheritance for gene: TTI1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Ataxia - paediatric v1.4 TTI1 Zornitza Stark Classified gene: TTI1 as Green List (high evidence)
Ataxia - paediatric v1.4 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Mendeliome v1.635 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Congenital Disorders of Glycosylation v1.31 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Congenital Disorders of Glycosylation. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to PMID: 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, OMIM #: 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Ocular and Oculocutaneous Albinism v1.7 TPCN2 Paul De Fazio edited their review of gene: TPCN2: Changed phenotypes: Hypopigmentation of the skin, TPCN2-related MONDO:0019290
Mendeliome v1.634 TTI1 Zornitza Stark Classified gene: TTI1 as Green List (high evidence)
Mendeliome v1.634 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Microcephaly v1.189 TTI1 Zornitza Stark Marked gene: TTI1 as ready
Microcephaly v1.189 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Microcephaly v1.189 TTI1 Zornitza Stark Classified gene: TTI1 as Green List (high evidence)
Microcephaly v1.189 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5162 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from Neurodevelopmental disorder, MONDO:0700092, TTI1-related to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Ocular and Oculocutaneous Albinism v1.7 TPCN2 Paul De Fazio gene: TPCN2 was added
gene: TPCN2 was added to Ocular and Oculocutaneous Albinism. Sources: Literature
Mode of inheritance for gene: TPCN2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TPCN2 were set to 36641477
Phenotypes for gene: TPCN2 were set to Hypopigmentation of the skin MONDO:0019290
Mode of pathogenicity for gene: TPCN2 was set to Other
Review for gene: TPCN2 was set to AMBER
gene: TPCN2 was marked as current diagnostic
Added comment: A de novo variant in TPCN2, R210C, was identified in a girl who exhibited white skin, blonde hair that darkened to brown with age, no apparent nystagmus and photophobia, and normal vision acuity. Color fundus photography and optical coherence tomography (OCT) showed normal and well-developed macula and fovea. The variant has 1 het in gnomad.

Mice harbouring the homologous variant recapitulate the phenotype. Functional testing indicates the variant has a gain of function effect.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5162 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Intellectual disability syndromic and non-syndromic v0.5161 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5161 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5162 OGDH Zornitza Stark Marked gene: OGDH as ready
Intellectual disability syndromic and non-syndromic v0.5162 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5162 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5162 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5161 TTI1 Zornitza Stark Classified gene: TTI1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5161 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5160 FICD Elena Savva Marked gene: FICD as ready
Intellectual disability syndromic and non-syndromic v0.5160 FICD Elena Savva Gene: ficd has been classified as Red List (Low Evidence).
Monogenic Diabetes v0.35 FICD Elena Savva Marked gene: FICD as ready
Monogenic Diabetes v0.35 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5160 FICD Elena Savva gene: FICD was added
gene: FICD was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36704923
Phenotypes for gene: FICD were set to Neurodevelopmental disorder, FICD-related (MONDO#0700092)
Review for gene: FICD was set to AMBER
Added comment: PMID: 36704923:
- five individuals (3 families) w/ infancy onset diabetes mellitus (5/5) and severe neurodevelopmental delay (4/5)
- all homozygous for p.R371S
- variant expression in E. coli showed loss of affinity, deregulates BiP-AMP and affects secretion
Sources: Literature
Mendeliome v1.633 PCK2 Ain Roesley Phenotypes for gene: PCK2 were changed from PEPCK deficiency, mitochondrial - MIM#261650 to PEPCK deficiency, mitochondrial - MIM#261650; peripheral neuropathy (MONDO#0005244), PCK2-related
Intellectual disability syndromic and non-syndromic v0.5160 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5160 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Mendeliome v1.632 PCK2 Ain Roesley reviewed gene: PCK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: peripheral neuropathy (MONDO#0005244), PCK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.5159 OGDH Zornitza Stark gene: OGDH was added
gene: OGDH was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: OGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDH were set to 36520152; 32383294
Phenotypes for gene: OGDH were set to Oxoglutarate dehydrogenase deficiency, MIM# 203740
Review for gene: OGDH was set to GREEN
Added comment: 6 individuals reported with bi-allelic variants in this gene and DD.
Sources: Literature
Arthrogryposis v0.358 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, OMIM #: 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Monogenic Diabetes v0.35 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Monogenic Diabetes v0.35 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Monogenic Diabetes v0.34 FICD Elena Savva gene: FICD was added
gene: FICD was added to Monogenic Diabetes. Sources: Literature
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36704923; 36136088
Phenotypes for gene: FICD were set to Monogenic diabetes, MONDO:0015967, FICD-related
Review for gene: FICD was set to AMBER
Added comment: PMID: 36704923:
- five individuals (3 families) w/ infancy onset diabetes mellitus (5/5) and severe neurodevelopmental delay (4/5)
- all homozygous for p.R371S
- variant expression in E. coli showed loss of affinity, deregulates BiP-AMP and affects secretion

PMID: 36136088:
- 1/5 with diabetes mellitus, affect sibling has no diabetes
Sources: Literature
Genetic Epilepsy v0.1830 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, OMIM #: 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Mitochondrial disease v0.854 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Mitochondrial disease v0.854 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Mitochondrial disease v0.853 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Mitochondrial disease v0.853 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Mendeliome v1.632 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to PMID: 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Mendeliome v1.632 OGDH Zornitza Stark Publications for gene: OGDH were set to 32383294
Mendeliome v1.631 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Mendeliome v1.631 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Ataxia - paediatric v1.3 TTI1 Ee Ming Wong reviewed gene: TTI1: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI:https://doi.org/10.1016/j.ajhg.2023.01.006; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TTI1-related to; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.630 HTR2C Zornitza Stark Marked gene: HTR2C as ready
Mendeliome v1.630 HTR2C Zornitza Stark Gene: htr2c has been classified as Green List (High Evidence).
Mendeliome v1.630 TRU-TCA1-1 Paul De Fazio gene: TRU-TCA1-1 was added
gene: TRU-TCA1-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRU-TCA1-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRU-TCA1-1 were set to 26854926; 34956927
Phenotypes for gene: TRU-TCA1-1 were set to Hyperthyroidism MONDO:0004425
Review for gene: TRU-TCA1-1 was set to AMBER
gene: TRU-TCA1-1 was marked as current diagnostic
Added comment: PMID 26854926: male 8 year old proband investigated for abdominal pain, fatigue, muscle weakness, and thyroid dysfunction (raised T4, normal T3, raised reverse T3) suggestive of impaired deiodinase activity in combination with low plasma selenium levels. Homozygosity mapping led to identification of a a single nucleotide change, C65G, in TRU-TCA1-1, a tRNA in the selenocysteine incorporation pathway. This mutation resulted in reduction in expression of stress-related selenoproteins. A methylribosylation defect at uridine 34 of mutant tRNA observed in patient cells was restored by cellular complementation with normal tRNA.

PMID 34956927: a 10 year old originally investigated for Hashimoto's disease was found to be homozygous for the same C65G variant identified in the previous paper, inherited from the father in what was concluded to be paternal isodisomy.
Sources: Literature
Mendeliome v1.630 HTR2C Zornitza Stark Classified gene: HTR2C as Green List (high evidence)
Mendeliome v1.630 HTR2C Zornitza Stark Gene: htr2c has been classified as Green List (High Evidence).
Mendeliome v1.629 HTR2C Zornitza Stark gene: HTR2C was added
gene: HTR2C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HTR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HTR2C were set to 36536256
Phenotypes for gene: HTR2C were set to Obesity disorder, MONDO:0011122, HTR2C-related
Review for gene: HTR2C was set to GREEN
Added comment: Exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Obesity was severe, childhood-onset. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity.
Sources: Literature
Hyperthyroidism v0.21 TRU-TCA1-1 Paul De Fazio gene: TRU-TCA1-1 was added
gene: TRU-TCA1-1 was added to Hyperthyroidism. Sources: Literature
Mode of inheritance for gene: TRU-TCA1-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRU-TCA1-1 were set to 26854926; 34956927
Phenotypes for gene: TRU-TCA1-1 were set to Hyperthyroidism MONDO:0004425
Review for gene: TRU-TCA1-1 was set to AMBER
gene: TRU-TCA1-1 was marked as current diagnostic
Added comment: PMID 26854926: male 8 year old proband investigated for abdominal pain, fatigue, muscle weakness, and thyroid dysfunction (raised T4, normal T3, raised reverse T3) suggestive of impaired deiodinase activity in combination with low plasma selenium levels. Homozygosity mapping led to identification of a a single nucleotide change, C65G, in TRU-TCA1-1, a tRNA in the selenocysteine incorporation pathway. This mutation resulted in reduction in expression of stress-related selenoproteins. A methylribosylation defect at uridine 34 of mutant tRNA observed in patient cells was restored by cellular complementation with normal tRNA.

PMID 34956927: a 10 year old originally investigated for Hashimoto's disease was found to be homozygous for the same C65G variant identified in the previous paper, inherited from the father in what was concluded to be paternal isodisomy.
Sources: Literature
Mendeliome v1.628 TTI1 Ee Ming Wong reviewed gene: TTI1: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI:https://doi.org/10.1016/j.ajhg.2023.01.006; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TTI1-related to; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe early-onset obesity v1.8 HTR2C Zornitza Stark Marked gene: HTR2C as ready
Severe early-onset obesity v1.8 HTR2C Zornitza Stark Gene: htr2c has been classified as Green List (High Evidence).
Severe early-onset obesity v1.8 HTR2C Zornitza Stark Classified gene: HTR2C as Green List (high evidence)
Severe early-onset obesity v1.8 HTR2C Zornitza Stark Gene: htr2c has been classified as Green List (High Evidence).
Severe early-onset obesity v1.7 HTR2C Zornitza Stark gene: HTR2C was added
gene: HTR2C was added to Severe early-onset obesity. Sources: Literature
Mode of inheritance for gene: HTR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HTR2C were set to 36536256
Phenotypes for gene: HTR2C were set to Obesity disorder, MONDO:0011122, HTR2C-related
Review for gene: HTR2C was set to GREEN
Added comment: Exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Obesity was severe, childhood-onset.
Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity.
Sources: Literature
Mendeliome v1.628 CCDC84 Lucy Spencer gene: CCDC84 was added
gene: CCDC84 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC84 were set to 34009673
Phenotypes for gene: CCDC84 were set to Mosaic variegated aneuploidy syndrome 4 (MIM#620153)
Review for gene: CCDC84 was set to AMBER
Added comment: PMID: 34009673- patients with constitutional mosaic aneuploidy were found to have biallelic mutations in CENATAC(CCDC84). 2 adult siblings with mosaic aneuploidies, microcephaly, dev delay, and maculopathy. Both chet for a missense and a splice site deletion- but the paper days these both result in the creation of a novel splice site that leads to frameshifts and loss of the c-terminal 64 amino acids.

Gene is shown to be part of a spliceosome. CENATAC depletion or expression of disease mutants resulted in retention of introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulation, and caused chromosome segregation errors.

Functional analysis in CENATAC-depleted HeLa cells demonstrated chromosome congression defects and subsequent mitotic arrest, which could be fully rescued by wildtype but not mutant CENATAC. Expression of the MVA-associated mutants exacerbated the phenotype, suggesting that the mutant proteins dominantly repress the function of any residual wildtype protein.
Sources: Literature
Microcephaly v1.188 CCDC84 Lucy Spencer gene: CCDC84 was added
gene: CCDC84 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: CCDC84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC84 were set to 34009673
Phenotypes for gene: CCDC84 were set to Mosaic variegated aneuploidy syndrome 4 (MIM#620153)
Review for gene: CCDC84 was set to AMBER
Added comment: PMID: 34009673- patients with constitutional mosaic aneuploidy were found to have biallelic mutations in CENATAC(CCDC84). 2 adult siblings with mosaic aneuploidies, microcephaly, dev delay, and maculopathy. Both chet for a missense and a splice site deletion- but the paper days these both result in the creation of a novel splice site that leads to frameshifts and loss of the c-terminal 64 amino acids.

Gene is shown to be part of a spliceosome. CENATAC depletion or expression of disease mutants resulted in retention of introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulation, and caused chromosome segregation errors.

Functional analysis in CENATAC-depleted HeLa cells demonstrated chromosome congression defects and subsequent mitotic arrest, which could be fully rescued by wildtype but not mutant CENATAC. Expression of the MVA-associated mutants exacerbated the phenotype, suggesting that the mutant proteins dominantly repress the function of any residual wildtype protein.
Sources: Literature
Microcephaly v1.188 TTI1 Ee Ming Wong gene: TTI1 was added
gene: TTI1 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: TTI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTI1 were set to DOI:https://doi.org/10.1016/j.ajhg.2023.01.006
Phenotypes for gene: TTI1 were set to Neurodevelopmental disorder, MONDO:0700092, TTI1-related to
Review for gene: TTI1 was set to GREEN
gene: TTI1 was marked as current diagnostic
Added comment: - Eleven individuals from nine unrelated families with biallelic variants in TTI1 (10x missense, 2x canonical splice, 2x nonsense and 1x frameshift)
- All present with ID, and most with microcephaly, short stature, and a movement disorder
- Missense mutant constructs transfected into HEK293T cells demonstrated impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5158 CCDC84 Lucy Spencer gene: CCDC84 was added
gene: CCDC84 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CCDC84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC84 were set to 34009673
Phenotypes for gene: CCDC84 were set to Mosaic variegated aneuploidy syndrome 4 (MIM#620153)
Review for gene: CCDC84 was set to AMBER
Added comment: PMID: 34009673- patients with constitutional mosaic aneuploidy were found to have biallelic mutations in CENATAC(CCDC84). 2 adult siblings with mosaic aneuploidies, microcephaly, dev delay, and maculopathy. Both chet for a missense and a splice site deletion- but the paper days these both result in the creation of a novel splice site that leads to frameshifts and loss of the c-terminal 64 amino acids.

Gene is shown to be part of a spliceosome. CENATAC depletion or expression of disease mutants resulted in retention of introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulation, and caused chromosome segregation errors.

Functional analysis in CENATAC-depleted HeLa cells demonstrated chromosome congression defects and subsequent mitotic arrest, which could be fully rescued by wildtype but not mutant CENATAC. Expression of the MVA-associated mutants exacerbated the phenotype, suggesting that the mutant proteins dominantly repress the function of any residual wildtype protein.
Sources: Literature
Mendeliome v1.628 THBS1 Zornitza Stark Marked gene: THBS1 as ready
Mendeliome v1.628 THBS1 Zornitza Stark Gene: thbs1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5158 TTI1 Ee Ming Wong reviewed gene: TTI1: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI:https://doi.org/10.1016/j.ajhg.2023.01.006; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TTI1-related to; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.628 THBS1 Zornitza Stark Classified gene: THBS1 as Green List (high evidence)
Mendeliome v1.628 THBS1 Zornitza Stark Gene: thbs1 has been classified as Green List (High Evidence).
Mitochondrial disease v0.852 OGDH Sarah Pantaleo reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36520152; Phenotypes: Oxoglutarate dehydrogenase deficiency, MIM# 203740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.627 OGDH Sarah Pantaleo reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36520152; Phenotypes: Oxoglutarate dehydrogenase deficiency, MIM# 203740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia - adult onset v1.2 NPTX1 Ain Roesley Marked gene: NPTX1 as ready
Ataxia - adult onset v1.2 NPTX1 Ain Roesley Gene: nptx1 has been classified as Green List (High Evidence).
Ataxia - adult onset v1.2 NPTX1 Ain Roesley Classified gene: NPTX1 as Green List (high evidence)
Ataxia - adult onset v1.2 NPTX1 Ain Roesley Gene: nptx1 has been classified as Green List (High Evidence).
Mendeliome v1.627 NPTX1 Ain Roesley Marked gene: NPTX1 as ready
Mendeliome v1.627 NPTX1 Ain Roesley Gene: nptx1 has been classified as Green List (High Evidence).
Mendeliome v1.627 NPTX1 Ain Roesley Classified gene: NPTX1 as Green List (high evidence)
Mendeliome v1.627 NPTX1 Ain Roesley Gene: nptx1 has been classified as Green List (High Evidence).
Ataxia - adult onset v1.1 NPTX1 Ain Roesley gene: NPTX1 was added
gene: NPTX1 was added to Ataxia - adult onset. Sources: Literature
Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPTX1 were set to 34788392; 35288776; 35285082; 35560436
Phenotypes for gene: NPTX1 were set to cerebellar ataxia MONDO#0000437, NPTX1-related
Review for gene: NPTX1 was set to GREEN
gene: NPTX1 was marked as current diagnostic
Added comment: PMID:34788392
5 families with multigenerational segregations - late onset ataxia
4 families with p.(Gly389Arg) + 1x p.(Glu327Gly)
functional studies done

Note: case report of a family member published elsewhere (PMID:35288776)

PMID:35285082
1x de novo in a male with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome
p.(Arg143Leu)

PMID:35560436
1x de novo in a female with early-onset ataxia and cerebellar atrophy since infancy
p.(Gln370Arg)
Sources: Literature
Mendeliome v1.626 THBS1 Zornitza Stark gene: THBS1 was added
gene: THBS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THBS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THBS1 were set to 36453543
Phenotypes for gene: THBS1 were set to Congenital glaucoma MONDO:0020366, THBS1-related
Review for gene: THBS1 was set to GREEN
Added comment: Missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma.

Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure.
Sources: Literature
Mendeliome v1.625 NPTX1 Ain Roesley gene: NPTX1 was added
gene: NPTX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPTX1 were set to 34788392; 35288776; 35285082; 35560436
Phenotypes for gene: NPTX1 were set to cerebellar ataxia MONDO#0000437, NPTX1-related
Review for gene: NPTX1 was set to GREEN
gene: NPTX1 was marked as current diagnostic
Added comment: PMID:34788392
5 families with multigenerational segregations - late onset ataxia
4 families with p.(Gly389Arg) + 1x p.(Glu327Gly)
functional studies done

Note: case report of a family member published elsewhere (PMID:35288776)

PMID:35285082
1x de novo in a male with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome
p.(Arg143Leu)

PMID:35560436
1x de novo in a female with early-onset ataxia and cerebellar atrophy since infancy
p.(Gln370Arg)
Sources: Literature
Glaucoma congenital v1.8 THBS1 Zornitza Stark Marked gene: THBS1 as ready
Glaucoma congenital v1.8 THBS1 Zornitza Stark Gene: thbs1 has been classified as Green List (High Evidence).
Glaucoma congenital v1.8 THBS1 Zornitza Stark Classified gene: THBS1 as Green List (high evidence)
Glaucoma congenital v1.8 THBS1 Zornitza Stark Gene: thbs1 has been classified as Green List (High Evidence).
Glaucoma congenital v1.7 THBS1 Zornitza Stark gene: THBS1 was added
gene: THBS1 was added to Glaucoma congenital. Sources: Literature
Mode of inheritance for gene: THBS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THBS1 were set to 36453543
Phenotypes for gene: THBS1 were set to Congenital glaucoma MONDO:0020366, THBS1-related
Review for gene: THBS1 was set to GREEN
Added comment: Missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma.

Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure.
Sources: Literature
Mendeliome v1.624 GET4 Elena Savva Marked gene: GET4 as ready
Mendeliome v1.624 GET4 Elena Savva Gene: get4 has been classified as Red List (Low Evidence).
Mendeliome v1.624 GET4 Elena Savva gene: GET4 was added
gene: GET4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GET4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GET4 were set to 32395830
Phenotypes for gene: GET4 were set to ?Congenital disorder of glycosylation,, type IIy MIM#620200
Review for gene: GET4 was set to RED
Added comment: PMID: 32395830
- chet patient (missense x2), functionally shown to result in downregulation of three TRC proteins in patient cell lines.
- patient phenotype included ID, DD, seizures, dysmorphism and delayed bone age.
- functional studies on missense themselves not performed
Sources: Literature
Congenital Disorders of Glycosylation v1.31 GET4 Elena Savva Marked gene: GET4 as ready
Congenital Disorders of Glycosylation v1.31 GET4 Elena Savva Gene: get4 has been classified as Red List (Low Evidence).
Congenital Disorders of Glycosylation v1.31 GET4 Elena Savva gene: GET4 was added
gene: GET4 was added to Congenital Disorders of Glycosylation. Sources: Literature
Mode of inheritance for gene: GET4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GET4 were set to 32395830
Phenotypes for gene: GET4 were set to ?Congenital disorder of glycosylation,, type IIy MIM#620200
Review for gene: GET4 was set to RED
Added comment: PMID: 32395830
- chet patient (missense x2), functionally shown to result in downregulation of three TRC proteins in patient cell lines.
- patient phenotype included ID, DD, seizures, dysmorphism and delayed bone age.
- functional studies on missense themselves not performed
Sources: Literature
Pierre Robin Sequence v0.46 ARCN1 Zornitza Stark Marked gene: ARCN1 as ready
Pierre Robin Sequence v0.46 ARCN1 Zornitza Stark Gene: arcn1 has been classified as Green List (High Evidence).
Pierre Robin Sequence v0.46 ARCN1 Zornitza Stark Classified gene: ARCN1 as Green List (high evidence)
Pierre Robin Sequence v0.46 ARCN1 Zornitza Stark Gene: arcn1 has been classified as Green List (High Evidence).
Pierre Robin Sequence v0.45 ARCN1 Zornitza Stark gene: ARCN1 was added
gene: ARCN1 was added to Pierre Robin Sequence. Sources: Expert Review
Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARCN1 were set to 35300924
Phenotypes for gene: ARCN1 were set to Short stature-micrognathia syndrome, MIM# 617164
Review for gene: ARCN1 was set to GREEN
Added comment: Significant PRS requiring surgical management is a feature.
Sources: Expert Review
Clefting disorders v0.190 ARCN1 Zornitza Stark reviewed gene: ARCN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35300924; Phenotypes: Short stature-micrognathia syndrome, MIM# 617164; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Deafness_Isolated v1.40 USP48 Zornitza Stark Phenotypes for gene: USP48 were changed from Nonsyndromic genetic deafness, MONDO:0019497 to Deafness, autosomal dominant 85, MIM# 620227
Deafness_Isolated v1.39 USP48 Zornitza Stark edited their review of gene: USP48: Changed phenotypes: Deafness, autosomal dominant 85, MIM# 620227
Deafness_IsolatedAndComplex v1.156 USP48 Zornitza Stark Phenotypes for gene: USP48 were changed from Nonsyndromic genetic deafness, MONDO:0019497 to Deafness, autosomal dominant 85, MIM# 620227
Deafness_IsolatedAndComplex v1.155 USP48 Zornitza Stark edited their review of gene: USP48: Changed phenotypes: Deafness, autosomal dominant 85, MIM# 620227
Mendeliome v1.623 USP48 Zornitza Stark Phenotypes for gene: USP48 were changed from non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497 to Deafness, autosomal dominant 85, MIM# 620227
Mendeliome v1.622 USP48 Zornitza Stark edited their review of gene: USP48: Changed rating: GREEN; Changed phenotypes: Deafness, autosomal dominant 85, MIM# 620227; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary Spastic Paraplegia - paediatric v1.55 UCHL1 Zornitza Stark Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related to Spastic paraplegia 79A, autosomal dominant, MIM# 620221; Spastic paraplegia 79, autosomal recessive, 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related
Hereditary Spastic Paraplegia - paediatric v1.54 UCHL1 Zornitza Stark edited their review of gene: UCHL1: Changed phenotypes: Spastic paraplegia 79A, autosomal dominant, MIM# 620221, Spastic paraplegia 79, autosomal recessive, MIM#615491, Neurodegenerative disease, MONDO:0005559, UCHL1-related
Incidentalome v0.223 UCHL1 Zornitza Stark Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, MIM# 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related to Spastic paraplegia 79A, autosomal dominant, MIM# 620221; Spastic paraplegia 79, autosomal recessive, MIM# 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related
Incidentalome v0.222 UCHL1 Zornitza Stark edited their review of gene: UCHL1: Changed phenotypes: Spastic paraplegia 79A, autosomal dominant, MIM# 620221, Spastic paraplegia 79, autosomal recessive, MIM# 615491, MONDO:0014209, Neurodegenerative disease, MONDO:0005559, UCHL1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5158 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder, MONDO:0700092, NAE1-related to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Intellectual disability syndromic and non-syndromic v0.5157 NAE1 Zornitza Stark edited their review of gene: NAE1: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Regression v0.520 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210 to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Regression v0.520 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder, MONDO:0700092, NAE1-related to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Regression v0.519 NAE1 Zornitza Stark edited their review of gene: NAE1: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Mendeliome v1.622 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder, MONDO:0700092, NAE1-related to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Mendeliome v1.621 NAE1 Zornitza Stark edited their review of gene: NAE1: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Retinitis pigmentosa_Autosomal Dominant v0.55 SAG Zornitza Stark edited their review of gene: SAG: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinitis pigmentosa_Autosomal Dominant v0.55 SAG Zornitza Stark Mode of inheritance for gene: SAG was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinitis pigmentosa_Autosomal Dominant v0.54 SAG Zornitza Stark changed review comment from: Autosomal recessive, homozygous founder variant.; to: Multiple families with same variant: founder effect?
Congenital Diarrhoea v1.12 AGR2 Zornitza Stark Phenotypes for gene: AGR2 were changed from CF-like disorder to Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Congenital Diarrhoea v1.11 AGR2 Zornitza Stark edited their review of gene: AGR2: Changed phenotypes: Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Ciliary Dyskinesia v1.25 AGR2 Zornitza Stark Phenotypes for gene: AGR2 were changed from CF-like disorder to Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Ciliary Dyskinesia v1.24 AGR2 Zornitza Stark edited their review of gene: AGR2: Changed phenotypes: Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Mendeliome v1.621 AGR2 Zornitza Stark Phenotypes for gene: AGR2 were changed from CF-like disorder to Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Mendeliome v1.620 AGR2 Zornitza Stark edited their review of gene: AGR2: Changed phenotypes: Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Short QT syndrome v1.5 SLC4A3 Zornitza Stark Phenotypes for gene: SLC4A3 were changed from Short QT syndrome to Short QT syndrome 7, MIM#620231
Short QT syndrome v1.4 SLC4A3 Zornitza Stark edited their review of gene: SLC4A3: Changed phenotypes: Short QT syndrome 7, MIM#620231
Mendeliome v1.620 SLC4A3 Zornitza Stark Phenotypes for gene: SLC4A3 were changed from Short QT syndrome to Short QT syndrome 7, MIM#620231
Dystonia - complex v0.220 NUP54 Zornitza Stark Marked gene: NUP54 as ready
Dystonia - complex v0.220 NUP54 Zornitza Stark Gene: nup54 has been classified as Amber List (Moderate Evidence).
Dystonia - complex v0.220 NUP54 Zornitza Stark Classified gene: NUP54 as Amber List (moderate evidence)
Dystonia - complex v0.220 NUP54 Zornitza Stark Gene: nup54 has been classified as Amber List (Moderate Evidence).
Dystonia - complex v0.219 NUP54 Zornitza Stark gene: NUP54 was added
gene: NUP54 was added to Dystonia - complex. Sources: Literature
Mode of inheritance for gene: NUP54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP54 were set to 36333996
Phenotypes for gene: NUP54 were set to Striatonigral degeneration, MONDO:0003122, NUP54-related; Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia
Review for gene: NUP54 was set to AMBER
Added comment: From PMID: 36333996.; Harrer, P. et al. (2022) Ann Neurol. doi: 10.1002/ana.26544.

Three patients from unrelated families with dystonia and/or Leigh(-like) syndromes, with biallelic variants in NUP54, in the C-terminal protein region that interacts with NUP62. Onset was between 12 months and 5 years. All had progressive neurological deterioration with dystonia, ataxia, dysarthria, dysphagia, hypotonia.

Patient / Family A (consanguineous) was homozygous for c.1073T>G p.(Ile358Ser).

Patient / Family B was compound heterozygous for c.1073T>G p.(Ile358Ser) and c.1126A>G p.(Lys376Glu).

Patient / Family C was compound heterozygosity for c.1410_1412del p.(Gln471del) and two missense variants c.1414G>A, p.(Glu472Lys); c.1420C>T, p.(Leu474Phe)

The phenotypes were similar to those of NUP62 including early-onset dystonia with dysphagic choreoathetosis, and T2-hyperintense lesions in striatum.

Brain MRIs showed T2/FLAIR hyperintensities in the dorsal putamina.

Western blots showing reduced expression of NUP54 and its interaction partners NUP62/NUP58 in patient fibroblasts.
Sources: Literature
Mendeliome v1.619 SARS Zornitza Stark Phenotypes for gene: SARS were changed from neurodevelopmental disorder MONDO#070009, SARS1-related to neurodevelopmental disorder MONDO#070009, SARS1-related; Genetic peripheral neuropathy MONDO#0020127, SARS1-related
Mendeliome v1.618 SARS Zornitza Stark Publications for gene: SARS were set to 28236339; 34570399; 35790048; 36041817
Mendeliome v1.617 SARS Zornitza Stark Mode of inheritance for gene: SARS was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1859 TMEM43 Zornitza Stark Tag for review was removed from gene: TMEM43.
BabyScreen+ newborn screening v0.1859 LAMP2 Zornitza Stark Tag for review was removed from gene: LAMP2.
BabyScreen+ newborn screening v0.1859 LOX Zornitza Stark Tag for review was removed from gene: LOX.
BabyScreen+ newborn screening v0.1859 TBX1 Zornitza Stark Classified gene: TBX1 as Red List (low evidence)
BabyScreen+ newborn screening v0.1859 TBX1 Zornitza Stark Gene: tbx1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1858 TBX1 Zornitza Stark reviewed gene: TBX1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: DiGeorge syndrome MIM# 188400, Velocardiofacial syndrome MIM# 192430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1858 TBX1 Zornitza Stark Tag for review was removed from gene: TBX1.
BabyScreen+ newborn screening v0.1858 PRKG1 Zornitza Stark Classified gene: PRKG1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1858 PRKG1 Zornitza Stark Gene: prkg1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1857 PRKG1 Zornitza Stark Tag for review was removed from gene: PRKG1.
BabyScreen+ newborn screening v0.1857 PRKG1 Zornitza Stark edited their review of gene: PRKG1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1857 MYH11 Zornitza Stark Classified gene: MYH11 as Green List (high evidence)
BabyScreen+ newborn screening v0.1857 MYH11 Zornitza Stark Gene: myh11 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1856 MYH11 Zornitza Stark Tag for review was removed from gene: MYH11.
BabyScreen+ newborn screening v0.1856 MYH11 Zornitza Stark edited their review of gene: MYH11: Changed rating: GREEN
BabyScreen+ newborn screening v0.1856 LOX Zornitza Stark Classified gene: LOX as Green List (high evidence)
BabyScreen+ newborn screening v0.1856 LOX Zornitza Stark Gene: lox has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1855 LOX Zornitza Stark edited their review of gene: LOX: Changed rating: GREEN
BabyScreen+ newborn screening v0.1855 KCNQ1 Zornitza Stark Tag for review was removed from gene: KCNQ1.
BabyScreen+ newborn screening v0.1855 KCNQ1 Zornitza Stark Classified gene: KCNQ1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1855 KCNQ1 Zornitza Stark Gene: kcnq1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1854 KCNQ1 Zornitza Stark edited their review of gene: KCNQ1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1854 DSG2 Zornitza Stark Tag for review was removed from gene: DSG2.
BabyScreen+ newborn screening v0.1854 COL3A1 Zornitza Stark Tag for review was removed from gene: COL3A1.
BabyScreen+ newborn screening v0.1854 JUP Zornitza Stark Mode of inheritance for gene: JUP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1853 JUP Zornitza Stark Classified gene: JUP as Green List (high evidence)
BabyScreen+ newborn screening v0.1853 JUP Zornitza Stark Gene: jup has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1852 JUP Zornitza Stark Tag for review was removed from gene: JUP.
BabyScreen+ newborn screening v0.1852 JUP Zornitza Stark edited their review of gene: JUP: Added comment: Screen for bi-allelic disease as can be earlier onset, more severe.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1852 DSP Zornitza Stark Mode of inheritance for gene: DSP was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1851 DSP Zornitza Stark Classified gene: DSP as Green List (high evidence)
BabyScreen+ newborn screening v0.1851 DSP Zornitza Stark Gene: dsp has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1850 DSP Zornitza Stark Tag for review was removed from gene: DSP.
BabyScreen+ newborn screening v0.1850 DSP Zornitza Stark edited their review of gene: DSP: Added comment: Screen for bi-allelic disease as can be more severe, earlier onset.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1850 CALM3 Zornitza Stark Phenotypes for gene: CALM3 were changed from Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782 to Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782; Long QT syndrome 16, MIM#618782
BabyScreen+ newborn screening v0.1849 CALM3 Zornitza Stark edited their review of gene: CALM3: Added comment: Variants in this gene also cause Long QT syndrome, and other Long QT syndrome genes have been included in the panel.; Changed phenotypes: Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782, Long QT syndrome 16, MIM#618782
BabyScreen+ newborn screening v0.1849 CALM3 Zornitza Stark Tag for review was removed from gene: CALM3.
BabyScreen+ newborn screening v0.1849 CALM2 Zornitza Stark Tag for review was removed from gene: CALM2.
BabyScreen+ newborn screening v0.1849 LAMP2 Zornitza Stark Tag cardiac tag was added to gene: LAMP2.
BabyScreen+ newborn screening v0.1849 TRPM4 Zornitza Stark Tag cardiac tag was added to gene: TRPM4.
BabyScreen+ newborn screening v0.1849 TMEM43 Zornitza Stark changed review comment from: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes.

ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF).

Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years.

Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended.

Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation.

Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including:

• Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism
• Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected
• Electrocardiography
• Cardiovascular imaging.

Penetrance:
In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.; to: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes.

ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF).

Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years.

Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended.

Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation.

Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including:

• Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism
• Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected
• Electrocardiography
• Cardiovascular imaging.

Penetrance:
In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.

Note founder variant in Newfoundland.
BabyScreen+ newborn screening v0.1849 TMEM43 Zornitza Stark edited their review of gene: TMEM43: Changed rating: RED
BabyScreen+ newborn screening v0.1849 SCN5A Zornitza Stark Classified gene: SCN5A as Green List (high evidence)
BabyScreen+ newborn screening v0.1849 SCN5A Zornitza Stark Gene: scn5a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1848 SCN5A Zornitza Stark Tag for review was removed from gene: SCN5A.
BabyScreen+ newborn screening v0.1848 SCN5A Zornitza Stark edited their review of gene: SCN5A: Changed rating: GREEN
BabyScreen+ newborn screening v0.1848 KCNH2 Zornitza Stark Classified gene: KCNH2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1848 KCNH2 Zornitza Stark Gene: kcnh2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1847 KCNH2 Zornitza Stark Tag for review was removed from gene: KCNH2.
BabyScreen+ newborn screening v0.1847 KCNH2 Zornitza Stark edited their review of gene: KCNH2: Changed rating: GREEN
BabyScreen+ newborn screening v0.1847 DSC2 Zornitza Stark Tag for review was removed from gene: DSC2.
BabyScreen+ newborn screening v0.1847 CASQ2 Zornitza Stark Mode of inheritance for gene: CASQ2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1846 CASQ2 Zornitza Stark Classified gene: CASQ2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1846 CASQ2 Zornitza Stark Gene: casq2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1845 CASQ2 Zornitza Stark Tag for review was removed from gene: CASQ2.
BabyScreen+ newborn screening v0.1845 CASQ2 Zornitza Stark changed review comment from: Well established gene-disease association.

ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

For review.; to: Well established gene-disease association.

ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.
BabyScreen+ newborn screening v0.1845 CASQ2 Zornitza Stark edited their review of gene: CASQ2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1845 CASQ2 Zornitza Stark edited their review of gene: CASQ2: Changed rating: GREEN
BabyScreen+ newborn screening v0.1845 ACTA2 Zornitza Stark Classified gene: ACTA2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1845 ACTA2 Zornitza Stark Gene: acta2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1844 ACTA2 Zornitza Stark Tag for review was removed from gene: ACTA2.
BabyScreen+ newborn screening v0.1844 ACTA2 Zornitza Stark edited their review of gene: ACTA2: Changed rating: GREEN
BabyScreen+ newborn screening v0.1844 TRDN Zornitza Stark Tag for review was removed from gene: TRDN.
BabyScreen+ newborn screening v0.1844 TECRL Zornitza Stark Tag for review was removed from gene: TECRL.
BabyScreen+ newborn screening v0.1844 RYR2 Zornitza Stark Tag for review was removed from gene: RYR2.
BabyScreen+ newborn screening v0.1844 CALM1 Zornitza Stark Tag for review was removed from gene: CALM1.
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.13 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Oligodontia v0.29 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Prepair 1000+ v1.0 AIRE Zornitza Stark changed review comment from: Highly variable phenotype in terms of severity and age of onset. Manifestations of the condition are generally treatable.; to: Highly variable phenotype in terms of severity and age of onset. Manifestations of the condition are generally treatable.
Leukodystrophy - paediatric v0.282 HMBS Zornitza Stark Marked gene: HMBS as ready
Leukodystrophy - paediatric v0.282 HMBS Zornitza Stark Gene: hmbs has been classified as Green List (High Evidence).
Leukodystrophy - paediatric v0.282 HMBS Zornitza Stark Publications for gene: HMBS were set to 27558376
Leukodystrophy - paediatric v0.281 HMBS Zornitza Stark Phenotypes for gene: HMBS were changed from Acute intermittent porphyria-related leukoencephalopathy to Porphyria, acute intermittent, MIM#176000; Acute intermittent porphyria-related leukoencephalopathy
Leukodystrophy - paediatric v0.280 HMBS Zornitza Stark Classified gene: HMBS as Green List (high evidence)
Leukodystrophy - paediatric v0.280 HMBS Zornitza Stark Gene: hmbs has been classified as Green List (High Evidence).
Leukodystrophy - paediatric v0.279 HMBS Zornitza Stark reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27558376, 34089223; Phenotypes: Porphyria, acute intermittent, MIM#176000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Aminoacidopathy v1.1 PPM1K Suliman Khan reviewed gene: PPM1K: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36706222; Phenotypes: Maple syrup urine disease (MSUD); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.616 DRC1 Zornitza Stark Phenotypes for gene: DRC1 were changed from Ciliary dyskinesia, primary, 21, MIM# 615294; Male infertility to Ciliary dyskinesia, primary, 21, MIM# 615294; Spermatogenic failure 80, MIM# 620222
Mendeliome v1.615 DRC1 Zornitza Stark edited their review of gene: DRC1: Changed phenotypes: Ciliary dyskinesia, primary, 21, MIM# 615294, Spermatogenic failure 80, MIM# 620222
Regression v0.519 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia; abnormal gait; developmental delay; intellectual disability; autism; dysmorphic facial features to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Regression v0.518 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1830 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features. to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Genetic Epilepsy v0.1829 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.5157 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia; abnormal gait; developmental delay; intellectual disability; autism; dysmorphic facial features to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Intellectual disability syndromic and non-syndromic v0.5156 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.615 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features. to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Mendeliome v1.614 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
BabyScreen+ newborn screening v0.1844 CAD Zornitza Stark Marked gene: CAD as ready
BabyScreen+ newborn screening v0.1844 CAD Zornitza Stark Gene: cad has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1844 CAD Zornitza Stark Classified gene: CAD as Green List (high evidence)
BabyScreen+ newborn screening v0.1844 CAD Zornitza Stark Gene: cad has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1843 CAD Zornitza Stark gene: CAD was added
gene: CAD was added to gNBS. Sources: Expert list
treatable, metabolic tags were added to gene: CAD.
Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAD were set to 28007989
Phenotypes for gene: CAD were set to Developmental and epileptic encephalopathy 50, MIM# 616457
Review for gene: CAD was set to GREEN
Added comment: Developmental and epileptic encephalopathy-50 (DEE50) is an autosomal recessive progressive neurodegenerative neurometabolic disorder characterized by delayed psychomotor development, early-onset refractory seizures, severe developmental regression, and normocytic anemia. Onset is within the first months or years of life.

Affected children can have a favourable response to treatment with uridine, PMID 28007989
Sources: Expert list
BabyScreen+ newborn screening v0.1842 CA12 Zornitza Stark Marked gene: CA12 as ready
BabyScreen+ newborn screening v0.1842 CA12 Zornitza Stark Gene: ca12 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1842 CA12 Zornitza Stark Classified gene: CA12 as Green List (high evidence)
BabyScreen+ newborn screening v0.1842 CA12 Zornitza Stark Gene: ca12 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1841 CA12 Zornitza Stark gene: CA12 was added
gene: CA12 was added to gNBS. Sources: Expert Review
treatable, metabolic tags were added to gene: CA12.
Mode of inheritance for gene: CA12 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CA12 were set to Hyperchlorhidrosis, isolated MIM#143860
Review for gene: CA12 was set to GREEN
Added comment: Glu143Lys found in 4 Israeli Bedouin families. 2 other unrelated families reported with 1 missense (LoF demonstrated), 1 splice (aberrant splicing proven) and 1 fs (protein truncating, not NMD).

Excessive salt wasting in sweat can result in severe infantile hyponatraemic dehydration and hyperkalaemia.

Treatment: sodium chloride supplementation
Sources: Expert Review
BabyScreen+ newborn screening v0.1840 AICDA Zornitza Stark Marked gene: AICDA as ready
BabyScreen+ newborn screening v0.1840 AICDA Zornitza Stark Gene: aicda has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1840 AICDA Zornitza Stark Classified gene: AICDA as Green List (high evidence)
BabyScreen+ newborn screening v0.1840 AICDA Zornitza Stark Gene: aicda has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1839 AICDA Zornitza Stark gene: AICDA was added
gene: AICDA was added to gNBS. Sources: Expert Review
treatable, immunological tags were added to gene: AICDA.
Mode of inheritance for gene: AICDA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AICDA were set to Immunodeficiency with hyper-IgM, type 2, MIM# 605258
Review for gene: AICDA was set to GREEN
Added comment: Hyper-IgM syndrome type 2 (HIGM2) is a rare immunodeficiency characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE, resulting in a profound susceptibility to bacterial infections. Well established gene-disease association.

Severe, congenital disorder.

Treatment: immunoglobulin replacement therapy.

Confirmatory testing: antibody levels.
Sources: Expert Review
BabyScreen+ newborn screening v0.1838 AGPAT2 Zornitza Stark Marked gene: AGPAT2 as ready
BabyScreen+ newborn screening v0.1838 AGPAT2 Zornitza Stark Gene: agpat2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1838 AGPAT2 Zornitza Stark Classified gene: AGPAT2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1838 AGPAT2 Zornitza Stark Gene: agpat2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1837 AGPAT2 Zornitza Stark gene: AGPAT2 was added
gene: AGPAT2 was added to gNBS. Sources: Expert list
for review, treatable, endocrine tags were added to gene: AGPAT2.
Mode of inheritance for gene: AGPAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGPAT2 were set to 29704234
Phenotypes for gene: AGPAT2 were set to Lipodystrophy, congenital generalized, type 1, MIM# 608594
Review for gene: AGPAT2 was set to AMBER
Added comment: Established gene-disease association.

Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia.

Leptin replacement therapy (metreleptin) has been found to improve metabolic parameters in many patients with lipodystrophy. Metreleptin is approved in the United States as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy and has been submitted for approval elsewhere.

For review regarding availability and use of treatment locally.
Sources: Expert list
Craniosynostosis v1.45 ADAMTSL4 Zornitza Stark Phenotypes for gene: ADAMTSL4 were changed from Ectopia lentis et pupillae MIM#225200 to Ectopia lentis et pupillae MIM#225200; Craniosynostosis with ectopia lentis MONDO#0011347, ADAMTSL4-related
Craniosynostosis v1.44 ADAMTSL4 Zornitza Stark Publications for gene: ADAMTSL4 were set to 22871183; 20702823
Craniosynostosis v1.43 ADAMTSL4 Zornitza Stark Classified gene: ADAMTSL4 as Green List (high evidence)
Craniosynostosis v1.43 ADAMTSL4 Zornitza Stark Gene: adamtsl4 has been classified as Green List (High Evidence).
Prepair 1000+ v1.0 BRIP1 Himanshu Goel gene: BRIP1 was added
gene: BRIP1 was added to Prepair 1000+. Sources: Literature
Mode of inheritance for gene: BRIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRIP1 were set to 16116423
Phenotypes for gene: BRIP1 were set to Fanconi Anaemia
Penetrance for gene: BRIP1 were set to Complete
Mode of pathogenicity for gene: BRIP1 was set to Other
Review for gene: BRIP1 was set to GREEN
gene: BRIP1 was marked as current diagnostic
Added comment: Sources: Literature
Craniosynostosis v1.42 ADAMTSL4 Michelle Torres reviewed gene: ADAMTSL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35378950, 28642162; Phenotypes: Craniosynostosis with ectopia lentis MONDO#0011347, ADAMTSL4-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.614 LY96 Zornitza Stark Marked gene: LY96 as ready
Mendeliome v1.614 LY96 Zornitza Stark Gene: ly96 has been classified as Red List (Low Evidence).
Mendeliome v1.614 LY96 Zornitza Stark gene: LY96 was added
gene: LY96 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LY96 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LY96 were set to 36462957
Phenotypes for gene: LY96 were set to Inborn error of immunity, MONDO:0003778, LY96-related
Review for gene: LY96 was set to RED
Added comment: Single individual with infantile colitis associated with failure-to-thrive, bloody diarrhoea, and perianal abscesses since the age of 4 months. Later developed bronchiectasis and persistent pneumonia, which required lobectomy at the age of 6 years. Found to have homozygous inflame deletion. Brother with same deletion presented with recurrent otitis media and pneumonia but exhibited no signs of intestinal inflammation.
Sources: Expert Review
Inflammatory bowel disease v0.88 LY96 Zornitza Stark Marked gene: LY96 as ready
Inflammatory bowel disease v0.88 LY96 Zornitza Stark Gene: ly96 has been classified as Red List (Low Evidence).
Inflammatory bowel disease v0.88 LY96 Zornitza Stark Phenotypes for gene: LY96 were changed from Colitis to Inborn error of immunity, MONDO:0003778, LY96-related; Colitis
Inflammatory bowel disease v0.87 LY96 Zornitza Stark Classified gene: LY96 as Red List (low evidence)
Inflammatory bowel disease v0.87 LY96 Zornitza Stark Gene: ly96 has been classified as Red List (Low Evidence).
Inflammatory bowel disease v0.86 LY96 Zornitza Stark reviewed gene: LY96: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn error of immunity, MONDO:0003778, LY96-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cardiomyopathy_Paediatric v0.154 SLC22A5 Zornitza Stark Marked gene: SLC22A5 as ready
Cardiomyopathy_Paediatric v0.154 SLC22A5 Zornitza Stark Gene: slc22a5 has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.154 SLC22A5 Zornitza Stark Phenotypes for gene: SLC22A5 were changed from HCM, mixed; Carnitine transporter deficiency (Disorders of carnitine transport and the carnitine cycle); Arrhythmia, muscle weakness or hypotonia, liver disease, hypoketotic hypoglycaemia; DCM; Carnitine transporter deficiency (primary carnitine deficiency); Propionicacidemia to Carnitine deficiency, systemic primary MIM#212140
Cardiomyopathy_Paediatric v0.153 SLC22A5 Zornitza Stark Publications for gene: SLC22A5 were set to 24816252; 27604308
Cardiomyopathy_Paediatric v0.152 SLC22A5 Zornitza Stark Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.86 LY96 Peter McNaughton gene: LY96 was added
gene: LY96 was added to Inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: LY96 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LY96 were set to PMID: 36462957
Phenotypes for gene: LY96 were set to Colitis
Review for gene: LY96 was set to RED
Added comment: Single patient with infantile colitis associated with failure-to-thrive, bloody diarrhea, and perianal abscesses since the age of 4 months. Later developed bronchiectasis and persistent pneumonia, which required lobectomy at the age of 6 years. Brother with same deletion presented with recurrent otitis media and pneumonia but exhibited no signs of intestinal inflammation.
Sources: Literature
Cardiomyopathy_Paediatric v0.151 SLC22A5 Paul De Fazio reviewed gene: SLC22A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22989098, 18337137, 27807682; Phenotypes: Carnitine deficiency, systemic primary MIM#212140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.5156 FGF13 Zornitza Stark Phenotypes for gene: FGF13 were changed from Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual disability; epilepsy to Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual developmental disorder, X-linked 110, MIM# 301095
Intellectual disability syndromic and non-syndromic v0.5155 FGF13 Zornitza Stark Publications for gene: FGF13 were set to 33245860
Intellectual disability syndromic and non-syndromic v0.5154 FGF13 Zornitza Stark Tag 5'UTR tag was added to gene: FGF13.
Intellectual disability syndromic and non-syndromic v0.5154 FGF13 Zornitza Stark edited their review of gene: FGF13: Added comment: PMID 34184986: 3 individuals reported with moderate to severe ID and maternally inherited 5' variant c.-32C-G; Changed publications: 33245860, 34184986; Changed phenotypes: Developmental and epileptic encephalopathy 90, MIM# 301058, Intellectual developmental disorder, X-linked 110, MIM# 301095
Mendeliome v1.613 FGF13 Zornitza Stark Phenotypes for gene: FGF13 were changed from Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual disability; epilepsy to Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual developmental disorder, X-linked 110, MIM# 301095
Mendeliome v1.612 FGF13 Zornitza Stark Publications for gene: FGF13 were set to 33245860
Mendeliome v1.611 FGF13 Zornitza Stark Tag 5'UTR tag was added to gene: FGF13.
Mendeliome v1.611 FGF13 Zornitza Stark edited their review of gene: FGF13: Added comment: PMID 34184986: 3 individuals reported with moderate to severe ID and maternally inherited 5' variant c.-32C-G; Changed publications: 33245860, 34184986
Mendeliome v1.611 FGF13 Zornitza Stark edited their review of gene: FGF13: Changed phenotypes: Developmental and epileptic encephalopathy 90, MIM# 301058, Intellectual developmental disorder, X-linked 110, MIM# 301095
BabyScreen+ newborn screening v0.1836 APC Zornitza Stark Classified gene: APC as Red List (low evidence)
BabyScreen+ newborn screening v0.1836 APC Zornitza Stark Gene: apc has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1835 APC Zornitza Stark Tag cancer tag was added to gene: APC.
BabyScreen+ newborn screening v0.1835 WT1 Zornitza Stark Classified gene: WT1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1835 WT1 Zornitza Stark Gene: wt1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1834 WT1 Zornitza Stark Tag for review was removed from gene: WT1.
BabyScreen+ newborn screening v0.1834 WT1 Zornitza Stark changed review comment from: Rated as 'moderate actionability' in paediatric patients by ClinGen.

Individuals with germline WT1 pathogenic variants are more likely to have bilateral or multicentric tumors and to develop tumors at an early age. The median age of diagnosis is between 3 and 4 years and both kidneys are affected in ~5% of children. Significantly more females than males have the bilateral disease. Adult forms are very rare. In the majority of cases, the prognosis is favorable with a survival rate of over 90%.

The goal of surveillance in individuals with a genetic predisposition to WT is to

detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk. WTs can double in size every week, leading to the recommendation that evaluation with abdominal ultrasound be performed every 3-4 months, with and no less frequently than 3 times a year, until age five years. Even at this frequency, occasional tumors may present clinically between scans and families should be made aware of this. However, there is no evidence to suggest that such tumors have a worse outcome.

No evidence was found on the effectiveness of surveillance in children with WT due to WT1 pathogenic variants. In addition, there is no clear evidence that surveillance results in a significant decrease in mortality or tumor stage generally. However, tumors detected by surveillance would be anticipated to be on average smaller than tumors that present clinically. There have been three small retrospective evaluations of WT surveillance published, only one of which reported a significant difference in stage distribution between screened and unscreened individuals. This report was a case series of children with Beckwith-Wiedemann syndrome and idiopathic hemihypertropy, where 0/12 screened children with WT had late-stage disease and 25/59 (42%) of unscreened children had late-stage WT (p<0.003). In addition, in Germany, where abdominal ultrasound in children is common and 10% of WT are diagnosed prior to symptoms, there are some data to suggest that asymptomatic tumors are of lower stage than those present due to clinical symptoms.

Penetrance is unclear. For review.; to: Rated as 'moderate actionability' in paediatric patients by ClinGen.

Individuals with germline WT1 pathogenic variants are more likely to have bilateral or multicentric tumors and to develop tumors at an early age. The median age of diagnosis is between 3 and 4 years and both kidneys are affected in ~5% of children. Significantly more females than males have the bilateral disease. Adult forms are very rare. In the majority of cases, the prognosis is favorable with a survival rate of over 90%.

The goal of surveillance in individuals with a genetic predisposition to WT is to

detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk. WTs can double in size every week, leading to the recommendation that evaluation with abdominal ultrasound be performed every 3-4 months, with and no less frequently than 3 times a year, until age five years. Even at this frequency, occasional tumors may present clinically between scans and families should be made aware of this. However, there is no evidence to suggest that such tumors have a worse outcome.

No evidence was found on the effectiveness of surveillance in children with WT due to WT1 pathogenic variants. In addition, there is no clear evidence that surveillance results in a significant decrease in mortality or tumor stage generally. However, tumors detected by surveillance would be anticipated to be on average smaller than tumors that present clinically. There have been three small retrospective evaluations of WT surveillance published, only one of which reported a significant difference in stage distribution between screened and unscreened individuals. This report was a case series of children with Beckwith-Wiedemann syndrome and idiopathic hemihypertropy, where 0/12 screened children with WT had late-stage disease and 25/59 (42%) of unscreened children had late-stage WT (p<0.003). In addition, in Germany, where abdominal ultrasound in children is common and 10% of WT are diagnosed prior to symptoms, there are some data to suggest that asymptomatic tumors are of lower stage than those present due to clinical symptoms.
BabyScreen+ newborn screening v0.1834 GLA Zornitza Stark Tag for review was removed from gene: GLA.
BabyScreen+ newborn screening v0.1834 GLA Zornitza Stark changed review comment from: Assessed as 'moderate actionability' in paediatric patients by ClinGen.

In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype.

Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population.

A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established.

Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition.

A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months.

There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started.; to: Assessed as 'moderate actionability' in paediatric patients by ClinGen.

In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype.

Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population.

A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established.

Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition.

A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months.

There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started. Note ERT is licensed in Australia from age 7 years.

However, carbamazepine relieves neuropathic pain, which has onset in early childhood. Overall, include.
BabyScreen+ newborn screening v0.1834 GLA Zornitza Stark edited their review of gene: GLA: Changed rating: GREEN
BabyScreen+ newborn screening v0.1834 SMAD2 Zornitza Stark Marked gene: SMAD2 as ready
BabyScreen+ newborn screening v0.1834 SMAD2 Zornitza Stark Gene: smad2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1834 SMAD2 Zornitza Stark Classified gene: SMAD2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1834 SMAD2 Zornitza Stark Gene: smad2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1833 SMAD2 Zornitza Stark Tag cardiac tag was added to gene: SMAD2.
Tag treatable tag was added to gene: SMAD2.
BabyScreen+ newborn screening v0.1833 SMAD2 Zornitza Stark gene: SMAD2 was added
gene: SMAD2 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SMAD2 were set to Loeys-Dietz syndrome 6, MIM# 619656
Review for gene: SMAD2 was set to GREEN
Added comment: 9 individuals from 5 unrelated families reported with LDS phenotype. Gene-disease association rated 'moderate' by ClinGen but this gene is included in our diagnostic testing.

LDS included in gNBS panel as in general medical actionability for the LDS group of disorders is considered established.

Can manifest in early childhood.

Treatment: different interventions, including beta-blockers, surgical and monitoring

Non-genetic confirmatory test: characteristic clinical findings
Sources: Expert Review
BabyScreen+ newborn screening v0.1832 SMAD3 Zornitza Stark Tag for review was removed from gene: SMAD3.
Tag treatable tag was added to gene: SMAD3.
BabyScreen+ newborn screening v0.1832 TGFB3 Zornitza Stark Tag for review was removed from gene: TGFB3.
BabyScreen+ newborn screening v0.1832 TGFB2 Zornitza Stark Tag for review was removed from gene: TGFB2.
BabyScreen+ newborn screening v0.1832 PMS2 Zornitza Stark Classified gene: PMS2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1832 PMS2 Zornitza Stark Gene: pms2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1831 PMS2 Zornitza Stark Tag for review was removed from gene: PMS2.
BabyScreen+ newborn screening v0.1831 PMS2 Zornitza Stark edited their review of gene: PMS2: Changed rating: GREEN
BabyScreen+ newborn screening v0.1831 MSH6 Zornitza Stark Classified gene: MSH6 as Green List (high evidence)
BabyScreen+ newborn screening v0.1831 MSH6 Zornitza Stark Gene: msh6 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1830 MSH6 Zornitza Stark Tag for review was removed from gene: MSH6.
BabyScreen+ newborn screening v0.1830 MSH6 Zornitza Stark edited their review of gene: MSH6: Changed rating: GREEN
BabyScreen+ newborn screening v0.1830 MSH2 Zornitza Stark Classified gene: MSH2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1830 MSH2 Zornitza Stark Gene: msh2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1829 MSH2 Zornitza Stark Tag for review was removed from gene: MSH2.
BabyScreen+ newborn screening v0.1829 MSH2 Zornitza Stark edited their review of gene: MSH2: Changed rating: GREEN
BabyScreen+ newborn screening v0.1829 MLH1 Zornitza Stark Classified gene: MLH1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1829 MLH1 Zornitza Stark Gene: mlh1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1828 MLH1 Zornitza Stark edited their review of gene: MLH1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1828 SLC13A5 Zornitza Stark Classified gene: SLC13A5 as Red List (low evidence)
BabyScreen+ newborn screening v0.1828 SLC13A5 Zornitza Stark Gene: slc13a5 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1827 PTCH1 Zornitza Stark Classified gene: PTCH1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1827 PTCH1 Zornitza Stark Gene: ptch1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1826 PTCH1 Zornitza Stark Tag for review was removed from gene: PTCH1.
BabyScreen+ newborn screening v0.1826 PMM2 Zornitza Stark Classified gene: PMM2 as Red List (low evidence)
BabyScreen+ newborn screening v0.1826 PMM2 Zornitza Stark Gene: pmm2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1825 PMM2 Zornitza Stark changed review comment from: Well established gene-disease association.

Two clinical presentations - solely neurologic form and a neurologic-multivisceral form
Mortality approximately 20% in first 2 years

Treatment: epalrestat

PMID 31636082: Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations.

For review: uncertain if in use for CDG; to: Well established gene-disease association.

Two clinical presentations - solely neurologic form and a neurologic-multivisceral form
Mortality approximately 20% in first 2 years

Treatment: epalrestat

PMID 31636082: Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations.

Treatment not well established in patients.
BabyScreen+ newborn screening v0.1825 PMM2 Zornitza Stark edited their review of gene: PMM2: Changed rating: RED
BabyScreen+ newborn screening v0.1825 PMM2 Zornitza Stark Tag for review was removed from gene: PMM2.
Tag metabolic was removed from gene: PMM2.
BabyScreen+ newborn screening v0.1825 PIK3CA Zornitza Stark Classified gene: PIK3CA as Red List (low evidence)
BabyScreen+ newborn screening v0.1825 PIK3CA Zornitza Stark Gene: pik3ca has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1824 PIK3CA Zornitza Stark Tag for review was removed from gene: PIK3CA.
BabyScreen+ newborn screening v0.1824 PIK3CA Zornitza Stark edited their review of gene: PIK3CA: Changed rating: RED
BabyScreen+ newborn screening v0.1824 MEN1 Zornitza Stark Tag for review was removed from gene: MEN1.
BabyScreen+ newborn screening v0.1824 HPRT1 Zornitza Stark Classified gene: HPRT1 as Red List (low evidence)
BabyScreen+ newborn screening v0.1824 HPRT1 Zornitza Stark Gene: hprt1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1823 HPRT1 Zornitza Stark changed review comment from: Uncertain if these are essentially symptomatic treatments.; to: Symptomatic treatments.
BabyScreen+ newborn screening v0.1823 HPRT1 Zornitza Stark edited their review of gene: HPRT1: Changed rating: RED
BabyScreen+ newborn screening v0.1823 GLDC Zornitza Stark Tag for review was removed from gene: GLDC.
Tag treatable tag was added to gene: GLDC.
Tag metabolic tag was added to gene: GLDC.
BabyScreen+ newborn screening v0.1823 GLDC Zornitza Stark edited their review of gene: GLDC: Changed rating: GREEN
BabyScreen+ newborn screening v0.1823 FBN1 Zornitza Stark Classified gene: FBN1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1823 FBN1 Zornitza Stark Gene: fbn1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1822 FBN1 Zornitza Stark Tag for review was removed from gene: FBN1.
Tag cardiac tag was added to gene: FBN1.
Tag treatable tag was added to gene: FBN1.
BabyScreen+ newborn screening v0.1822 FBN1 Zornitza Stark edited their review of gene: FBN1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1822 DICER1 Zornitza Stark Classified gene: DICER1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1822 DICER1 Zornitza Stark Gene: dicer1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1821 DICER1 Zornitza Stark Tag for review was removed from gene: DICER1.
BabyScreen+ newborn screening v0.1821 DICER1 Zornitza Stark edited their review of gene: DICER1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1821 TP53 Zornitza Stark Tag for review was removed from gene: TP53.
BabyScreen+ newborn screening v0.1821 SLC5A6 Zornitza Stark Tag for review was removed from gene: SLC5A6.
Tag treatable tag was added to gene: SLC5A6.
Tag metabolic tag was added to gene: SLC5A6.
BabyScreen+ newborn screening v0.1821 RET Zornitza Stark Tag for review was removed from gene: RET.
BabyScreen+ newborn screening v0.1821 RET Zornitza Stark changed review comment from: Established gene-disease associations.

Assessed as 'strong actionability' in paediatric patients by ClinGen.

Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A.

PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age.

For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age.

Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients.

Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants.

For review: actionable in first 5 years of life?; to: Established gene-disease associations.

Assessed as 'strong actionability' in paediatric patients by ClinGen.

Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A.

PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age.

For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age.

Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients.

Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants.

For review: some actionability in first 5 years, variants can be stratified in terms of risk.
BabyScreen+ newborn screening v0.1821 RB1 Zornitza Stark Tag for review was removed from gene: RB1.
BabyScreen+ newborn screening v0.1821 PRKAR1A Zornitza Stark Tag for review was removed from gene: PRKAR1A.
BabyScreen+ newborn screening v0.1821 NF1 Zornitza Stark Classified gene: NF1 as Red List (low evidence)
BabyScreen+ newborn screening v0.1821 NF1 Zornitza Stark Gene: nf1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1820 NF1 Zornitza Stark changed review comment from: For review: does this meet the definition of 'treatable'?; to: Mainly surveillance.
BabyScreen+ newborn screening v0.1820 NF1 Zornitza Stark edited their review of gene: NF1: Changed rating: RED
BabyScreen+ newborn screening v0.1820 MCEE Zornitza Stark Tag for review was removed from gene: MCEE.
Renal cancer v0.4 Zornitza Stark HPO terms changed from to Renal neoplasm, HP:0009726
List of related panels changed from to Renal neoplasm; HP:0009726
Renal Glomerular Disease_SuperPanel v1.68 Zornitza Stark HPO terms changed from to Abnormal glomerular filtration rate, HP:0012212; Hematuria, HP:0000790;Proteinuria, HP:0000093
List of related panels changed from to Abnormal glomerular filtration rate; HP:0012212; Hematuria; HP:0000790;Proteinuria; HP:0000093
Renal Ciliopathies and Nephronophthisis v1.19 Zornitza Stark HPO terms changed from Abnormality of renal medullary morphology, HP:0025361 to Abnormality of renal medullary morphology, HP:0025361; Renal cyst, HP:0000107
List of related panels changed from Abnormality of renal medullary morphology; HP:0025361 to Abnormality of renal medullary morphology; HP:0025361; Renal cyst; HP:0000107
Renal Cystic Disease_SuperPanel v1.47 Zornitza Stark HPO terms changed from to Renal cyst, HP:0000107
List of related panels changed from to Renal cyst; HP:0000107
Renal Macrocystic Disease v0.66 Zornitza Stark HPO terms changed from to Renal cyst, HP:0000107
List of related panels changed from to Renal cyst; HP:0000107
Renal Tubulointerstitial Disease v1.3 Zornitza Stark HPO terms changed from to Abnormal tubulointerstitial morphology, HP:0001969
List of related panels changed from to Abnormal tubulointerstitial morphology; HP:0001969
Renal Tubulopathies and related disorders v1.4 Zornitza Stark HPO terms changed from to Renal tubular dysfunction, HP:0000124; Nephrolithiasis, HP:0000787; Abnormal circulating aldosterone, HP:0040085
List of related panels changed from to Renal tubular dysfunction; HP:0000124; Nephrolithiasis; HP:0000787; Abnormal circulating aldosterone; HP:0040085
Retinal Disorders Superpanel v6.156 Zornitza Stark HPO terms changed from to Abnormal retinal morphology, HP:0000479
List of related panels changed from to Abnormal retinal morphology; HP:0000479
Retinitis pigmentosa_Autosomal Dominant v0.54 Zornitza Stark HPO terms changed from to Abnormal retinal morphology, HP:0000479
List of related panels changed from to Abnormal retinal morphology; HP:0000479
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.131 Zornitza Stark HPO terms changed from to Abnormal retinal morphology, HP:0000479
List of related panels changed from to Abnormal retinal morphology; HP:0000479
Retinitis Pigmentosa Superpanel v0.185 Zornitza Stark HPO terms changed from to Abnormal retinal morphology, HP:0000479
List of related panels changed from to Abnormal retinal morphology; HP:0000479
Rhabdomyolysis and Metabolic Myopathy v0.92 Zornitza Stark HPO terms changed from to Rhabdomyolysis, HP:0003201
List of related panels changed from to Rhabdomyolysis; HP:0003201
Rhabdomyolysis and Metabolic Myopathy v0.92 Zornitza Stark HPO terms changed from to Rhabdomyolysis, HP:0003201
List of related panels changed from to Rhabdomyolysis; HP:0003201
Sarcoma v0.3 Zornitza Stark HPO terms changed from to Sarcoma, HP:0100242
List of related panels changed from to Sarcoma; HP:0100242
Schwannomatosis v0.16 Zornitza Stark HPO terms changed from to Schwannoma, HP:0100008
List of related panels changed from to Schwannoma; HP:0100008
Severe Combined Immunodeficiency (absent T absent B cells) v1.4 Zornitza Stark HPO terms changed from to Severe combined immunodeficiency, HP:0004430
List of related panels changed from to Severe combined immunodeficiency; HP:0004430
Severe Combined Immunodeficiency (absent T present B cells) v1.1 Zornitza Stark HPO terms changed from to Severe combined immunodeficiency, HP:0004430
List of related panels changed from to Severe combined immunodeficiency; HP:0004430
Panel types changed to Melbourne Genomics; Victorian Clinical Genetics Services; Rare Disease
Severe early-onset obesity v1.6 Zornitza Stark HPO terms changed from to Obesity, HP:0001513
List of related panels changed from to Obesity; HP:0001513
Short QT syndrome v1.4 Zornitza Stark HPO terms changed from to Shortened QT interval, HP:0012232
List of related panels changed from to Shortened QT interval; HP:0012232
Short Rib Polydactyly_Jeune Asphyxiating Thoracic Dystrophy_Skeletal Ciliopathy v1.8 Zornitza Stark HPO terms changed from Short rib, HP:0000773; Polydactyly, HP:0010442 to Short rib, HP:0000773; Polydactyly, HP:0010442; Bell-shaped thorax, HP:0001591
List of related panels changed from Short rib; HP:0000773; Polydactyly; HP:0010442 to Short rib; HP:0000773; Polydactyly; HP:0010442; Bell-shaped thorax; HP:0001591
Short Rib Polydactyly_Jeune Asphyxiating Thoracic Dystrophy_Skeletal Ciliopathy v1.7 Zornitza Stark HPO terms changed from to Short rib, HP:0000773; Polydactyly, HP:0010442
List of related panels changed from to Short rib; HP:0000773; Polydactyly; HP:0010442
Sick sinus syndrome v1.1 Zornitza Stark HPO terms changed from to Sick sinus syndrome, HP:0011704
List of related panels changed from to Sick sinus syndrome; HP:0011704
Skeletal dysplasia v0.229 Zornitza Stark HPO terms changed from to Skeletal dysplasia, HP:0002652
List of related panels changed from to Skeletal dysplasia; HP:0002652
Skeletal Muscle Channelopathies v1.1 Zornitza Stark HPO terms changed from to Periodic paralysis, HP:0003768; Myotonia, HP:0002486
List of related panels changed from to Periodic paralysis; HP:0003768; Myotonia; HP:0002486
Spondylocostal Dysostosis v0.9 Zornitza Stark HPO terms changed from to Spondylocostal dysostosis, MONDO:0000359
List of related panels changed from to Spondylocostal dysostosis; MONDO:0000359
Stickler Syndrome v1.5 Zornitza Stark HPO terms changed from to Myopia, HP:0000545; Retinal detachment, HP:0000541; Cleft palate, HP:0000175
List of related panels changed from to Myopia; HP:0000545; Retinal detachment; HP:0000541; Cleft palate; HP:0000175
Stroke v1.8 Zornitza Stark HPO terms changed from to Stroke, HP:0001297
List of related panels changed from to Stroke; HP:0001297
Susceptibility to Fungal Infections v1.7 Zornitza Stark HPO terms changed from to Recurrent fungal infections, HP:0002841
List of related panels changed from to Recurrent fungal infections; HP:0002841
Susceptibility to Viral Infections v0.109 Zornitza Stark HPO terms changed from to Recurrent viral infections, HP:0004429; Severe viral infection, HP:0031691
List of related panels changed from to Recurrent viral infections; HP:0004429; Severe viral infection; HP:0031691
Syndromic Retinopathy v0.197 Zornitza Stark HPO terms changed from to Retinopathy, HP:0000488
List of related panels changed from to Retinopathy; HP:0000488
Tubulinopathies v1.1 Zornitza Stark HPO terms changed from to Abnormal cortical gyration, HP:0002536
List of related panels changed from to Abnormal cortical gyration; HP:0002536
Usher Syndrome v1.5 Zornitza Stark HPO terms changed from to Usher syndrome, MONDO:0019501
List of related panels changed from to Usher syndrome; MONDO:0019501
Vascular Malformations SuperPanel v1.21 Zornitza Stark HPO terms changed from to Abnormal vascular morphology HP:0025015
List of related panels changed from to Abnormal vascular morphology HP:0025015
Vitreoretinopathy v1.4 Zornitza Stark HPO terms changed from to Abnormal posterior eye segment morphology, HP:0004329
List of related panels changed from to Abnormal posterior eye segment morphology; HP:0004329
Wilms Tumour Predisposition v0.39 Zornitza Stark HPO terms changed from to Wilms tumour, MONDO:0006058
List of related panels changed from to Wilms tumour; MONDO:0006058
Fetal anomalies v1.84 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Growth failure v1.59 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Intellectual disability syndromic and non-syndromic v0.5154 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Microcephaly v1.188 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Mendeliome v1.611 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Mendeliome v1.610 ZNF668 Zornitza Stark reviewed gene: ZNF668: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v1.58 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Growth failure v1.57 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Intellectual disability syndromic and non-syndromic v0.5153 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Intellectual disability syndromic and non-syndromic v0.5152 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Microcephaly v1.187 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Microcephaly v1.186 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Mendeliome v1.610 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Mendeliome v1.609 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Chromosome Breakage Disorders v1.17 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Chromosome Breakage Disorders v1.16 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Growth failure v1.57 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Growth failure v1.56 SLF2 Zornitza Stark edited their review of gene: SLF2: Changed phenotypes: Atelis syndrome 1, MIM# 620184
Intellectual disability syndromic and non-syndromic v0.5152 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Intellectual disability syndromic and non-syndromic v0.5151 SLF2 Zornitza Stark edited their review of gene: SLF2: Changed phenotypes: Atelis syndrome 1, MIM# 620184
Microcephaly v1.186 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Mendeliome v1.609 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Mendeliome v1.608 SLF2 Zornitza Stark edited their review of gene: SLF2: Changed phenotypes: Atelis syndrome 1, MIM# 620184
Chromosome Breakage Disorders v1.16 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Chromosome Breakage Disorders v1.15 SLF2 Zornitza Stark edited their review of gene: SLF2: Changed phenotypes: Atelis syndrome 1, MIM# 620184
Renal Tubulopathies and related disorders v1.3 SLC6A6 Zornitza Stark Marked gene: SLC6A6 as ready
Renal Tubulopathies and related disorders v1.3 SLC6A6 Zornitza Stark Gene: slc6a6 has been classified as Red List (Low Evidence).
Renal Tubulopathies and related disorders v1.3 SLC6A6 Zornitza Stark gene: SLC6A6 was added
gene: SLC6A6 was added to Renal Tubulopathies and related disorders. Sources: Literature
Mode of inheritance for gene: SLC6A6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC6A6 were set to 35115415; 21170874; 32660969
Phenotypes for gene: SLC6A6 were set to Primary hyperoxaluria, MONDO:0002474, SLC26A6-related
Review for gene: SLC6A6 was set to RED
Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969)
Sources: Literature
Regression v0.518 NAE1 Zornitza Stark Marked gene: NAE1 as ready
Regression v0.518 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Regression v0.518 NAE1 Zornitza Stark Classified gene: NAE1 as Green List (high evidence)
Regression v0.518 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Regression v0.517 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Regression. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Marked gene: NAE1 as ready
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Classified gene: NAE1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5150 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Mendeliome v1.608 NAE1 Zornitza Stark Marked gene: NAE1 as ready
Mendeliome v1.608 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Mendeliome v1.608 NAE1 Zornitza Stark Classified gene: NAE1 as Green List (high evidence)
Mendeliome v1.608 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Mendeliome v1.607 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Mendeliome v1.606 SLC26A6 Zornitza Stark Marked gene: SLC26A6 as ready
Mendeliome v1.606 SLC26A6 Zornitza Stark Gene: slc26a6 has been classified as Red List (Low Evidence).
Mendeliome v1.606 SLC26A6 Zornitza Stark Phenotypes for gene: SLC26A6 were changed from Enteric hyperoxaluria and nephrolithiasis to Primary hyperoxaluria, MONDO:0002474, SLC26A6-related
Mendeliome v1.605 SLC26A6 Zornitza Stark Classified gene: SLC26A6 as Red List (low evidence)
Mendeliome v1.605 SLC26A6 Zornitza Stark Gene: slc26a6 has been classified as Red List (Low Evidence).
Mendeliome v1.604 SLC26A6 Zornitza Stark reviewed gene: SLC26A6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary hyperoxaluria, MONDO:0002474, SLC26A6-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Marked gene: TRPC5 as ready
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Classified gene: TRPC5 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5148 TRPC5 Zornitza Stark gene: TRPC5 was added
gene: TRPC5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to 36323681; 24817631; 23033978; 33504798; 28191890
Phenotypes for gene: TRPC5 were set to Neurodevelopmental disorder, MONDO:0700092, TRPC5-related
Review for gene: TRPC5 was set to AMBER
Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570:
Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents.
Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened).
(This variant is absent in gnomAD v2.1.1).

Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted.

Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include:
PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested).

In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*).
NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1).

However, looking further into the three references, the evidence is not as clear or as accurate as was stated.

The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929).

Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned.

Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2).
Sources: Literature
Mendeliome v1.604 TRPC5 Zornitza Stark Marked gene: TRPC5 as ready
Mendeliome v1.604 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.604 TRPC5 Zornitza Stark Phenotypes for gene: TRPC5 were changed from Intellectual disability; autistic spectrum disorder to Neurodevelopmental disorder, MONDO:0700092, TRPC5-related
Mendeliome v1.603 TRPC5 Zornitza Stark Classified gene: TRPC5 as Amber List (moderate evidence)
Mendeliome v1.603 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Cardiomyopathy_Paediatric v0.151 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Intellectual disability syndromic and non-syndromic v0.5147 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Deafness_IsolatedAndComplex v1.155 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Mitochondrial disease v0.852 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Mendeliome v1.602 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Mendeliome v1.601 CRLS1 Zornitza Stark edited their review of gene: CRLS1: Changed phenotypes: Combined oxidative phosphorylation deficiency 57, MIM# 620167
Mendeliome v1.601 TRPC5 Hazel Phillimore gene: TRPC5 was added
gene: TRPC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890
Phenotypes for gene: TRPC5 were set to Intellectual disability; autistic spectrum disorder
Review for gene: TRPC5 was set to AMBER
Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570:
Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents.
Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened).
(This variant is absent in gnomAD v2.1.1).

Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted.

Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include:
PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested).

In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*).
NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1).

However, looking further into the three references, the evidence is not as clear or as accurate as was stated.

The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929).

Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned.

Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2).
Sources: Literature
Mendeliome v1.601 ZMYM3 Zornitza Stark Marked gene: ZMYM3 as ready
Mendeliome v1.601 ZMYM3 Zornitza Stark Gene: zmym3 has been classified as Green List (High Evidence).
Renal Ciliopathies and Nephronophthisis v1.18 Zornitza Stark HPO terms changed from to Abnormality of renal medullary morphology, HP:0025361
List of related panels changed from to Abnormality of renal medullary morphology; HP:0025361
Renal Amyloidosis v0.22 Zornitza Stark HPO terms changed from to Renal amyloidosis, HP:0001917
List of related panels changed from to Renal amyloidosis; HP:0001917
Regression v0.516 Zornitza Stark HPO terms changed from to Developmental regression, HP:0002376
List of related panels changed from to Developmental regression; HP:0002376
Regression v0.516 Zornitza Stark HPO terms changed from to Developmental regression, HP:0002376
List of related panels changed from to Developmental regression; HP:0002376
Red cell disorders v1.19 Zornitza Stark HPO terms changed from to Abnormal erythrocyte morphology, HP:0001877
List of related panels changed from to Abnormal erythrocyte morphology; HP:0001877
Rasopathy v0.97 Zornitza Stark HPO terms changed from to Rasopathy, MONDO:0021060
List of related panels changed from to Rasopathy; MONDO:0021060
Radial Ray Abnormalities v1.5 Zornitza Stark HPO terms changed from to Abnormality of radial ray, HP:0410049
List of related panels changed from to Abnormality of radial ray; HP:0410049
Mendeliome v1.601 BSN Krithika Murali changed review comment from: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature; to: Ye et al 2022, Neurogenetics - https://jmg.bmj.com/content/early/2022/12/12/jmg-2022-108865
Identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature
Genetic Epilepsy v0.1829 BSN Krithika Murali changed review comment from: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature; to: Ye et al 2022, Neurogenetics https://jmg.bmj.com/content/early/2022/12/12/jmg-2022-108865
Identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature
Mendeliome v1.601 RIC1 Paul De Fazio reviewed gene: RIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36493769; Phenotypes: Cleft lip/palate MONDO:0016044, RIC1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.601 UHRF1 Zornitza Stark Phenotypes for gene: UHRF1 were changed from Multi locus imprinting disturbance in offspring to Multi locus imprinting disturbance in offspring; chromosome instability
Mendeliome v1.600 UHRF1 Zornitza Stark Publications for gene: UHRF1 were set to 29574422; 28976982
Mendeliome v1.599 UHRF1 Zornitza Stark Mode of inheritance for gene: UHRF1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5146 SLC31A1 Zornitza Stark Publications for gene: SLC31A1 were set to PMID: 35913762
Intellectual disability syndromic and non-syndromic v0.5145 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: RED; Mode of pathogenicity: None; Publications: 36562171; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.598 SLC31A1 Zornitza Stark Publications for gene: SLC31A1 were set to PMID: 35913762
Mendeliome v1.597 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36562171; Phenotypes: Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.83 SLC31A1 Zornitza Stark Marked gene: SLC31A1 as ready
Fetal anomalies v1.83 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.83 SLC31A1 Zornitza Stark Classified gene: SLC31A1 as Amber List (moderate evidence)
Fetal anomalies v1.83 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.597 BSN Zornitza Stark Marked gene: BSN as ready
Mendeliome v1.597 BSN Zornitza Stark Added comment: Comment when marking as ready: We are aware of additional mono-allelic cases.
Mendeliome v1.597 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Mendeliome v1.597 BSN Zornitza Stark Mode of inheritance for gene: BSN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.596 BSN Zornitza Stark Classified gene: BSN as Green List (high evidence)
Mendeliome v1.596 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Mendeliome v1.595 UHRF1 Chern Lim changed review comment from: PMID: 29574422 Begemann et al. 2018
- Het missense in mother and proband, family recruited due to detection of multilocus imprinting disturbance (MLID) in offspring. Proband is one of discordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia. Variant present in both twins, no functional studies done on the missense.; to: PMID: 29574422 Begemann et al. 2018
- Het missense in mother and proband, family recruited due to detection of multilocus imprinting disturbance (MLID) in offspring. Proband is one of discordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia. Variant present in both twins, no functional studies done on the missense. Her cotwin was clinically and epigenetically normal
Genetic Epilepsy v0.1829 BSN Zornitza Stark Marked gene: BSN as ready
Genetic Epilepsy v0.1829 BSN Zornitza Stark Added comment: Comment when marking as ready: We are aware of additional mono allelic cases.
Genetic Epilepsy v0.1829 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1829 BSN Zornitza Stark Mode of inheritance for gene: BSN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1828 BSN Zornitza Stark Classified gene: BSN as Green List (high evidence)
Genetic Epilepsy v0.1828 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v0.140 COQ7 Zornitza Stark Marked gene: COQ7 as ready
Hereditary Neuropathy - complex v0.140 COQ7 Zornitza Stark Gene: coq7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.595 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092 to neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related
Mendeliome v1.594 ARHGAP35 Zornitza Stark Publications for gene: ARHGAP35 were set to 33057194
Mendeliome v1.593 UHRF1 Chern Lim edited their review of gene: UHRF1: Changed publications: 36458887, 29574422; Changed phenotypes: chromosome instability, Multi locus imprinting disturbance in offspring; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.82 SLC31A1 Daniel Flanagan gene: SLC31A1 was added
gene: SLC31A1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to PMID: 35913762; 36562171
Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092)
Review for gene: SLC31A1 was set to AMBER
Added comment: PMID:36562171
Homozygous c.236T>C; p.(Leu79Pro) identified in a newborn of consanguineous parents. Variant absent from gnomAD. Prenatal ultrasound showed a male fetus with short femoral bones, an apparently enlarged heart-to-thorax ratio, and a wide cisterna magna. The infant was born with pulmonary hypoplasia. At 2 weeks of age, multifocal brain hemorrhages were diagnosed and the infant developed seizures. The infant died at 1 month of age. The Mother had three healthy children while nine pregnancies had been extrauterine gravidities or ended in first or mid-trimester spontaneous abortions.

PMID: 35913762
SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert list
Mendeliome v1.593 ARHGEF38 Zornitza Stark Marked gene: ARHGEF38 as ready
Mendeliome v1.593 ARHGEF38 Zornitza Stark Gene: arhgef38 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.593 UHRF1 Chern Lim edited their review of gene: UHRF1: Added comment: PMID: 36458887 Unoki et al. 2022
- One patient with compound het missense and nonsense variants, both parents are carriers (hets).
- The patient has chromosome instability with hypomethylation of the pericentromeric satellite-2 repeats and facial anomalies as typical symptoms of the ICF syndrome, but did not exhibit immunodeficiency, and developed an adrenocortical adenoma; characteristics that were atypical.
- Genome-wide methylation analysis revealed the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes.
- Structural and biochemical analyses revealed that the R296W variant disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1, and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and PAF15.; Changed publications: 36458887; Changed phenotypes: chromosome instability; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.593 ARHGEF38 Zornitza Stark Mode of inheritance for gene: ARHGEF38 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.592 ARHGEF38 Zornitza Stark Classified gene: ARHGEF38 as Amber List (moderate evidence)
Mendeliome v1.592 ARHGEF38 Zornitza Stark Gene: arhgef38 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5145 CDK16 Zornitza Stark Publications for gene: CDK16 were set to 25644381
Mendeliome v1.591 UHRF1 Chern Lim reviewed gene: UHRF1: Rating: RED; Mode of pathogenicity: None; Publications: 29574422; Phenotypes: Multi locus imprinting disturbance in offspring; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1827 EIF4A2 Zornitza Stark Marked gene: EIF4A2 as ready
Genetic Epilepsy v0.1827 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1827 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Genetic Epilepsy v0.1827 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Mendeliome v1.591 EIF4A2 Zornitza Stark Marked gene: EIF4A2 as ready
Mendeliome v1.591 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Mendeliome v1.591 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Mendeliome v1.591 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5144 ZMYM3 Zornitza Stark Mode of inheritance for gene: ZMYM3 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.590 ARHGAP35 Dean Phelan reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36450800; Phenotypes: Developmental defect of the eye (MONDO:0020145), ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.590 SLC31A1 Alison Yeung Classified gene: SLC31A1 as Amber List (moderate evidence)
Mendeliome v1.590 SLC31A1 Alison Yeung Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia - adult onset v1.4 COQ7 Elena Savva gene: COQ7 was added
gene: COQ7 was added to Hereditary Spastic Paraplegia - adult onset. Sources: Literature
Mode of inheritance for gene: COQ7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ7 were set to PMID: 33215859
Phenotypes for gene: COQ7 were set to Hereditary spastic paraplegia, COQ7-related (MONDO#0019064)
Review for gene: COQ7 was set to RED
Added comment: PMID: 33215859: review of current and previous cohort finds three homozygous families with missense variants (p.(Leu111Pro) recurring, likely Iranian founder), with mod-severe progressive spastic paraplegia, moderate spastic paraparesis or moderate progressive spastic paraparesis .
- No supportive functional studies to validate missense variants.
Sources: Literature
Genetic Epilepsy v0.1826 SLC31A1 Alison Yeung Classified gene: SLC31A1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1826 SLC31A1 Alison Yeung Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.589 ARHGEF38 Paul De Fazio gene: ARHGEF38 was added
gene: ARHGEF38 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGEF38 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARHGEF38 were set to 36493769
Phenotypes for gene: ARHGEF38 were set to Cleft lip/palate MONDO:0016044, ARHGEF38-related
Review for gene: ARHGEF38 was set to AMBER
gene: ARHGEF38 was marked as current diagnostic
Added comment: PMID:36493769 identified an intragenic deletion by high-res microarray of the same exon (exon 3) in 4 individuals with non-syndromic cleft lip/palate. Deletion of exon 3 is present in 6 individuals in gnomAD. Inheritance information was not available.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Genetic Epilepsy v0.1825 SLC31A1 Alison Yeung Classified gene: SLC31A1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1825 SLC31A1 Alison Yeung Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Incidentalome v0.222 CHEK2 Seb Lunke Phenotypes for gene: CHEK2 were changed from Li-Fraumeni syndrome 2 (MIM#609265); {Breast cancer, susceptibility to} (MIM#114480); {Colorectal cancer, susceptibility to} (MIM#114500); {Prostate cancer, familial, susceptibility to} (MIM#176807) to Li-Fraumeni syndrome 2 (MIM#609265); {Breast cancer, susceptibility to} (MIM#114480); {Colorectal cancer, susceptibility to} (MIM#114500); {Prostate cancer, familial, susceptibility to} (MIM#176807)
Mendeliome v1.589 COBLL1 Zornitza Stark Marked gene: COBLL1 as ready
Mendeliome v1.589 COBLL1 Zornitza Stark Gene: cobll1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.589 COBLL1 Zornitza Stark Classified gene: COBLL1 as Amber List (moderate evidence)
Mendeliome v1.589 COBLL1 Zornitza Stark Gene: cobll1 has been classified as Amber List (Moderate Evidence).
Incidentalome v0.221 CHEK2 Seb Lunke Phenotypes for gene: CHEK2 were changed from Breast cancer to Li-Fraumeni syndrome 2 (MIM#609265); {Breast cancer, susceptibility to} (MIM#114480); {Colorectal cancer, susceptibility to} (MIM#114500); {Prostate cancer, familial, susceptibility to} (MIM#176807)
Clefting disorders v0.190 COBLL1 Zornitza Stark Marked gene: COBLL1 as ready
Clefting disorders v0.190 COBLL1 Zornitza Stark Gene: cobll1 has been classified as Amber List (Moderate Evidence).
Clefting disorders v0.190 COBLL1 Zornitza Stark Classified gene: COBLL1 as Amber List (moderate evidence)
Clefting disorders v0.190 COBLL1 Zornitza Stark Gene: cobll1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.588 COBLL1 Paul De Fazio edited their review of gene: COBLL1: Changed rating: AMBER
Incidentalome v0.221 CHEK2 Seb Lunke Publications for gene: CHEK2 were set to
Mendeliome v1.588 COBLL1 Paul De Fazio gene: COBLL1 was added
gene: COBLL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COBLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COBLL1 were set to 36493769
Phenotypes for gene: COBLL1 were set to Cleft lip/palate MONDO:0016044, COBLL1-related
gene: COBLL1 was marked as current diagnostic
Added comment: PMID:36493769 identified the same multi-exon intragenic deletion by high-res microarray in 3 individuals with non-syndromic cleft lip/palate. The deletion is absent from gnomAD. Inheritance information was only available for 1 individual, in whom it was inherited from an unaffected father. Note that the gene is not quite LOF constrained in gnomAD.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Incidentalome v0.221 CHEK2 Zornitza Stark Mode of inheritance for gene: CHEK2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary Neuropathy - complex v0.140 COQ7 Elena Savva Classified gene: COQ7 as Amber List (moderate evidence)
Hereditary Neuropathy - complex v0.140 COQ7 Elena Savva Gene: coq7 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1824 SLC31A1 Daniel Flanagan edited their review of gene: SLC31A1: Added comment: Homozygous c.236T>C; p.(Leu79Pro) identified in a newborn of consanguineous parents. Variant absent from gnomAD. Prenatal ultrasound showed a male fetus with short femoral bones, an apparently enlarged heart-to-thorax ratio, and a wide cisterna magna. The infant was born with pulmonary hypoplasia. At 2 weeks of age, multifocal brain hemorrhages were diagnosed and the infant developed seizures. The infant died at 1 month of age. The Mother had three healthy children while nine pregnancies had been extrauterine gravidities or ended in first or mid-trimester spontaneous abortions.; Changed rating: AMBER; Changed publications: PMID: 35913762, 36562171
Incidentalome v0.220 CHEK2 Seb Lunke Mode of inheritance for gene: CHEK2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Clefting disorders v0.189 COBLL1 Paul De Fazio changed review comment from: PMID:36493769 identified the same multi-exon intragenic deletion by high-res microarray in 3 individuals with non-syndromic cleft lip/palate. The deletion is absent from gnomAD. Inheritance information was only available for 1 individual, in whom it was inherited from an unaffected father.
Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature; to: PMID:36493769 identified the same multi-exon intragenic deletion by high-res microarray in 3 individuals with non-syndromic cleft lip/palate. The deletion is absent from gnomAD. Inheritance information was only available for 1 individual, in whom it was inherited from an unaffected father. Note that the gene is not quite LOF constrained in gnomAD.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Mendeliome v1.588 BSN Krithika Murali gene: BSN was added
gene: BSN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BSN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BSN were set to Epilepsy MONDO:0005027
Review for gene: BSN was set to GREEN
Added comment: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature
Incidentalome v0.220 CHEK2 Zornitza Stark Mode of inheritance for gene: CHEK2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.588 EIF4A2 Dean Phelan gene: EIF4A2 was added
gene: EIF4A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIF4A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EIF4A2 were set to PMID: 36528028
Phenotypes for gene: EIF4A2 were set to Neurodevelopmental disorder (MONDO:0700092), EIF4A2-related
Mode of pathogenicity for gene: EIF4A2 was set to Other
Review for gene: EIF4A2 was set to GREEN
Added comment: PMID: 36528028
- EIF4A2 variants were observed in 15 individuals from 14 families. Affected individuals had a range of symptoms including global developmental delay (9/15), ID (7/15), epilepsy (11/15) and structural brain alterations (10/15). Monoallelic and biallelic variants were reported and functional studies showed both LOF and GOF disease mechanisms.
Sources: Literature
Genetic Epilepsy v0.1824 BSN Krithika Murali gene: BSN was added
gene: BSN was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: BSN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BSN were set to Epilepsy MONDO:0005027
Review for gene: BSN was set to GREEN
Added comment: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature
Clefting disorders v0.189 COBLL1 Paul De Fazio gene: COBLL1 was added
gene: COBLL1 was added to Clefting disorders. Sources: Literature
Mode of inheritance for gene: COBLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COBLL1 were set to 36493769
Phenotypes for gene: COBLL1 were set to Cleft lip/palate MONDO:0016044, COBLL1-related
Review for gene: COBLL1 was set to AMBER
gene: COBLL1 was marked as current diagnostic
Added comment: PMID:36493769 identified the same multi-exon intragenic deletion by high-res microarray in 3 individuals with non-syndromic cleft lip/palate. The deletion is absent from gnomAD. Inheritance information was only available for 1 individual, in whom it was inherited from an unaffected father.
Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Clefting disorders v0.189 RIC1 Zornitza Stark Marked gene: RIC1 as ready
Clefting disorders v0.189 RIC1 Zornitza Stark Gene: ric1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1824 EIF4A2 Dean Phelan gene: EIF4A2 was added
gene: EIF4A2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: EIF4A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EIF4A2 were set to PMID: 36528028
Phenotypes for gene: EIF4A2 were set to Neurodevelopmental disorder (MONDO:0700092), EIF4A2-related
Mode of pathogenicity for gene: EIF4A2 was set to Other
Review for gene: EIF4A2 was set to GREEN
Added comment: PMID: 36528028
- EIF4A2 variants were observed in 15 individuals from 14 families. Affected individuals had a range of symptoms including global developmental delay (9/15), ID (7/15), epilepsy (11/15) and structural brain alterations (10/15). Monoallelic and biallelic variants were reported and functional studies showed both LOF and GOF disease mechanisms.
Sources: Literature
Renal Tubulopathies and related disorders v1.2 OXGR1 Sarah Pantaleo edited their review of gene: OXGR1: Changed phenotypes: Nephrolithiasis/nephrocalcinosis, MONDO:0008171, OXGR1-related, MONDO:0001567, OXGR1-related
Clefting disorders v0.189 RIC1 Zornitza Stark Classified gene: RIC1 as Green List (high evidence)
Clefting disorders v0.189 RIC1 Zornitza Stark Gene: ric1 has been classified as Green List (High Evidence).
Incidentalome v0.219 CHEK2 Lucy Spencer reviewed gene: CHEK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 36529819; Phenotypes: Li-Fraumeni syndrome 2 (MIM#609265), {Breast cancer, susceptibility to} (MIM#114480), {Colorectal cancer, susceptibility to} (MIM#114500), {Prostate cancer, familial, susceptibility to} (MIM#176807); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.588 OXGR1 Sarah Pantaleo edited their review of gene: OXGR1: Changed phenotypes: Nephrolithiasis/nephrocalcinosis, MONDO:0008171, OXGR1-related, MONDO:0001567, OXGR1-related
Hereditary Neuropathy - complex v0.139 COQ7 Elena Savva gene: COQ7 was added
gene: COQ7 was added to Hereditary Neuropathy - complex. Sources: Literature
Mode of inheritance for gene: COQ7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ7 were set to PMID: 36454683
Phenotypes for gene: COQ7 were set to Distal hereditary motor neuropathy, COQ7-related (MONDO#0018894)
Review for gene: COQ7 was set to AMBER
Added comment: PMID: 36454683 - 1 family (3 sibs) with a homozygous start-loss. Functional studies showed 85% loss of protein of the main isoform 1 (NM_016138) in patient fibroblasts and accumulation of protein substrate. Patients had a motor neuropathy
Sources: Literature
Anophthalmia_Microphthalmia_Coloboma v1.31 ARHGAP35 Alison Yeung Marked gene: ARHGAP35 as ready
Anophthalmia_Microphthalmia_Coloboma v1.31 ARHGAP35 Alison Yeung Gene: arhgap35 has been classified as Green List (High Evidence).
Clefting disorders v0.188 RIC1 Paul De Fazio gene: RIC1 was added
gene: RIC1 was added to Clefting disorders. Sources: Literature
Mode of inheritance for gene: RIC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RIC1 were set to 36493769
Phenotypes for gene: RIC1 were set to Cleft lip/palate MONDO:0016044, RIC1-related
Review for gene: RIC1 was set to GREEN
gene: RIC1 was marked as current diagnostic
Added comment: PMID:36493769 identified an intragenic deletion by high-res microarray of exons 1-2 in 3 individuals with non-syndromic cleft lip/palate. This deleton is not present in gnomAD. Inheritance information was available in 2 individuals; one was de novo, the other inherited from an affected mother. Note that the gene is not LOF constrained in gnomAD.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Anophthalmia_Microphthalmia_Coloboma v1.31 ARHGAP35 Alison Yeung Classified gene: ARHGAP35 as Green List (high evidence)
Anophthalmia_Microphthalmia_Coloboma v1.31 ARHGAP35 Alison Yeung Gene: arhgap35 has been classified as Green List (High Evidence).
Mendeliome v1.588 PHLDB1 Seb Lunke Marked gene: PHLDB1 as ready
Mendeliome v1.588 PHLDB1 Seb Lunke Gene: phldb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.588 PHLDB1 Seb Lunke Classified gene: PHLDB1 as Amber List (moderate evidence)
Mendeliome v1.588 PHLDB1 Seb Lunke Gene: phldb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.587 PHLDB1 Seb Lunke gene: PHLDB1 was added
gene: PHLDB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PHLDB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PHLDB1 were set to 36543534
Phenotypes for gene: PHLDB1 were set to osteogenesis imperfecta, MONDO:0019019
Review for gene: PHLDB1 was set to AMBER
Added comment: 5 children from two consanguineous families with recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment.

Two independent nonsense variants were identified in the families, NM_001144758.3:c.2392dup (p.Leu798Profs*4) and NM_001144758.3:c.2690_2693del (p.Leu897Glnfs*24). RT-PCR and western blot analysis confirmed loss of transcript and protein product, respectively, but no further functional data provided.
Sources: Literature
Anophthalmia_Microphthalmia_Coloboma v1.30 ARHGAP35 Dean Phelan gene: ARHGAP35 was added
gene: ARHGAP35 was added to Anophthalmia_Microphthalmia_Coloboma. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to PMID: 36450800
Phenotypes for gene: ARHGAP35 were set to Developmental defect of the eye (MONDO:0020145), ARHGAP35-related
Added comment: PMID: 36450800
- ARHGAP35 variants were found in five individuals from four families with human developmental eye phenotypes. The affected individuals had anophthalmia, microphthalmia, coloboma and/or anterior segment dysgenesis disorders, together with variable non-ocular phenotypes in some families including renal, neurological, or cardiac anomalies.
Sources: Literature
Osteogenesis Imperfecta and Osteoporosis v0.88 PHLDB1 Seb Lunke Marked gene: PHLDB1 as ready
Osteogenesis Imperfecta and Osteoporosis v0.88 PHLDB1 Seb Lunke Gene: phldb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.586 OXGR1 Zornitza Stark Marked gene: OXGR1 as ready
Mendeliome v1.586 OXGR1 Zornitza Stark Gene: oxgr1 has been classified as Amber List (Moderate Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.88 PHLDB1 Seb Lunke Classified gene: PHLDB1 as Amber List (moderate evidence)
Osteogenesis Imperfecta and Osteoporosis v0.88 PHLDB1 Seb Lunke Gene: phldb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.586 OXGR1 Zornitza Stark Classified gene: OXGR1 as Amber List (moderate evidence)
Mendeliome v1.586 OXGR1 Zornitza Stark Gene: oxgr1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.585 CDK16 Alison Yeung Phenotypes for gene: CDK16 were changed from Intellectual disability to Neurodevelopmental disorder (MONDO#0700092) CDK16-related
Mendeliome v1.584 CDK16 Alison Yeung Publications for gene: CDK16 were set to 25644381
Mendeliome v1.583 OXGR1 Sarah Pantaleo gene: OXGR1 was added
gene: OXGR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OXGR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OXGR1 were set to PMID:35671463
Phenotypes for gene: OXGR1 were set to Nephrolithiasis/nephrocalcinosis MONDO:0008171, OXGR1-related
Penetrance for gene: OXGR1 were set to unknown
Review for gene: OXGR1 was set to AMBER
Added comment: Candidate disease gene for human calcium oxalate nephrolithiasis.

Performed exome sequencing and directed sequencing of the OXGR1 locus in a worldwide nephrolithiasis/nephrocalcinosis (NL/NC) cohort, and putatively deleterious rare OXGR1 variants were functionally characterised.

A heterozygous OXGR1 missense variant (c.371T>G; p.Leu124Arg) co-segregated with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multi-generational family with five affected individuals.

Interrogation of the OXGR1 locus in 1,107 additional NL/NC families identified five additional deleterious dominant variants in five families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in NL/NC subjects relative to ExAC controls. Four missense variants and one frameshift variant.

Four of five NL/NC-associated missense variants revealed impaired AKG-dependent calcium ion uptake, demonstrating loss of function.

Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease. Six potentially deleterious variants were identified in six of 1,108 NL/NC families (0.54%).

Limitations: only probands were able to be recruited for four of six families. In the future, it will be important to determine whether any of the affected family members share the identified OXGR1 variant. They also observe OXGR1 variants in 0.16% of ExAC subjects (selected on the basis of the absence of paediatric disease).
Sources: Literature
Mendeliome v1.583 CDK16 Alison Yeung reviewed gene: CDK16: Rating: GREEN; Mode of pathogenicity: None; Publications: 36323681, 31981491, 25644381; Phenotypes: Neurodevelopmental disorder (MONDO#0700092) CDK16-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Clefting disorders v0.188 ARHGEF38 Zornitza Stark Marked gene: ARHGEF38 as ready
Clefting disorders v0.188 ARHGEF38 Zornitza Stark Gene: arhgef38 has been classified as Amber List (Moderate Evidence).
Clefting disorders v0.188 ARHGEF38 Zornitza Stark Classified gene: ARHGEF38 as Amber List (moderate evidence)
Clefting disorders v0.188 ARHGEF38 Zornitza Stark Gene: arhgef38 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.583 CDK16 Alison Yeung Classified gene: CDK16 as Green List (high evidence)
Mendeliome v1.583 CDK16 Alison Yeung Gene: cdk16 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5143 CDK16 Alison Yeung Phenotypes for gene: CDK16 were changed from Neurodevelopmental disorder (MONDO#0700092) CDK16-related to Neurodevelopmental disorder (MONDO#0700092) CDK16-related
Intellectual disability syndromic and non-syndromic v0.5142 CDK16 Alison Yeung Phenotypes for gene: CDK16 were changed from Intellectual disability to Neurodevelopmental disorder (MONDO#0700092) CDK16-related
Mendeliome v1.582 CCIN Seb Lunke Marked gene: CCIN as ready
Mendeliome v1.582 CCIN Seb Lunke Gene: ccin has been classified as Green List (High Evidence).
Clefting disorders v0.187 ARHGEF38 Paul De Fazio gene: ARHGEF38 was added
gene: ARHGEF38 was added to Clefting disorders. Sources: Literature
Mode of inheritance for gene: ARHGEF38 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARHGEF38 were set to 36493769
Phenotypes for gene: ARHGEF38 were set to Cleft lip/palate MONDO:0016044, ARHGEF38-related
Review for gene: ARHGEF38 was set to AMBER
gene: ARHGEF38 was marked as current diagnostic
Added comment: PMID:36493769 identified an intragenic deletion by high-res microarray of the same exon (exon 3) in 4 individuals with non-syndromic cleft lip/palate. Deletion of exon 3 is present in 6 individuals in gnomAD. Inheritance information was not available.

Knockdown and knockout of the gene in Xenopus and Zebrafish resulted in craniofacial malformations in a large proportion (but not 100%) of embryos.
Sources: Literature
Mendeliome v1.582 CCIN Seb Lunke Phenotypes for gene: CCIN were changed from Teratozoospermia to male infertility with teratozoospermia due to single gene mutation, MONDO:0018394
Renal Tubulopathies and related disorders v1.2 OXGR1 Zornitza Stark Marked gene: OXGR1 as ready
Renal Tubulopathies and related disorders v1.2 OXGR1 Zornitza Stark Gene: oxgr1 has been classified as Amber List (Moderate Evidence).
Renal Tubulopathies and related disorders v1.2 OXGR1 Zornitza Stark Phenotypes for gene: OXGR1 were changed from Nephrolithiasis/nephrocalcinosis to Nephrolithiasis/nephrocalcinosis, MONDO:0008171, OXGR1-related
Mendeliome v1.581 CCIN Seb Lunke Classified gene: CCIN as Green List (high evidence)
Mendeliome v1.581 CCIN Seb Lunke Gene: ccin has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5141 CDK16 Alison Yeung Classified gene: CDK16 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5141 CDK16 Alison Yeung Gene: cdk16 has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.1 OXGR1 Zornitza Stark Classified gene: OXGR1 as Amber List (moderate evidence)
Renal Tubulopathies and related disorders v1.1 OXGR1 Zornitza Stark Gene: oxgr1 has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia - paediatric v1.54 NFU1 Seb Lunke Marked gene: NFU1 as ready
Hereditary Spastic Paraplegia - paediatric v1.54 NFU1 Seb Lunke Gene: nfu1 has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.0 OXGR1 Sarah Pantaleo gene: OXGR1 was added
gene: OXGR1 was added to Renal Tubulopathies and related disorders. Sources: Literature
Mode of inheritance for gene: OXGR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OXGR1 were set to PMID:35671463
Phenotypes for gene: OXGR1 were set to Nephrolithiasis/nephrocalcinosis
Penetrance for gene: OXGR1 were set to unknown
Review for gene: OXGR1 was set to AMBER
Added comment: Candidate disease gene for human calcium oxalate nephrolithiasis.

Performed exome sequencing and directed sequencing of the OXGR1 locus in a worldwide nephrolithiasis/nephrocalcinosis (NL/NC) cohort, and putatively deleterious rare OXGR1 variants were functionally characterised.

A heterozygous OXGR1 missense variant (c.371T>G; p.Leu124Arg) co-segregated with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multi-generational family with five affected individuals.

Interrogation of the OXGR1 locus in 1,107 additional NL/NC families identified five additional deleterious dominant variants in five families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in NL/NC subjects relative to ExAC controls. Four missense variants and one frameshift variant.

Four of five NL/NC-associated missense variants revealed impaired AKG-dependent calcium ion uptake, demonstrating loss of function.

Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease. Six potentially deleterious variants were identified in six of 1,108 NL/NC families (0.54%).

Limitations: only probands were able to be recruited for four of six families. In the future, it will be important to determine whether any of the affected family members share the identified OXGR1 variant. They also observe OXGR1 variants in 0.16% of ExAC subjects (selected on the basis of the absence of paediatric disease).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5140 TRA2B Seb Lunke Phenotypes for gene: TRA2B were changed from Neurodevelopmental disorder, TRA2B-related, MONDO# 0700092 to Neurodevelopmental disorder, TRA2B-related, MONDO# 0700092
Intellectual disability syndromic and non-syndromic v0.5140 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5140 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5139 TRA2B Seb Lunke Phenotypes for gene: TRA2B were changed from Neurodevelopmental disorder, TRA2B-related (MONDO#0700092) to Neurodevelopmental disorder, TRA2B-related, MONDO# 0700092
Genetic Epilepsy v0.1824 TRA2B Seb Lunke Classified gene: TRA2B as Green List (high evidence)
Genetic Epilepsy v0.1824 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Hereditary Spastic Paraplegia - paediatric v1.54 NFU1 Alison Yeung Classified gene: NFU1 as Green List (high evidence)
Hereditary Spastic Paraplegia - paediatric v1.54 NFU1 Alison Yeung Gene: nfu1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Hereditary Spastic Paraplegia - paediatric v1.53 NFU1 Alison Yeung Classified gene: NFU1 as Green List (high evidence)
Hereditary Spastic Paraplegia - paediatric v1.53 NFU1 Alison Yeung Gene: nfu1 has been classified as Green List (High Evidence).
Microcephaly v1.185 TRA2B Seb Lunke Phenotypes for gene: TRA2B were changed from Neurodevelopmental disorder, TRA2B-related (MONDO#0700092) to Neurodevelopmental disorder, TRA2B-related, MONDO# 0700092
Genetic Epilepsy v0.1824 TRA2B Seb Lunke Classified gene: TRA2B as Green List (high evidence)
Genetic Epilepsy v0.1824 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5139 TRA2B Seb Lunke Marked gene: TRA2B as ready
Intellectual disability syndromic and non-syndromic v0.5139 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Mendeliome v1.580 CCIN Chern Lim gene: CCIN was added
gene: CCIN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCIN were set to 36546111; 36527329
Phenotypes for gene: CCIN were set to Teratozoospermia
Review for gene: CCIN was set to GREEN
gene: CCIN was marked as current diagnostic
Added comment: Two papers with three unrelated patients with teratozoospermia:

PMID: 36546111
- Two families reported: One with homozygous missense (fam is consanguineous) and another with compound heterozygous missense + nonsense variants, patients suffering from teratozoospermia.
- Homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* knock-in mice generated. Spermatozoa from homozygous male mice exhibited abnormalities of sperm head shape revealed by Diff-Quick staining. When mated with WT mice, both homozygous CcinH42L/H42L and compound heterozygous CcinR432W/C447* male mice were infertile, whereas the mutant female mice could generate offspring and displayed no defects in fertility.

PMID: 36527329
- One consanguineous family reported: homozygous missense, with asthenoteratozoospermia.
- Transfected HEK cells showed reduced CCIN protein level.
Sources: Literature
Mendeliome v1.580 TRA2B Seb Lunke Marked gene: TRA2B as ready
Mendeliome v1.580 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Mendeliome v1.580 TRA2B Seb Lunke Phenotypes for gene: TRA2B were changed from Neurodevelopmental disorder, TRA2B-related (MONDO#0700092) to Neurodevelopmental disorder, TRA2B-related, MONDO# 0700092
Microcephaly v1.184 TRA2B Seb Lunke Marked gene: TRA2B as ready
Microcephaly v1.184 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Marked gene: EIF4A2 as ready
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1823 TRA2B Seb Lunke Marked gene: TRA2B as ready
Genetic Epilepsy v0.1823 TRA2B Seb Lunke Gene: tra2b has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5139 CDK16 Belinda Chong changed review comment from: Total of 3 families with ID 1 with ASD.
PMID 36323681:
Identified a nonsense variant (c.961 G > T, p.(Glu321*)) in a 42-year-old patient with ID and spasticity.
A missense variant (c.1039G > T, p.(Gly347Cys)) affecting a highly conserved amino acid of the kinase domain (CADD PHRED score: 32) was identified by genome sequencing in a male patient with ID, ASD, and epilepsy, whose family history was compatible with X-linked inheritance.

PMID 31981491:
In addition, a nonsense variant (c.46C > T, p.(Arg16*)) was recently reported in a patient with ASD.

PMID 25644381:
Single family described in this manuscript describing multiple candidate genes for XLID.; to: 3 families with ID 1 with ASD.
PMID 36323681:
Identified a nonsense variant (c.961 G > T, p.(Glu321*)) in a 42-year-old patient with ID and spasticity.
A missense variant (c.1039G > T, p.(Gly347Cys)) affecting a highly conserved amino acid of the kinase domain (CADD PHRED score: 32) was identified by genome sequencing in a male patient with ID, ASD, and epilepsy, whose family history was compatible with X-linked inheritance.

PMID 31981491:
In addition, a nonsense variant (c.46C > T, p.(Arg16*)) was recently reported in a patient with ASD.

PMID 25644381:
Single family described in this manuscript describing multiple candidate genes for XLID.
Intellectual disability syndromic and non-syndromic v0.5139 CDK16 Belinda Chong changed review comment from: Total of 3 families with ID i with ASD.
PMID 36323681:
Identified a nonsense variant (c.961 G > T, p.(Glu321*)) in a 42-year-old patient with ID and spasticity.
A missense variant (c.1039G > T, p.(Gly347Cys)) affecting a highly conserved amino acid of the kinase domain (CADD PHRED score: 32) was identified by genome sequencing in a male patient with ID, ASD, and epilepsy, whose family history was compatible with X-linked inheritance.

PMID 31981491:
In addition, a nonsense variant (c.46C > T, p.(Arg16*)) was recently reported in a patient with ASD.

PMID 25644381:
Single family described in this manuscript describing multiple candidate genes for XLID.; to: Total of 3 families with ID 1 with ASD.
PMID 36323681:
Identified a nonsense variant (c.961 G > T, p.(Glu321*)) in a 42-year-old patient with ID and spasticity.
A missense variant (c.1039G > T, p.(Gly347Cys)) affecting a highly conserved amino acid of the kinase domain (CADD PHRED score: 32) was identified by genome sequencing in a male patient with ID, ASD, and epilepsy, whose family history was compatible with X-linked inheritance.

PMID 31981491:
In addition, a nonsense variant (c.46C > T, p.(Arg16*)) was recently reported in a patient with ASD.

PMID 25644381:
Single family described in this manuscript describing multiple candidate genes for XLID.
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5139 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Mendeliome v1.579 TRA2B Seb Lunke Classified gene: TRA2B as Green List (high evidence)
Mendeliome v1.579 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Microcephaly v1.184 TRA2B Seb Lunke Classified gene: TRA2B as Green List (high evidence)
Microcephaly v1.184 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5138 CDK16 Belinda Chong commented on gene: CDK16: Total of 3 families with ID i with ASD.
PMID 36323681:
Identified a nonsense variant (c.961 G > T, p.(Glu321*)) in a 42-year-old patient with ID and spasticity.
A missense variant (c.1039G > T, p.(Gly347Cys)) affecting a highly conserved amino acid of the kinase domain (CADD PHRED score: 32) was identified by genome sequencing in a male patient with ID, ASD, and epilepsy, whose family history was compatible with X-linked inheritance.

PMID 31981491:
In addition, a nonsense variant (c.46C > T, p.(Arg16*)) was recently reported in a patient with ASD.

PMID 25644381:
Single family described in this manuscript describing multiple candidate genes for XLID.
Intellectual disability syndromic and non-syndromic v0.5138 TRA2B Seb Lunke Classified gene: TRA2B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5138 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5138 CDK16 Belinda Chong reviewed gene: CDK16: Rating: GREEN; Mode of pathogenicity: None; Publications: 36323681, 31981491, 25644381; Phenotypes: Neurodevelopmental disorder (MONDO#0700092) CDK16-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.5138 TRA2B Seb Lunke Classified gene: TRA2B as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5138 TRA2B Seb Lunke Gene: tra2b has been classified as Green List (High Evidence).
Fetal anomalies v1.82 TGFBR1 Alison Yeung reviewed gene: TGFBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36584339; Phenotypes: Loeys-Dietz syndrome 1, MIM# 609192; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Fetal anomalies v1.82 TGFBR1 Alison Yeung Mode of inheritance for gene: TGFBR1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.578 ZMYM3 Zornitza Stark Mode of inheritance for gene: ZMYM3 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.577 ZMYM3 Zornitza Stark Phenotypes for gene: ZMYM3 were changed from Neurodevelopmental disorders (NDDs) to Neurodevelopmental disorder, MONDO:0700092, ZMYM3-related
Mendeliome v1.576 TRA2B Elena Savva gene: TRA2B was added
gene: TRA2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRA2B were set to PMID: 36549593
Phenotypes for gene: TRA2B were set to Neurodevelopmental disorder, TRA2B-related (MONDO#0700092)
Review for gene: TRA2B was set to GREEN
Added comment: PMID: 36549593
- 12 individuals with ID and dev delay. Additional features include infantile spams 6/12, hypotonia 12/12, dilated brain ventricles 6/12, microcephaly 5/12
- All variants result in the loss of 1/2 transcripts (start-losses or PTCs upstream of a second translation start position). Shorter transcript expression is increased, longer transcript expression is decreased.
- Apparently het mice K/O are normal, but complete K/O cannot develop embryonically.
- DN mechanism suggested
Sources: Literature
Mendeliome v1.575 ZMYM3 Zornitza Stark Classified gene: ZMYM3 as Green List (high evidence)
Mendeliome v1.575 ZMYM3 Zornitza Stark Gene: zmym3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5137 ZMYM3 Zornitza Stark Publications for gene: ZMYM3 were set to 24721225
Intellectual disability syndromic and non-syndromic v0.5136 ZMYM3 Zornitza Stark Phenotypes for gene: ZMYM3 were changed from to Neurodevelopmental disorder, MONDO:0700092, ZMYM3-related
Hereditary Spastic Paraplegia - paediatric v1.52 NFU1 Lucy Spencer gene: NFU1 was added
gene: NFU1 was added to Hereditary Spastic Paraplegia - paediatric. Sources: Literature
Mode of inheritance for gene: NFU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFU1 were set to 36256512
Phenotypes for gene: NFU1 were set to Multiple mitochondrial dysfunctions syndrome 1 (MIM#605711)
Review for gene: NFU1 was set to GREEN
Added comment: Adding to the phenotypic continuum of this gene. 19 affected individuals from 10 independent families with biallelic missense variants associated with a spectrum of early‐onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other.
Sources: Literature
Genetic Epilepsy v0.1823 TRA2B Elena Savva gene: TRA2B was added
gene: TRA2B was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRA2B were set to PMID: 36549593
Phenotypes for gene: TRA2B were set to Neurodevelopmental disorder, TRA2B-related (MONDO#0700092)
Review for gene: TRA2B was set to GREEN
Added comment: PMID: 36549593
- 12 individuals with ID and dev delay. Additional features include infantile spams 6/12, hypotonia 12/12, dilated brain ventricles 6/12, microcephaly 5/12
- All variants result in the loss of 1/2 transcripts (start-losses or PTCs upstream of a second translation start position). Shorter transcript expression is increased, longer transcript expression is decreased.
- Apparently het mice K/O are normal, but complete K/O cannot develop embryonically.
- DN mechanism suggested
Sources: Literature
Mendeliome v1.574 TUFT1 Zornitza Stark Marked gene: TUFT1 as ready
Mendeliome v1.574 TUFT1 Zornitza Stark Gene: tuft1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5135 ZMYM3 Zornitza Stark Classified gene: ZMYM3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5135 ZMYM3 Zornitza Stark Gene: zmym3 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.87 PHLDB1 Seb Lunke gene: PHLDB1 was added
gene: PHLDB1 was added to Osteogenesis Imperfecta. Sources: Literature
Mode of inheritance for gene: PHLDB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PHLDB1 were set to 36543534
Review for gene: PHLDB1 was set to AMBER
Added comment: 5 children from two consanguineous families with recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment.

Two independent nonsense variants were identified in the families, NM_001144758.3:c.2392dup (p.Leu798Profs*4) and NM_001144758.3:c.2690_2693del (p.Leu897Glnfs*24). RT-PCR and western blot analysis confirmed loss of transcript and protein product, respectively, but no further functional data provided.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.76 TGFBR1 Alison Yeung Mode of inheritance for gene: TGFBR1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Microcephaly v1.183 TRA2B Elena Savva gene: TRA2B was added
gene: TRA2B was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRA2B were set to PMID: 36549593
Phenotypes for gene: TRA2B were set to Neurodevelopmental disorder, TRA2B-related (MONDO#0700092)
Review for gene: TRA2B was set to GREEN
Added comment: PMID: 36549593
- 12 individuals with ID and dev delay. Additional features include infantile spams 6/12, hypotonia 12/12, dilated brain ventricles 6/12, microcephaly 5/12
- All variants result in the loss of 1/2 transcripts (start-losses or PTCs upstream of a second translation start position). Shorter transcript expression is increased, longer transcript expression is decreased.
- Apparently het mice K/O are normal, but complete K/O cannot develop embryonically.
- DN mechanism suggested
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5134 EIF4A2 Dean Phelan gene: EIF4A2 was added
gene: EIF4A2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: EIF4A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EIF4A2 were set to PMID: 36528028
Phenotypes for gene: EIF4A2 were set to Neurodevelopmental disorder (MONDO:0700092), EIF4A2-related
Mode of pathogenicity for gene: EIF4A2 was set to Other
Review for gene: EIF4A2 was set to GREEN
Added comment: PMID: 36528028
- EIF4A2 variants were observed in 15 individuals from 14 families. Affected individuals had a range of symptoms including global developmental delay (9/15), ID (7/15), epilepsy (11/15) and structural brain alterations (10/15). Monoallelic and biallelic variants were reported and functional studies showed both LOF and GOF disease mechanisms.
Sources: Literature
Osteogenesis Imperfecta and Osteoporosis v0.87 PHLDB1 Seb Lunke gene: PHLDB1 was added
gene: PHLDB1 was added to Osteogenesis Imperfecta. Sources: Literature
Mode of inheritance for gene: PHLDB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PHLDB1 were set to 36543534
Phenotypes for gene: PHLDB1 were set to osteogenesis imperfecta, MONDO:0019019
Review for gene: PHLDB1 was set to AMBER
Added comment: 5 children from two consanguineous families with recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment.

Two independent nonsense variants were identified in the families, NM_001144758.3:c.2392dup (p.Leu798Profs*4) and NM_001144758.3:c.2690_2693del (p.Leu897Glnfs*24). RT-PCR and western blot analysis confirmed loss of transcript and protein product, respectively, but no further functional data provided.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5134 TRA2B Elena Savva gene: TRA2B was added
gene: TRA2B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRA2B were set to PMID: 36549593
Phenotypes for gene: TRA2B were set to Neurodevelopmental disorder, TRA2B-related (MONDO#0700092)
Review for gene: TRA2B was set to GREEN
Added comment: PMID: 36549593
- 12 individuals with ID and dev delay. Additional features include infantile spams 6/12, hypotonia 12/12, dilated brain ventricles 6/12, microcephaly 5/12
- All variants result in the loss of 1/2 transcripts (start-losses or PTCs upstream of a second translation start position). Shorter transcript expression is increased, longer transcript expression is decreased.
- Apparently het mice K/O are normal, but complete K/O cannot develop embryonically.
- DN mechanism suggested
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.76 TGFBR1 Alison Yeung Mode of inheritance for gene: TGFBR1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Polymicrogyria and Schizencephaly v0.186 RAC1 Zornitza Stark changed review comment from: Additional individuals reported in PMID 35139179: polymicrogyria observed.
Sources: Literature; to: Additional individuals reported in PMID 35139179: polymicrogyria observed. Variants clustered between Q61 and R68 within the switch II region of RAC1, and are postulated to be activating.
Sources: Literature
Polymicrogyria and Schizencephaly v0.186 RAC1 Zornitza Stark Marked gene: RAC1 as ready
Polymicrogyria and Schizencephaly v0.186 RAC1 Zornitza Stark Gene: rac1 has been classified as Green List (High Evidence).
Polymicrogyria and Schizencephaly v0.186 RAC1 Zornitza Stark Classified gene: RAC1 as Green List (high evidence)
Polymicrogyria and Schizencephaly v0.186 RAC1 Zornitza Stark Gene: rac1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.75 TGFBR1 Alison Yeung reviewed gene: TGFBR1: Rating: ; Mode of pathogenicity: None; Publications: 36584339; Phenotypes: Loeys-Dietz syndrome 1, MIM# 609192; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Polymicrogyria and Schizencephaly v0.185 RAC1 Zornitza Stark gene: RAC1 was added
gene: RAC1 was added to Polymicrogyria and Schizencephaly. Sources: Literature
Mode of inheritance for gene: RAC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAC1 were set to 35139179
Phenotypes for gene: RAC1 were set to Mental retardation, autosomal dominant 48, MIM# 617751
Review for gene: RAC1 was set to GREEN
Added comment: Additional individuals reported in PMID 35139179: polymicrogyria observed.
Sources: Literature
Microcephaly v1.182 RAC1 Zornitza Stark Publications for gene: RAC1 were set to 30042656; 29276006; 30293988
Microcephaly v1.181 RAC1 Zornitza Stark Classified gene: RAC1 as Green List (high evidence)
Microcephaly v1.181 RAC1 Zornitza Stark Gene: rac1 has been classified as Green List (High Evidence).
Microcephaly v1.180 RAC1 Zornitza Stark edited their review of gene: RAC1: Added comment: Additional patients reported. Microcephaly is a feature, though variable one, and some individuals have macrocephaly.; Changed rating: GREEN; Changed publications: 30042656, 29276006, 30293988, 35139179
Mendeliome v1.574 TUFT1 Zornitza Stark Classified gene: TUFT1 as Amber List (moderate evidence)
Mendeliome v1.574 TUFT1 Zornitza Stark Gene: tuft1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.573 TUFT1 Zornitza Stark gene: TUFT1 was added
gene: TUFT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TUFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUFT1 were set to https://doi.org/10.1093/bjd/ljac026
Phenotypes for gene: TUFT1 were set to Ectodermal dysplasia, MONDO:0019287, TUFT1-related
Review for gene: TUFT1 was set to AMBER
Added comment: 9 individuals from three families reported with woolly hair and skin fragility. One of the variants, c.60+1G>A was present in two of the families, founder effect demonstrated by haplotype analysis. Another loss of function variant present in the third family. Some functional data but mostly expression studies.
Sources: Literature
Mendeliome v1.572 ZMYM3 Belinda Chong gene: ZMYM3 was added
gene: ZMYM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZMYM3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ZMYM3 were set to 36586412; 24721225
Phenotypes for gene: ZMYM3 were set to Neurodevelopmental disorders (NDDs)
Review for gene: ZMYM3 was set to GREEN
Added comment: PMID: 36586412
Using the MatchMaker Exchange - Described 27 individuals with rare, variation in the ZMYM3. Most individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) with de novo variants.
Overlapping features included developmental delay, intellectual disability, behavioural abnormalities, and a specific facial gestalt in a subset of males.
Variants in almost all individuals are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441 (R441W), a site at which variation has been previously seen in NDD-affected siblings (24721225), and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T).
ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5133 ZMYM3 Belinda Chong reviewed gene: ZMYM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586412, 24721225; Phenotypes: Neurodevelopmental disorders (NDDs); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Ectodermal Dysplasia v0.77 TUFT1 Zornitza Stark Marked gene: TUFT1 as ready
Ectodermal Dysplasia v0.77 TUFT1 Zornitza Stark Gene: tuft1 has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.77 TUFT1 Zornitza Stark Classified gene: TUFT1 as Amber List (moderate evidence)
Ectodermal Dysplasia v0.77 TUFT1 Zornitza Stark Gene: tuft1 has been classified as Amber List (Moderate Evidence).
Ectodermal Dysplasia v0.76 TUFT1 Zornitza Stark gene: TUFT1 was added
gene: TUFT1 was added to Ectodermal Dysplasia. Sources: Expert Review
Mode of inheritance for gene: TUFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUFT1 were set to https://doi.org/10.1093/bjd/ljac026
Phenotypes for gene: TUFT1 were set to Ectodermal dysplasia, MONDO:0019287, TUFT1-related
Review for gene: TUFT1 was set to AMBER
Added comment: 9 individuals from three families reported with woolly hair and skin fragility. One of the variants, c.60+1G>A was present in two of the families, founder effect demonstrated by haplotype analysis. Another loss of function variant present in the third family. Some functional data but mostly expression studies.
Sources: Expert Review
Deafness_IsolatedAndComplex v1.154 KMT2D Zornitza Stark Marked gene: KMT2D as ready
Deafness_IsolatedAndComplex v1.154 KMT2D Zornitza Stark Gene: kmt2d has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.154 KMT2D Zornitza Stark Classified gene: KMT2D as Green List (high evidence)
Deafness_IsolatedAndComplex v1.154 KMT2D Zornitza Stark Gene: kmt2d has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.153 KMT2D Zornitza Stark gene: KMT2D was added
gene: KMT2D was added to Deafness_IsolatedAndComplex. Sources: Expert Review
Mode of inheritance for gene: KMT2D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KMT2D were set to 31949313; 32083401
Phenotypes for gene: KMT2D were set to Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH), MIM#620186
Review for gene: KMT2D was set to GREEN
Added comment: Note new association between missense variants located in a specific region of KMT2D spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from Kabuki syndrome, through a dominant negative mechanism.
- >10 unrelated families with choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability.
Sources: Expert Review
Congenital hypothyroidism v0.37 KMT2D Zornitza Stark Marked gene: KMT2D as ready
Congenital hypothyroidism v0.37 KMT2D Zornitza Stark Gene: kmt2d has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.37 KMT2D Zornitza Stark Classified gene: KMT2D as Green List (high evidence)
Congenital hypothyroidism v0.37 KMT2D Zornitza Stark Gene: kmt2d has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.36 KMT2D Zornitza Stark gene: KMT2D was added
gene: KMT2D was added to Congenital hypothyroidism. Sources: Expert Review
Mode of inheritance for gene: KMT2D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KMT2D were set to 31949313; 32083401
Phenotypes for gene: KMT2D were set to Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH), MIM#620186
Review for gene: KMT2D was set to GREEN
Added comment: Note new association between missense variants located in a specific region of KMT2D spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from Kabuki syndrome, through a dominant negative mechanism.
- >10 unrelated families with choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability.
Sources: Expert Review
Choanal atresia v1.5 KMT2D Zornitza Stark Publications for gene: KMT2D were set to 27991736; 24705355
Choanal atresia v1.4 KMT2D Zornitza Stark Classified gene: KMT2D as Green List (high evidence)
Choanal atresia v1.4 KMT2D Zornitza Stark Gene: kmt2d has been classified as Green List (High Evidence).
Choanal atresia v1.3 KMT2D Zornitza Stark edited their review of gene: KMT2D: Added comment: Note new association between missense variants located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from Kabuki syndrome, through a dominant negative mechanism. - >10 unrelated families with choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability.; Changed rating: GREEN; Changed publications: 24705355, 27991736, 31949313, 32083401; Changed phenotypes: Kabuki syndrome 1, MIM# 147920
Mendeliome v1.572 KMT2D Zornitza Stark Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, MIM# 147920; KMT2D-associated syndrome to Kabuki syndrome 1, MIM# 147920; Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH), MIM#620186
Mendeliome v1.571 KMT2D Zornitza Stark edited their review of gene: KMT2D: Changed phenotypes: Kabuki syndrome 1, MIM# 147920, Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH), MIM#620186
Pulmonary Fibrosis_Interstitial Lung Disease v0.48 Zornitza Stark HPO terms changed from to Pulmonary fibrosis, HP:0002206; Abnormal pulmonary interstitial morphology, HP:0006530
List of related panels changed from to Pulmonary fibrosis; HP:0002206; Abnormal pulmonary interstitial morphology; HP:0006530
Pulmonary Arterial Hypertension v1.14 Zornitza Stark HPO terms changed from to Pulmonary arterial hypertension, HP:0002092
List of related panels changed from to Pulmonary arterial hypertension; HP:0002092
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.12 Zornitza Stark List of related panels changed from to Pseudohypoparathyroidism; HP:0000093
Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Progressive Myoclonic Epilepsy v0.16 Zornitza Stark HPO terms changed from to Myoclonic seizure, HP:0032794
List of related panels changed from to Myoclonic seizure; HP:0032794
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.307 Zornitza Stark HPO terms changed from to Premature ovarian insufficiency, HP:0008209
List of related panels changed from to Premature ovarian insufficiency; HP:0008209
Predominantly Antibody Deficiency v0.125 Zornitza Stark HPO terms changed from to Decreased immunoglobulin level, HP:0041078
List of related panels changed from to Decreased immunoglobulin level; HP:0041078
Haem degradation and bilirubin metabolism defects v0.13 Zornitza Stark HPO terms changed from to Porphyria, MONDO:0037939;Abnormal circulating porphyrin concentration, HP:0010472
List of related panels changed from to Porphyria; MONDO:0037939;Abnormal circulating porphyrin concentration; HP:0010472
Polymicrogyria and Schizencephaly v0.184 Zornitza Stark HPO terms changed from to Polymicrogyria, HP:0002126;Schizencephaly, HP:0010636
List of related panels changed from to Polymicrogyria; HP:0002126;Schizencephaly; HP:0010636
Polydactyly v0.264 Zornitza Stark HPO terms changed from to Polydactyly, HP:0010442
List of related panels changed from to Polydactyly; HP:0010442
Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Polycystic liver disease v1.8 Zornitza Stark HPO terms changed from to Polycystic liver disease, HP:0006557
List of related panels changed from to Polycystic liver disease; HP:0006557
Pituitary hormone deficiency v0.31 Zornitza Stark HPO terms changed from to Hypopituitarism, HP:0040075
List of related panels changed from to Hypopituitarism; HP:0040075
Pierre Robin Sequence v0.44 Zornitza Stark HPO terms changed from to Pierre Robin sequence, HP:0000201
List of related panels changed from to Pierre Robin sequence; HP:0000201
Photosensitivity Syndromes v1.3 Zornitza Stark HPO terms changed from to Cutaneous photosensitivity, HP:0000992
List of related panels changed from to Cutaneous photosensitivity; HP:0000992
Phagocyte Defects v1.10 Zornitza Stark HPO terms changed from to Unusual infection, HP:0032101
List of related panels changed from to Unusual infection; HP:0032101
Peroxisomal Disorders v0.43 Zornitza Stark HPO terms changed from to Peroxisomal disease, MONDO:0019053
List of related panels changed from to Peroxisomal disease; MONDO:0019053
Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Periventricular Grey Matter Heterotopia v1.2 Zornitza Stark HPO terms changed from to Grey matter heterotopia, HP:0002282
List of related panels changed from to Grey matter heterotopia; HP:0002282
Paroxysmal Dyskinesia v0.104 Zornitza Stark HPO terms changed from to Paroxysmal dyskinesia, HP:0007166
List of related panels changed from to Paroxysmal dyskinesia; HP:0007166
Pancreatitis v1.4 Zornitza Stark HPO terms changed from to Pancreatitis, HP:0001733
List of related panels changed from to Pancreatitis; HP:0001733
Palmoplantar Keratoderma and Erythrokeratoderma v0.127 Zornitza Stark HPO terms changed from to Palmoplantar keratoderma, HP:0000982; Erythrokeratoderma, MONDO:0019270
List of related panels changed from to Palmoplantar keratoderma; HP:0000982; Erythrokeratoderma; MONDO:0019270
Pain syndromes v0.33 Zornitza Stark HPO terms changed from to Pain, HP:0012531
List of related panels changed from to Pain; HP:0012531
Overgrowth v1.9 Zornitza Stark HPO terms changed from to Overgrowth, HP:0001548; Tall stature, HP:0000098; Increased body weight, HP:0004324
List of related panels changed from to Overgrowth; HP:0001548; Tall stature; HP:0000098; Increased body weight; HP:0004324
Osteopetrosis v0.30 Zornitza Stark HPO terms changed from to Increased bone mineral density, HP:0011001
List of related panels changed from to Increased bone mineral density; HP:0011001
Osteogenesis Imperfecta and Osteoporosis v0.86 Zornitza Stark HPO terms changed from to Increased susceptibility to fractures, HP:0002659
List of related panels changed from to Increased susceptibility to fractures; HP:0002659
Optic Atrophy v1.12 Zornitza Stark HPO terms changed from to Optic atrophy, HP:0000648
List of related panels changed from to Optic atrophy; HP:0000648
Ocular and Oculocutaneous Albinism v1.7 Zornitza Stark HPO terms changed from to Albinism HP:0001022; Ocular albinism, HP:0001107
List of related panels changed from Albinism HP:0001022 to Albinism HP:0001022; Ocular albinism; HP:0001107
Neurotransmitter Defects v1.6 Zornitza Stark HPO terms changed from to Abnormal CSF metabolite concentration, HP:0025454
List of related panels changed from to Abnormal CSF metabolite concentration; HP:0025454
Neurodegeneration with brain iron accumulation v0.9 Zornitza Stark HPO terms changed from HP:0012675 to Iron accumulation in brain, HP:0012675
List of related panels changed from HP:0012675 to Iron accumulation in brain; HP:0012675
Neurodegenerative disease - adult onset v2.4 Zornitza Stark HPO terms changed from to Neurodegeneration, HP:0002180
List of related panels changed from to Neurodegeneration; HP:0002180
Myopathy Superpanel v1.144 Zornitza Stark HPO terms changed from to Myopathy, HP:0003198; Muscle weakness, HP:0001324
List of related panels changed from to Myopathy; HP:0003198; Muscle weakness; HP:0001324
Muscular dystrophy and myopathy_Paediatric v0.124 Zornitza Stark HPO terms changed from to Muscular dystrophy, HP:0003560; Elevated circulating creatine kinase concentration, HP:0003236
List of related panels changed from to Muscular dystrophy; HP:0003560; Elevated circulating creatine kinase concentration; HP:0003236
Multiple pterygium syndrome_Fetal akinesia sequence v1.1 Zornitza Stark HPO terms changed from to Pterygium, HP:0001059; Akinesia, HP:0002304; Fetal akinesia sequence, HP:0001989
List of related panels changed from to Pterygium; HP:0001059; Akinesia; HP:0002304; Fetal akinesia sequence; HP:0001989
Multiple joint dislocations and laxity v0.8 Zornitza Stark HPO terms changed from to Joint dislocation, HP:0001373; Joint laxity, HP:0001388
List of related panels changed from to Joint dislocation; HP:0001373; Joint laxity; HP:0001388
Multiple epiphyseal dysplasia and pseudoachondroplasia v0.8 Zornitza Stark HPO terms changed from to Multiple epiphyseal dysplasia, HP:0002654
List of related panels changed from to Multiple epiphyseal dysplasia; HP:0002654
Mosaic skin disorders v1.1 Zornitza Stark HPO terms changed from to Abnormality of skin pigmentation, HP:0001000
List of related panels changed from to Abnormality of skin pigmentation; HP:0001000
Monogenic Diabetes v0.33 Zornitza Stark HPO terms changed from to Diabetes mellitus, HP:0000819
List of related panels changed from to Diabetes mellitus; HP:0000819
Mitochondrial disease v0.851 Zornitza Stark HPO terms changed from to Increased serum lactate, HP:0002151; Abnormality of mitochondrial metabolism, HP:0003287
List of related panels changed from to Increased serum lactate; HP:0002151; Abnormality of mitochondrial metabolism; HP:0003287
Microcephaly v1.180 Zornitza Stark HPO terms changed from to Microcephaly, HP:0000252
List of related panels changed from to Microcephaly; HP:0000252
Microcephalic Primordial Dwarfism and Slender bone dysplasias v0.24 Zornitza Stark List of related panels changed from Slender long bone; HP:0003100 to Slender long bone; HP:0003100; Microcephalic primordial dwarfism; MONDO:0017950
Microcephalic Primordial Dwarfism and Slender bone dysplasias v0.23 Zornitza Stark HPO terms changed from to Slender long bone, HP:0003100
List of related panels changed from to Slender long bone; HP:0003100
Metaphyseal dysplasias v0.5 Zornitza Stark HPO terms changed from to Metaphyseal dysplasia, HP:0100255
List of related panels changed from to Metaphyseal dysplasia; HP:0100255
Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Metabolic Disorders Superpanel v6.125 Zornitza Stark HPO terms changed from to Abnormality of metabolism/homeostasis, HP:0001939
List of related panels changed from to Abnormality of metabolism/homeostasis; HP:0001939
Changed child panels to: Congenital Disorders of Glycosylation; Miscellaneous Metabolic Disorders; Hypertension and Aldosterone disorders; Lysosomal Storage Disorder; Fatty Acid Oxidation Defects; Neurotransmitter Defects; Glycogen Storage Diseases; Disorders of branched chain amino acid metabolism; Mitochondrial disease; Rhabdomyolysis; Calcium and Phosphate disorders; Peroxisomal Disorders; Dyslipidaemia; Iron metabolism disorders; Vitamin C Pathway Disorders; Porphyria; Hyperammonaemia
Mendelian susceptibility to Immune Disorders v0.35 Zornitza Stark HPO terms changed from to Unusual infection, HP:0032101
List of related panels changed from to Unusual infection; HP:0032101
Melanoma v0.4 Zornitza Stark HPO terms changed from to Melanoma, HP:0002861
List of related panels changed from to Melanoma; HP:0002861
Medulloblastoma v0.10 Zornitza Stark HPO terms changed from to Medulloblastoma, HP:0002885
List of related panels changed from to Medulloblastoma; HP:0002885
Maturity-onset Diabetes of the Young v1.3 Zornitza Stark HPO terms changed from to Diabetes mellitus, HP:0000819
List of related panels changed from to Diabetes mellitus; HP:0000819
Mandibulofacial Acrofacial dysostosis v1.5 Zornitza Stark HPO terms changed from to Craniofacial dysostosis, HP:0004439
List of related panels changed from to Craniofacial dysostosis; HP:0004439
Malignant Hyperthermia Susceptibility v1.7 Zornitza Stark HPO terms changed from to Malignant hyperthermia, HP:0002047; Rhabdomyolysis, HP:0003201
List of related panels changed from to Malignant hyperthermia; HP:0002047; Rhabdomyolysis; HP:0003201
Malformations of cortical development_Superpanel v4.44 Zornitza Stark HPO terms changed from to Abnormal cerebral cortex morphology, HP:0002538
List of related panels changed from to Abnormal cerebral cortex morphology; HP:0002538
Macular Dystrophy/Stargardt Disease v0.41 Zornitza Stark HPO terms changed from to Macular dystrophy, HP:0007754
List of related panels changed from to Macular dystrophy; HP:0007754
Macrocephaly_Megalencephaly v0.122 Zornitza Stark HPO terms changed from to Macrocephaly, HP:0000256; Megalencephaly, HP:0001355
List of related panels changed from to Macrocephaly; HP:0000256; Megalencephaly; HP:0001355
Additional findings_Paediatric v0.277 PLS1 Zornitza Stark Marked gene: PLS1 as ready
Additional findings_Paediatric v0.277 PLS1 Zornitza Stark Gene: pls1 has been classified as Green List (High Evidence).
Additional findings_Paediatric v0.277 PLS1 Zornitza Stark Classified gene: PLS1 as Green List (high evidence)
Additional findings_Paediatric v0.277 PLS1 Zornitza Stark Gene: pls1 has been classified as Green List (High Evidence).
Lysosomal Storage Disorder v1.10 Zornitza Stark HPO terms changed from to Lysosomal storage disorder, MONDO:0002561; Visceromegaly, HP:0003271
List of related panels changed from to Lysosomal storage disorder; MONDO:0002561; Visceromegaly; HP:0003271
Lymphoedema_syndromic v0.12 Zornitza Stark HPO terms changed from to Lymphedema, HP:0001004
List of related panels changed from to Lymphedema; HP:0001004
Lymphoedema_nonsyndromic v0.31 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Lymphoedema_nonsyndromic v0.30 Zornitza Stark HPO terms changed from to Lymphedema, HP:0001004
List of related panels changed from to Lymphedema; HP:0001004
Long QT Syndrome v0.61 Zornitza Stark HPO terms changed from to Prolonged QT interval, HP:0001657
List of related panels changed from to Prolonged QT interval; HP:0001657
Liver Failure_Paediatric v1.20 Zornitza Stark HPO terms changed from to Liver failure, HP:0001399
List of related panels changed from to Liver failure; HP:0001399
Lipodystrophy_Lipoatrophy v1.8 Zornitza Stark HPO terms changed from to Lipodystrophy, HP:0009125
List of related panels changed from to Lipodystrophy; HP:0009125
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.70 Zornitza Stark HPO terms changed from to Limb-girdle muscular dystrophy, MONDO:0016971; Proximal muscle weakness, HP:0003701
List of related panels changed from to Limb-girdle muscular dystrophy; MONDO:0016971;Proximal muscle weakness; HP:0003701
Limb and Digital Malformations SuperPanel v0.50 Zornitza Stark HPO terms changed from to Limb abnormality, HP:0040064
List of related panels changed from to Limb abnormality; HP:0040064
Leukodystrophy_Superpanel v0.390 Zornitza Stark HPO terms changed from to Leukodystrophy, HP:0002415; Abnormal cerebral white matter morphology, HP:0002500; Abnormal CNS myelination, HP:0011400
List of related panels changed from to Leukodystrophy; HP:0002415; Abnormal cerebral white matter morphology; HP:0002500; Abnormal CNS myelination; HP:0011400
Leukodystrophy - paediatric v0.279 Zornitza Stark List of related panels changed from to Leukodystrophy; HP:0002415; Abnormal cerebral white matter morphology; HP:0002500; Abnormal CNS myelination; HP:0011400
Leukodystrophy - adult onset v0.106 Zornitza Stark List of related panels changed from to Leukodystrophy; HP:0002415; Abnormal cerebral white matter morphology; HP:0002500; Abnormal CNS myelination; HP:0011400
Kidneyome_SuperPanel v8.3 Zornitza Stark HPO terms changed from to Abnormality of the kidney, HP:0000077
List of related panels changed from to Abnormality of the kidney; HP:0000077
Kabuki syndrome v0.13 Zornitza Stark List of related panels changed from to Kabuki syndrome; MONDO:0016512
Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Joubert syndrome and other neurological ciliopathies v1.24 Zornitza Stark HPO terms changed from to Molar tooth sign on MRI, HP:0002419; Joubert syndrome, MONDO:0018772
List of related panels changed from to Molar tooth sign on MRI; HP:0002419; Joubert syndrome; MONDO:0018772
Metal Metabolism Disorders v0.32 Zornitza Stark HPO terms changed from to Abnormality of iron homeostasis, HP:0011031
List of related panels changed from to Abnormality of iron homeostasis; HP:0011031
Inflammatory bowel disease v0.86 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Inflammatory bowel disease v0.85 Zornitza Stark HPO terms changed from to Gastrointestinal inflammation, HP:0004386
List of related panels changed from to Gastrointestinal inflammation; HP:0004386
Immunological disorders_SuperPanel v9.58 Zornitza Stark HPO terms changed from to Abnormality of the immune system, HP:0002715
List of related panels changed from to Abnormality of the immune system; HP:0002715
Ichthyosis v1.3 Zornitza Stark HPO terms changed from to Ichthyosis, HP:0008064
List of related panels changed from to Ichthyosis; HP:0008064
Hypertrophic cardiomyopathy_HCM v0.171 Zornitza Stark HPO terms changed from to Hypertrophic cardiomyopathy, HP:0001639
List of related panels changed from to Hypertrophic cardiomyopathy; HP:0001639
Hypertrichosis syndromes v0.40 Zornitza Stark HPO terms changed from to Hypertrichosis, HP:0000998
List of related panels changed from to Hypertrichosis; HP:0000998
Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Hyperthyroidism v0.21 Zornitza Stark HPO terms changed from to Hyperthyroidism HP:0000836
Hypertension and Aldosterone disorders v1.13 Zornitza Stark HPO terms changed from to Hypertension, HP:0000822; Abnormal circulating aldosterone, HP:0040085
List of related panels changed from to Hypertension; HP:0000822; Abnormal circulating aldosterone; HP:0040085
Hyperinsulinism v1.7 Zornitza Stark HPO terms changed from to Hyperinsulinaemia, HP:0000842;Hypoglycemia, HP:0001943
List of related panels changed from to Hyperinsulinaemia; HP:0000842;Hypoglycemia; HP:0001943
Hyper-IgE syndrome v1.5 Zornitza Stark HPO terms changed from to Increased circulating IgE level, HP:0003212
Hyper-IgE syndrome v1.4 Zornitza Stark List of related panels changed from to Increased circulating IgE level; HP:0003212
Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Hypercalcaemia v1.2 Zornitza Stark HPO terms changed from to Hypercalcemia, HP:0003072
List of related panels changed from to Hypercalcemia; HP:0003072
Hyperammonaemia v0.7 Zornitza Stark HPO terms changed from to Hyperammonaemia, HP:0001987
List of related panels changed from to Hyperammonaemia; HP:0001987
Hydrops fetalis v0.294 Zornitza Stark HPO terms changed from to Hydrops fetalis, HP:0001789
List of related panels changed from to Hydrops fetalis; HP:0001789
Hydrocephalus_Ventriculomegaly v0.119 Zornitza Stark HPO terms changed from to Hydrocephalus, HP:0000238; Ventriculomegaly, HP:0002119
List of related panels changed from to Hydrocephalus; HP:0000238; Ventriculomegaly; HP:0002119
Holoprosencephaly and septo-optic dysplasia v1.7 Zornitza Stark HPO terms changed from to Holoprosencephaly, HP:0001360; Septo-optic dysplasia, HP:0100842
List of related panels changed from to Holoprosencephaly; HP:0001360; Septo-optic dysplasia; HP:0100842
Hirschsprung disease v0.23 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Hirschsprung disease v0.22 Zornitza Stark HPO terms changed from to Aganglionic megacolon, HP:0002251
List of related panels changed from to Aganglionic megacolon; HP:0002251
Heterotaxy v1.26 Zornitza Stark HPO terms changed from to Heterotaxy, HP:0030853; Dextrocardia, HP:0001651; Asplenia, HP:0001746; Abnormal spatial orientation of cardiac segments, HP:0011534; Polysplenia, HP:0001748;Midline liver, HP:0034188
List of related panels changed from to Heterotaxy; HP:0030853; Dextrocardia; HP:0001651; Asplenia; HP:0001746; Abnormal spatial orientation of cardiac segments; HP:0011534; Polysplenia; HP:0001748;Midline liver; HP:0034188
Hereditary Spastic Paraplegia Superpanel v2.54 Zornitza Stark HPO terms changed from to Spasticity, HP:0001257
List of related panels changed from to Spasticity; HP:0001257
Hereditary Spastic Paraplegia - paediatric v1.52 Zornitza Stark HPO terms changed from to Spasticity, HP:0001257
List of related panels changed from to Spasticity; HP:0001257
Hereditary Spastic Paraplegia - adult onset v1.3 Zornitza Stark HPO terms changed from to Spasticity, HP:0001257
List of related panels changed from to Spasticity; HP:0001257
Hereditary Neuropathy_CMT_IsolatedAndComplex v1.55 Zornitza Stark HPO terms changed from to Peripheral neuropathy, HP:0009830
List of related panels changed from to Peripheral neuropathy; HP:0009830
Hereditary Neuropathy - complex v0.138 Zornitza Stark HPO terms changed from to Peripheral neuropathy, HP:0009830
List of related panels changed from to Peripheral neuropathy; HP:0009830
Hereditary Neuropathy_CMT - isolated v1.25 Zornitza Stark HPO terms changed from to Peripheral neuropathy, HP:0009830
List of related panels changed from to Peripheral neuropathy; HP:0009830
Hereditary Haemorrhagic Telangiectasia v1.5 Zornitza Stark HPO terms changed from to Telangiectasia, HP:0001009
List of related panels changed from to Telangiectasia; HP:0001009
Hereditary angioedema v1.5 Zornitza Stark HPO terms changed from to Angioedema, HP:0100665
List of related panels changed from to Angioedema; HP:0100665
Hand and foot malformations v0.71 Zornitza Stark HPO terms changed from to Abnormal hand morphology, HP:0005922; Abnormal foot morphology, HP:0001760
List of related panels changed from to Abnormal hand morphology; HP:0005922; Abnormal foot morphology; HP:0001760
Hair disorders v0.67 Zornitza Stark HPO terms changed from to Abnormal hair morphology, HP:0001595
List of related panels changed from to Abnormal hair morphology; HP:0001595
Haematuria_Alport v1.1 Zornitza Stark HPO terms changed from to Hematuria, HP:0000790; Proteinuria, HP:0000093
List of related panels changed from to Hematuria; HP:0000790; Proteinuria; HP:0000093
Growth failure v1.56 Zornitza Stark HPO terms changed from to Failure to thrive, HP:0001508; Growth delay, HP:0001510
List of related panels changed from to Failure to thrive; HP:0001508; Growth delay; HP:0001510
Glycogen Storage Diseases v1.2 Zornitza Stark HPO terms changed from to Abnormal hepatic glycogen storage, HP:0500030; Abnormal muscle glycogen content, HP:0012269; Visceromegaly, HP:0003271;Hypoglycemia, HP:0001943
List of related panels changed from to Abnormal hepatic glycogen storage; HP:0500030; Abnormal muscle glycogen content; HP:0012269; Visceromegaly; HP:0003271;Hypoglycemia; HP:0001943
Glaucoma congenital v1.6 Zornitza Stark HPO terms changed from to Glaucoma, HP:0000501
List of related panels changed from to Glaucoma; HP:0000501
Gastrointestinal neuromuscular disease v1.19 Zornitza Stark HPO terms changed from to Gastrointestinal dysmotility, HP:0002579
List of related panels changed from to Gastrointestinal dysmotility; HP:0002579
Frontonasal dysplasia v1.1 Zornitza Stark HPO terms changed from to Midline defect of the nose, HP:0004122; Midline facial cleft, HP:0100629; Cranium bifidum occultum, HP:0004423
List of related panels changed from to Midline defect of the nose; HP:0004122; Midline facial cleft; HP:0100629; Cranium bifidum occultum; HP:0004423
Foveal Hypoplasia v0.8 Zornitza Stark HPO terms changed from to Abnormal foveal morphology, HP:0000493
List of related panels changed from to Abnormal foveal morphology; HP:0000493
Focal Epilepsy v0.13 Zornitza Stark HPO terms changed from to Focal seizure, HP:0007359
List of related panels changed from to Focal seizure; HP:0007359
Fatty Acid Oxidation Defects v1.9 Zornitza Stark HPO terms changed from to Abnormal circulating fatty acid concentration, HP:0004359; Rhabdomyolysis, HP:0003201; Hypoglycaemia, HP:0001943
List of related panels changed from to Abnormal circulating fatty acid concentration; HP:0004359; Rhabdomyolysis; HP:0003201; Hypoglycaemia; HP:0001943
Familial hypoparathyroidism v1.3 Zornitza Stark HPO terms changed from to Hypoparathyroidism, HP:0000829
List of related panels changed from to Hypoparathyroidism; HP:0000829
Familial hypercholesterolaemia v0.27 Zornitza Stark HPO terms changed from to Abnormal circulating cholesterol concentration, HP:0003107
List of related panels changed from to Abnormal circulating cholesterol concentration; HP:0003107
Genetic Epilepsy v0.1822 Zornitza Stark List of related panels changed from to Seizure; HP:0001250
Familial Generalised Epilepsy v0.13 Zornitza Stark HPO terms changed from to Seizure, HP:0001250
List of related panels changed from to Seizure; HP:0001250
Eye Anterior Segment Abnormalities v1.3 Zornitza Stark HPO terms changed from to Abnormal anterior eye segment morphology, HP:0004328
List of related panels changed from to Abnormal anterior eye segment morphology; HP:0004328
Episodic Ataxia v1.1 Zornitza Stark HPO terms changed from to Ataxia, HP:0001251
List of related panels changed from to Ataxia; HP:0001251
Epidermolysis bullosa v1.5 Zornitza Stark HPO terms changed from to Abnormal blistering of the skin, HP:0008066
List of related panels changed from to Abnormal blistering of the skin; HP:0008066
Ehlers Danlos syndromes v1.3 Zornitza Stark HPO terms changed from to Joint dislocation, HP:0001373; Poor wound healing, HP:0001058; Uterine rupture, HP:0001058; Abnormality of connective tissue, HP:0003549
List of related panels changed from to Joint dislocation; HP:0001373; Poor wound healing; HP:0001058; Uterine rupture; HP:0001058; Abnormality of connective tissue; HP:0003549
Ectodermal Dysplasia v0.75 Zornitza Stark HPO terms changed from to Ectodermal dysplasia, HP:0000968
List of related panels changed from to Ectodermal dysplasia; HP:0000968
Early-onset Parkinson disease v0.237 Zornitza Stark HPO terms changed from to Abnormality of extrapyramidal motor function, HP:0002071
List of related panels changed from to Abnormality of extrapyramidal motor function; HP:0002071
Early-onset Dementia v0.159 Zornitza Stark HPO terms changed from to Cognitive impairment, HP:0100543
List of related panels changed from to Cognitive impairment; HP:0100543
Dystonia_Superpanel v1.80 Zornitza Stark HPO terms changed from to Dystonia, HP:0001332
List of related panels changed from to Dystonia; HP:0001332
Dystonia - isolated/combined v1.28 Zornitza Stark HPO terms changed from to Dystonia, HP:0001332
List of related panels changed from to Dystonia; HP:0001332
Dystonia - complex v0.218 Zornitza Stark HPO terms changed from to Dystonia, HP:0001332
List of related panels changed from to Dystonia; HP:0001332
Dyslipidaemia v0.36 Zornitza Stark HPO terms changed from to Abnormal circulating lipid concentration, HP:0003119
List of related panels changed from to Abnormal circulating lipid concentration; HP:0003119
Disorders of immune dysregulation v0.164 Zornitza Stark HPO terms changed from to Immune dysregulation, HP:0002958
List of related panels changed from to Immune dysregulation; HP:0002958
Aminoacidopathy v1.1 Zornitza Stark HPO terms changed from to Abnormality of amino acid metabolism, HP:0004337
List of related panels changed from to Abnormality of amino acid metabolism; HP:0004337
Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Dilated Cardiomyopathy v1.15 Zornitza Stark HPO terms changed from to Dilated cardiomyopathy, HP:0001644
List of related panels changed from to Dilated cardiomyopathy; HP:0001644
Differences of Sex Development v0.269 Zornitza Stark HPO terms changed from to Abnormality of the genital system, HP:0000078
List of related panels changed from to Abnormality of the genital system; HP:0000078
Diamond Blackfan anaemia v1.7 Zornitza Stark HPO terms changed from to Anemia, HP:0001903; Abnormality of thumb morphology, HP:0001172
List of related panels changed from to Anemia; HP:0001903; Abnormality of thumb morphology; HP:0001172
Diabetes Insipidus v1.3 Zornitza Stark HPO terms changed from to Polydipsia, HP:0001959; Polyuria, HP:0000103
Diabetes Insipidus v1.2 Zornitza Stark List of related panels changed from to Polydipsia; HP:0001959; Polyuria; HP:0000103
Desmosomal disorders v0.33 Zornitza Stark HPO terms changed from to Abnormal blistering of the skin, HP:0008066; Alopecia, HP:0001596
Desmosomal disorders v0.32 Zornitza Stark List of related panels changed from to Abnormal blistering of the skin; HP:0008066; Alopecia; HP:0001596
Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Defects of innate immunity v0.128 Zornitza Stark HPO terms changed from to Unusual infections, HP:0032101
List of related panels changed from to Unusual infections; HP:0032101
Deafness_IsolatedAndComplex v1.152 Zornitza Stark HPO terms changed from to Hearing impairment, HP:0000365
List of related panels changed from to Hearing impairment; HP:0000365
Deafness_Isolated v1.39 Zornitza Stark HPO terms changed from to Hearing impairment, HP:0000365
List of related panels changed from to Hearing impairment; HP:0000365
Corneal Dystrophy v1.8 Zornitza Stark HPO terms changed from to Abnormal corneal morphology, HP:0000481
List of related panels changed from to Abnormal corneal morphology; HP:0000481
Congenital Stationary Night Blindness v0.22 Zornitza Stark HPO terms changed from to Congenital stationary night blindness, HP:0007642; Retinal dystrophy, HP:0000556
List of related panels changed from to Congenital stationary night blindness; HP:0007642; Retinal dystrophy; HP:0000556
Congenital ophthalmoplegia v1.7 Zornitza Stark List of related panels changed from to Abnormality of eye movement; HP:0000496
Congenital Disorders of Glycosylation v1.30 Zornitza Stark List of related panels changed from to Abnormal transferrin saturation; HP:0040135
Cone-rod Dystrophy v0.48 Zornitza Stark List of related panels changed from to Retinal dystrophy; HP:0000556
Complement Deficiencies v0.73 Zornitza Stark HPO terms changed from to Abnormality of complement system, HP:0005339
List of related panels changed from to Abnormality of complement system; HP:0005339
Common Variable Immunodeficiency v1.4 Zornitza Stark HPO terms changed from to Recurrent bacterial infections, HP:0002718; Abnormal immunoglobulin level, HP:0010701
List of related panels changed from to Common variable immunodeficiency; MONDO:0015517; Recurrent bacterial infections; HP:0002718; Abnormal immunoglobulin level; HP:0010701
Combined Immunodeficiency v1.32 Zornitza Stark HPO terms changed from to Combined immunodeficiency, HP:0005387
List of related panels changed from to Combined immunodeficiency; MONDO:0015131; Combined immunodeficiency; HP:0005387
Ciliopathies v1.41 Zornitza Stark List of related panels changed from to Ciliopathy; MONDO:0005308
Chronic granulomatous disease v1.3 Zornitza Stark HPO terms changed from to Recurrent bacterial infections, HP:0002718
List of related panels changed from Chronic granulomatous disease; MONDO:0018305 to Chronic granulomatous disease; MONDO:0018305; Recurrent bacterial infections; HP:0002718
Chronic granulomatous disease v1.2 Zornitza Stark List of related panels changed from to Chronic granulomatous disease; MONDO:0018305
Chondrodysplasia Punctata v1.1 Zornitza Stark List of related panels changed from to Chondrodysplasia punctata; MONDO:0019701
Cardiomyopathy_Paediatric v0.150 Zornitza Stark List of related panels changed from Cardiomyopathy; HP:0001638 to Cardiomyopathy; HP:0001638;Abnormality of the myocardium; HP:0001637
Calcium and Phosphate disorders v0.80 Zornitza Stark HPO terms changed from to Abnormal blood calcium levels, HP:0004363; Abnormal blood phosphate levels, HP:0100529
List of related panels changed from to Abnormal blood calcium levels; HP:0004363; Abnormal blood phosphate levels; HP:0100529
Atypical Haemolytic Uraemic Syndrome_MPGN v0.48 Zornitza Stark HPO terms changed from to Haemolytic anaemia, HP:0001878
List of related panels changed from to Haemolytic anaemia; HP:0001878
BabyScreen+ newborn screening v0.1820 ECHS1 Zornitza Stark Marked gene: ECHS1 as ready
BabyScreen+ newborn screening v0.1820 ECHS1 Zornitza Stark Gene: echs1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1820 ECHS1 Zornitza Stark Classified gene: ECHS1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1820 ECHS1 Zornitza Stark Gene: echs1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1819 ECHS1 Zornitza Stark gene: ECHS1 was added
gene: ECHS1 was added to gNBS. Sources: Expert list
treatable, metabolic tags were added to gene: ECHS1.
Mode of inheritance for gene: ECHS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ECHS1 were set to 32642440
Phenotypes for gene: ECHS1 were set to Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency MIM# 616277
Review for gene: ECHS1 was set to GREEN
Added comment: Well established gene-disease association.

Usually presents in infancy.

Treatable-ID – level 4 evidence: valine restriction improves psychomotor/cognitive development/IQ; improves neurological manifestations (incl. neuro-imaging); improves systemic manifestations (PMID: 32642440)
Sources: Expert list
BabyScreen+ newborn screening v0.1818 DHFR Zornitza Stark Marked gene: DHFR as ready
BabyScreen+ newborn screening v0.1818 DHFR Zornitza Stark Gene: dhfr has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1818 DHFR Zornitza Stark Classified gene: DHFR as Green List (high evidence)
BabyScreen+ newborn screening v0.1818 DHFR Zornitza Stark Gene: dhfr has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1817 DHFR Zornitza Stark gene: DHFR was added
gene: DHFR was added to gNBS. Sources: Expert Review
treatable, metabolic tags were added to gene: DHFR.
Mode of inheritance for gene: DHFR was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DHFR were set to Megaloblastic anaemia due to dihydrofolate reductase deficiency, MIM# 613839
Review for gene: DHFR was set to GREEN
Added comment: Established gene-disease association.

Congenital onset.

Treatment: folinic acid.

Non-genetic confirmatory testing: complete blood count with MCV and CSF 5-methyltetrahydrofolate level.
Sources: Expert Review
BabyScreen+ newborn screening v0.1816 DNAJC12 Zornitza Stark Marked gene: DNAJC12 as ready
BabyScreen+ newborn screening v0.1816 DNAJC12 Zornitza Stark Gene: dnajc12 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1816 DNAJC12 Zornitza Stark Classified gene: DNAJC12 as Green List (high evidence)
BabyScreen+ newborn screening v0.1816 DNAJC12 Zornitza Stark Gene: dnajc12 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1815 DNAJC12 Zornitza Stark gene: DNAJC12 was added
gene: DNAJC12 was added to gNBS. Sources: Expert Review
treatable, metabolic tags were added to gene: DNAJC12.
Mode of inheritance for gene: DNAJC12 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNAJC12 were set to Hyperphenylalaninemia, mild, non-BH4-deficient, MIM#617384
Review for gene: DNAJC12 was set to GREEN
Added comment: Established gene-disease association.

Manifests as mild hyperphenylalaninaemia that would be detected on NBS – untreated results in axial hypotonia, dystonia, nystagmus, global developmental delay,
and intellectual disability.

From Treatable-ID, level 4 evidence that BH4, L-dopa + carbidopa +/-, 5-
hydroxytryptophan improves psychomotor/cognitive development/IQ; prevents, halts, or slows clinical deterioration and improves neurological manifestations.
Sources: Expert Review
BabyScreen+ newborn screening v0.1814 GALM Zornitza Stark Marked gene: GALM as ready
BabyScreen+ newborn screening v0.1814 GALM Zornitza Stark Gene: galm has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1814 GALM Zornitza Stark Classified gene: GALM as Green List (high evidence)
BabyScreen+ newborn screening v0.1814 GALM Zornitza Stark Gene: galm has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1813 GALM Zornitza Stark gene: GALM was added
gene: GALM was added to gNBS. Sources: Expert Review
treatable, metabolic tags were added to gene: GALM.
Mode of inheritance for gene: GALM was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GALM were set to Galactosemia IV MIM#618881
Review for gene: GALM was set to GREEN
Added comment: Established gene-disease association.

Congenital onset.

Treatment: galactose/lactose-restricted diet.

Non-genetic confirmatory testing: galactose level.
Sources: Expert Review
BabyScreen+ newborn screening v0.1812 GCH1 Zornitza Stark Marked gene: GCH1 as ready
BabyScreen+ newborn screening v0.1812 GCH1 Zornitza Stark Gene: gch1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1812 GCH1 Zornitza Stark Phenotypes for gene: GCH1 were changed from Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230; Dystonia, dopa-responsive to Hyperphenylalaninemia, BH4-deficient, B, MIM# 233910; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230
BabyScreen+ newborn screening v0.1811 GCH1 Zornitza Stark Publications for gene: GCH1 were set to
BabyScreen+ newborn screening v0.1810 GCH1 Zornitza Stark Mode of inheritance for gene: GCH1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1809 GCH1 Zornitza Stark Classified gene: GCH1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1809 GCH1 Zornitza Stark Gene: gch1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1808 GCH1 Zornitza Stark Tag treatable tag was added to gene: GCH1.
Tag metabolic tag was added to gene: GCH1.
BabyScreen+ newborn screening v0.1808 GCH1 Zornitza Stark reviewed gene: GCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperphenylalaninemia, BH4-deficient, B, MIM# 233910, Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1807 PMS2 Zornitza Stark Marked gene: PMS2 as ready
BabyScreen+ newborn screening v0.1807 PMS2 Zornitza Stark Gene: pms2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1807 PMS2 Zornitza Stark Phenotypes for gene: PMS2 were changed from Lynch syndrome to Mismatch repair cancer syndrome 4, MIM# 619101
BabyScreen+ newborn screening v0.1806 PMS2 Zornitza Stark Mode of inheritance for gene: PMS2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1805 PMS2 Zornitza Stark Classified gene: PMS2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1805 PMS2 Zornitza Stark Gene: pms2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1804 PMS2 Zornitza Stark Tag for review tag was added to gene: PMS2.
Tag cancer tag was added to gene: PMS2.
Tag treatable tag was added to gene: PMS2.
BabyScreen+ newborn screening v0.1804 PMS2 Zornitza Stark reviewed gene: PMS2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mismatch repair cancer syndrome 4, MIM# 619101; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1804 MSH6 Zornitza Stark Marked gene: MSH6 as ready
BabyScreen+ newborn screening v0.1804 MSH6 Zornitza Stark Gene: msh6 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1804 MSH6 Zornitza Stark Phenotypes for gene: MSH6 were changed from Lynch syndrome to Mismatch repair cancer syndrome 3, MIM# 619097
BabyScreen+ newborn screening v0.1803 MSH6 Zornitza Stark Mode of inheritance for gene: MSH6 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1802 MSH6 Zornitza Stark Classified gene: MSH6 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1802 MSH6 Zornitza Stark Gene: msh6 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1801 MSH6 Zornitza Stark Tag for review tag was added to gene: MSH6.
Tag cancer tag was added to gene: MSH6.
Tag treatable tag was added to gene: MSH6.
BabyScreen+ newborn screening v0.1801 MSH6 Zornitza Stark reviewed gene: MSH6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mismatch repair cancer syndrome 3, MIM# 619097; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1801 MLH1 Zornitza Stark changed review comment from: Note mono-allelic variants are associated with adult-onset cancer risk.

MMRCS rated as 'strong actionability' in paediatric patients by ClinGen.

The hallmark of MMRCS is early onset cancer, most often in childhood or young adulthood. The median age of onset of the first tumor is 7.5 years, with a wide range observed (0.4-39 years). A large portion (up to 40%) of patients develop metachronous second malignancies. The median survival after diagnosis of the primary tumor is less than 30 months. Prognosis depends on the possibility of complete resection, making early detection paramount. It is unclear what tumor spectrum will emerge among adults with MMRCS. Brain tumors are frequent and often diagnosed in the first decade of life. The rate of progression appears to be rapid in the brain tumors. The median age at diagnosis of brain tumors is 9 years (range, 2-40 years). Brain tumors are by far the most common cause of death. Colonic adenomatous oligopolyposis typically is diagnosed between 5 and 10 years of age. The progression of adenomas to malignancy in MMRCS is the most rapid of any inherited colorectal cancer syndrome. Among MMRCS patients presenting with colorectal cancer (CRC), the median age at diagnosis was 16 years (range, 8-48 years) with more than half of patients classified as pediatric-onset CRC. The age of onset of small-bowel adenomas is later; they typically develop in the second decade of life. The median age at diagnosis of small-bowel cancer was 28 years, with a range of 11-42 years. The lifetime risk of gastrointestinal cancer among MMRCS patients is the highest reported of all gastrointestinal cancer predisposition syndromes as a function of age. The median age at diagnosis of hematologic malignancy is 6.6 years. Endometrial cancer has been diagnosed between 19 and 44 years. The age at diagnosis of urinary tract tumors has ranged from 10 to 22 years.

The management of MMRCS is based on the current estimates of neoplasia risk and the early age of onset for the cancers, which have led to tentative guidelines for the management of these patients. The age at which to begin surveillance varies by guideline and is represented below as age ranges. In patients with MMRCS, the following surveillance is suggested:

•Screening for CRC by colonoscopy is recommended annually beginning at age 6 to 8 years. Once polyps are identified, colonoscopy every 6 months is recommended.
•Annual surveillance for small-bowel cancer by upper endoscopy and video capsule endoscopy is suggested beginning at 8 to 10 years of age. Monitoring of hemoglobin levels every 6 months also is suggested, beginning at 8 years of age.
•Surveillance for brain tumors by brain MRI every 6 to 12 months is suggested starting at the time of diagnosis even in the first year of life to age 2 years.
•Currently, no proven surveillance modalities for leukemia or lymphoma have been identified. Complete blood count to screen for leukemia is suggested every 6 months beginning at 1 year of age. Clinical examinations and abdominal ultrasounds to screen for lymphoma every 6 months may be considered by the treating physician.
•For individuals with a uterus, surveillance for endometrial cancer is suggested by transvaginal ultrasound, pelvic examination, and endometrial sampling annually starting at age 20 years.
•Surveillance for cancer of the urinary tract is suggested, with annual urinalysis starting at age 10 to 20 years.
•To screen for other types of tumors, whole-body MRI could be considered once a year starting at 6 years of age or when anesthesia is not needed. This method should not replace the need for ultrasound and brain MRI.

Estimated penetrance in MMRCS:

•50% develop small-bowel adenomas
•>90% develop colorectal adenomas
•59 to 70% develop colorectal cancer
•58 to 70% develop high-grade brain tumours
•20-40% develop lymphoma
•10-40% develop leukemia
•10 to 18% develop small-bowel cancer
•<10% develop endometrial cancer
•<10% develop urinary tract cancer

•<10% develop cancer of other sites; to: Note mono-allelic variants are associated with adult-onset cancer risk.

MMRCS rated as 'strong actionability' in paediatric patients by ClinGen.

The hallmark of MMRCS is early onset cancer, most often in childhood or young adulthood. The median age of onset of the first tumor is 7.5 years, with a wide range observed (0.4-39 years). A large portion (up to 40%) of patients develop metachronous second malignancies. The median survival after diagnosis of the primary tumor is less than 30 months. Prognosis depends on the possibility of complete resection, making early detection paramount. It is unclear what tumor spectrum will emerge among adults with MMRCS. Brain tumors are frequent and often diagnosed in the first decade of life. The rate of progression appears to be rapid in the brain tumors. The median age at diagnosis of brain tumors is 9 years (range, 2-40 years). Brain tumors are by far the most common cause of death. Colonic adenomatous oligopolyposis typically is diagnosed between 5 and 10 years of age. The progression of adenomas to malignancy in MMRCS is the most rapid of any inherited colorectal cancer syndrome. Among MMRCS patients presenting with colorectal cancer (CRC), the median age at diagnosis was 16 years (range, 8-48 years) with more than half of patients classified as pediatric-onset CRC. The age of onset of small-bowel adenomas is later; they typically develop in the second decade of life. The median age at diagnosis of small-bowel cancer was 28 years, with a range of 11-42 years. The lifetime risk of gastrointestinal cancer among MMRCS patients is the highest reported of all gastrointestinal cancer predisposition syndromes as a function of age. The median age at diagnosis of hematologic malignancy is 6.6 years. Endometrial cancer has been diagnosed between 19 and 44 years. The age at diagnosis of urinary tract tumors has ranged from 10 to 22 years.

The management of MMRCS is based on the current estimates of neoplasia risk and the early age of onset for the cancers, which have led to tentative guidelines for the management of these patients. The age at which to begin surveillance varies by guideline and is represented below as age ranges. In patients with MMRCS, the following surveillance is suggested:

•Screening for CRC by colonoscopy is recommended annually beginning at age 6 to 8 years. Once polyps are identified, colonoscopy every 6 months is recommended.
•Annual surveillance for small-bowel cancer by upper endoscopy and video capsule endoscopy is suggested beginning at 8 to 10 years of age. Monitoring of hemoglobin levels every 6 months also is suggested, beginning at 8 years of age.
•Surveillance for brain tumors by brain MRI every 6 to 12 months is suggested starting at the time of diagnosis even in the first year of life to age 2 years.
•Currently, no proven surveillance modalities for leukemia or lymphoma have been identified. Complete blood count to screen for leukemia is suggested every 6 months beginning at 1 year of age. Clinical examinations and abdominal ultrasounds to screen for lymphoma every 6 months may be considered by the treating physician.
•For individuals with a uterus, surveillance for endometrial cancer is suggested by transvaginal ultrasound, pelvic examination, and endometrial sampling annually starting at age 20 years.
•Surveillance for cancer of the urinary tract is suggested, with annual urinalysis starting at age 10 to 20 years.
•To screen for other types of tumors, whole-body MRI could be considered once a year starting at 6 years of age or when anesthesia is not needed. This method should not replace the need for ultrasound and brain MRI.

Estimated penetrance in MMRCS:

•50% develop small-bowel adenomas
•>90% develop colorectal adenomas
•59 to 70% develop colorectal cancer
•58 to 70% develop high-grade brain tumours
•20-40% develop lymphoma
•10-40% develop leukemia
•10 to 18% develop small-bowel cancer
•<10% develop endometrial cancer
•<10% develop urinary tract cancer
•<10% develop cancer of other sites
BabyScreen+ newborn screening v0.1801 MLH1 Zornitza Stark Marked gene: MLH1 as ready
BabyScreen+ newborn screening v0.1801 MLH1 Zornitza Stark Gene: mlh1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1801 MLH1 Zornitza Stark Phenotypes for gene: MLH1 were changed from Lynch syndrome to Mismatch repair cancer syndrome 1, MIM# 276300
BabyScreen+ newborn screening v0.1800 MLH1 Zornitza Stark Mode of inheritance for gene: MLH1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1799 TMPRSS3 Seb Lunke Marked gene: TMPRSS3 as ready
BabyScreen+ newborn screening v0.1799 TMPRSS3 Seb Lunke Gene: tmprss3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1799 TMPRSS3 Seb Lunke Phenotypes for gene: TMPRSS3 were changed from Deafness, autosomal recessive to deafness, autosomal recessive MIM#601072
BabyScreen+ newborn screening v0.1798 TMPRSS3 Seb Lunke Publications for gene: TMPRSS3 were set to
BabyScreen+ newborn screening v0.1797 MSH2 Zornitza Stark Marked gene: MSH2 as ready
BabyScreen+ newborn screening v0.1797 MSH2 Zornitza Stark Gene: msh2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1797 MSH2 Zornitza Stark Phenotypes for gene: MSH2 were changed from Lynch syndrome to Mismatch repair cancer syndrome 2, MIM# 619096
BabyScreen+ newborn screening v0.1796 MLH1 Zornitza Stark Classified gene: MLH1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1796 MLH1 Zornitza Stark Gene: mlh1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1795 MSH2 Zornitza Stark Mode of inheritance for gene: MSH2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1794 MSH2 Zornitza Stark Classified gene: MSH2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1794 MSH2 Zornitza Stark Gene: msh2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1793 MSH2 Zornitza Stark Tag for review tag was added to gene: MSH2.
Tag cancer tag was added to gene: MSH2.
Tag treatable tag was added to gene: MSH2.
BabyScreen+ newborn screening v0.1793 LYST Seb Lunke Marked gene: LYST as ready
BabyScreen+ newborn screening v0.1793 LYST Seb Lunke Gene: lyst has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1793 MSH2 Zornitza Stark reviewed gene: MSH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mismatch repair cancer syndrome 2, MIM# 619096; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1793 COL9A2 Seb Lunke Marked gene: COL9A2 as ready
BabyScreen+ newborn screening v0.1793 COL9A2 Seb Lunke Gene: col9a2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1793 MLH1 Zornitza Stark Tag for review tag was added to gene: MLH1.
Tag cancer tag was added to gene: MLH1.
Tag treatable tag was added to gene: MLH1.
BabyScreen+ newborn screening v0.1793 MLH1 Zornitza Stark reviewed gene: MLH1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mismatch repair cancer syndrome 1, MIM# 276300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1793 TPRN Zornitza Stark Marked gene: TPRN as ready
BabyScreen+ newborn screening v0.1793 TPRN Zornitza Stark Gene: tprn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1793 TPRN Zornitza Stark Phenotypes for gene: TPRN were changed from Deafness, autosomal recessive to Deafness, autosomal recessive 79, MIM# 613307
BabyScreen+ newborn screening v0.1792 TPRN Zornitza Stark Classified gene: TPRN as Green List (high evidence)
BabyScreen+ newborn screening v0.1792 TPRN Zornitza Stark Gene: tprn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1791 TPRN Zornitza Stark Tag deafness tag was added to gene: TPRN.
BabyScreen+ newborn screening v0.1791 TPRN Zornitza Stark reviewed gene: TPRN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 79, MIM# 613307; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1791 STRC Zornitza Stark Classified gene: STRC as Green List (high evidence)
BabyScreen+ newborn screening v0.1791 STRC Zornitza Stark Gene: strc has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1790 STRC Zornitza Stark Tag for review was removed from gene: STRC.
Tag deafness tag was added to gene: STRC.
BabyScreen+ newborn screening v0.1790 STRC Zornitza Stark reviewed gene: STRC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 16, MIM# 603720; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1790 S1PR2 Zornitza Stark Marked gene: S1PR2 as ready
BabyScreen+ newborn screening v0.1790 S1PR2 Zornitza Stark Gene: s1pr2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1790 S1PR2 Zornitza Stark Classified gene: S1PR2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1790 S1PR2 Zornitza Stark Gene: s1pr2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1789 S1PR2 Zornitza Stark gene: S1PR2 was added
gene: S1PR2 was added to gNBS. Sources: ClinGen
deafness tags were added to gene: S1PR2.
Mode of inheritance for gene: S1PR2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: S1PR2 were set to Deafness, autosomal recessive 68, MIM# 610419
Review for gene: S1PR2 was set to GREEN
Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen, onset of deafness is generally pre-lingual, therefore include.
Sources: ClinGen
BabyScreen+ newborn screening v0.1788 PTPRQ Zornitza Stark Marked gene: PTPRQ as ready
BabyScreen+ newborn screening v0.1788 PTPRQ Zornitza Stark Gene: ptprq has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1788 PTPRQ Zornitza Stark Classified gene: PTPRQ as Green List (high evidence)
BabyScreen+ newborn screening v0.1788 PTPRQ Zornitza Stark Gene: ptprq has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1787 PTPRQ Zornitza Stark gene: PTPRQ was added
gene: PTPRQ was added to gNBS. Sources: ClinGen
deafness tags were added to gene: PTPRQ.
Mode of inheritance for gene: PTPRQ was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: PTPRQ were set to Deafness, autosomal recessive 84A, MIM# 613391; Deafness, autosomal dominant 73, MIM# 617663
Review for gene: PTPRQ was set to GREEN
Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen, onset of deafness is generally pre-lingual, therefore include.
Sources: ClinGen
BabyScreen+ newborn screening v0.1786 POU3F4 Zornitza Stark Classified gene: POU3F4 as Green List (high evidence)
BabyScreen+ newborn screening v0.1786 POU3F4 Zornitza Stark Gene: pou3f4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1785 POU3F4 Zornitza Stark Tag deafness tag was added to gene: POU3F4.
BabyScreen+ newborn screening v0.1785 POU3F4 Zornitza Stark Deleted their comment
BabyScreen+ newborn screening v0.1785 POU3F4 Zornitza Stark edited their review of gene: POU3F4: Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen, onset is generally pre-lingual, therefore include.; Changed rating: GREEN
BabyScreen+ newborn screening v0.1785 OTOG Zornitza Stark Marked gene: OTOG as ready
BabyScreen+ newborn screening v0.1785 OTOG Zornitza Stark Gene: otog has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1785 OTOG Zornitza Stark Phenotypes for gene: OTOG were changed from Deafness, autosomal recessive to Deafness, autosomal recessive 18B - MIM#614945
BabyScreen+ newborn screening v0.1784 OTOG Zornitza Stark Classified gene: OTOG as Green List (high evidence)
BabyScreen+ newborn screening v0.1784 OTOG Zornitza Stark Gene: otog has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1783 OTOG Zornitza Stark Tag deafness tag was added to gene: OTOG.
BabyScreen+ newborn screening v0.1783 OTOG Zornitza Stark reviewed gene: OTOG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 18B - MIM#614945; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1783 MYO3A Zornitza Stark Classified gene: MYO3A as Green List (high evidence)
BabyScreen+ newborn screening v0.1783 MYO3A Zornitza Stark Gene: myo3a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1782 MYO3A Zornitza Stark Tag deafness tag was added to gene: MYO3A.
BabyScreen+ newborn screening v0.1782 MYO3A Zornitza Stark edited their review of gene: MYO3A: Added comment: Assessed by ClinGen as 'strong actionability' in paediatric patients.

Included as a cause of pre-lingual deafness, therefore include in this panel, noting some reports of later onset.; Changed rating: GREEN
BabyScreen+ newborn screening v0.1782 PRKG1 Zornitza Stark Marked gene: PRKG1 as ready
BabyScreen+ newborn screening v0.1782 PRKG1 Zornitza Stark Gene: prkg1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1782 PRKG1 Zornitza Stark Classified gene: PRKG1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1782 PRKG1 Zornitza Stark Gene: prkg1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1781 PRKG1 Zornitza Stark gene: PRKG1 was added
gene: PRKG1 was added to gNBS. Sources: ClinGen
for review, cardiac, treatable tags were added to gene: PRKG1.
Mode of inheritance for gene: PRKG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PRKG1 were set to Aortic aneurysm, familial thoracic 8, MIM#615436
Penetrance for gene: PRKG1 were set to Incomplete
Review for gene: PRKG1 was set to AMBER
Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%).
Sources: ClinGen
BabyScreen+ newborn screening v0.1780 MYH11 Zornitza Stark Marked gene: MYH11 as ready
BabyScreen+ newborn screening v0.1780 MYH11 Zornitza Stark Gene: myh11 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1780 MYH11 Zornitza Stark Phenotypes for gene: MYH11 were changed from Aortic aneurysm, familial thoracic 4 to Aortic aneurysm, familial thoracic 4, MIM#160745
BabyScreen+ newborn screening v0.1779 MYH11 Zornitza Stark Tag for review tag was added to gene: MYH11.
Tag cardiac tag was added to gene: MYH11.
Tag treatable tag was added to gene: MYH11.
BabyScreen+ newborn screening v0.1779 MYH11 Zornitza Stark reviewed gene: MYH11: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Aortic aneurysm, familial thoracic 4, MIM#160745; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1779 LOX Zornitza Stark Marked gene: LOX as ready
BabyScreen+ newborn screening v0.1779 LOX Zornitza Stark Gene: lox has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1779 LOX Zornitza Stark Classified gene: LOX as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1779 LOX Zornitza Stark Gene: lox has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1778 LOX Zornitza Stark gene: LOX was added
gene: LOX was added to gNBS. Sources: ClinGen
for review, cardiac, treatable tags were added to gene: LOX.
Mode of inheritance for gene: LOX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: LOX were set to Aortic aneurysm, familial thoracic 10, MIM#617168
Penetrance for gene: LOX were set to Incomplete
Review for gene: LOX was set to AMBER
Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection.
Sources: ClinGen
BabyScreen+ newborn screening v0.1777 ACTA2 Zornitza Stark Marked gene: ACTA2 as ready
BabyScreen+ newborn screening v0.1777 ACTA2 Zornitza Stark Gene: acta2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1777 ACTA2 Zornitza Stark Phenotypes for gene: ACTA2 were changed from Aortic aneurysm, familial thoracic to Aortic aneurysm, familial thoracic 6, MIM# 611788
BabyScreen+ newborn screening v0.1776 ACTA2 Zornitza Stark Tag for review tag was added to gene: ACTA2.
Tag cardiac tag was added to gene: ACTA2.
Tag treatable tag was added to gene: ACTA2.
BabyScreen+ newborn screening v0.1776 ACTA2 Zornitza Stark reviewed gene: ACTA2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Aortic aneurysm, familial thoracic 6, MIM# 611788; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1776 STK11 Zornitza Stark Classified gene: STK11 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1776 STK11 Zornitza Stark Gene: stk11 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1775 STK11 Zornitza Stark Tag cancer tag was added to gene: STK11.
Tag treatable tag was added to gene: STK11.
BabyScreen+ newborn screening v0.1775 STK11 Zornitza Stark reviewed gene: STK11: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Peutz-Jeghers syndrome, MIM# 175200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1775 MCEE Zornitza Stark Marked gene: MCEE as ready
BabyScreen+ newborn screening v0.1775 MCEE Zornitza Stark Gene: mcee has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1775 MCEE Zornitza Stark Phenotypes for gene: MCEE were changed from Methylmalonyl-CoA epimerase deficiency to Methylmalonyl-CoA epimerase deficiency MIM#251120
BabyScreen+ newborn screening v0.1774 MCEE Zornitza Stark Classified gene: MCEE as Green List (high evidence)
BabyScreen+ newborn screening v0.1774 MCEE Zornitza Stark Gene: mcee has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1773 MCEE Zornitza Stark Tag for review tag was added to gene: MCEE.
Tag treatable tag was added to gene: MCEE.
Tag metabolic tag was added to gene: MCEE.
BabyScreen+ newborn screening v0.1773 MCEE Zornitza Stark reviewed gene: MCEE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Methylmalonyl-CoA epimerase deficiency MIM#251120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1773 RUNX1 Zornitza Stark Marked gene: RUNX1 as ready
BabyScreen+ newborn screening v0.1773 RUNX1 Zornitza Stark Gene: runx1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1773 RUNX1 Zornitza Stark Classified gene: RUNX1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1773 RUNX1 Zornitza Stark Gene: runx1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1772 RUNX1 Zornitza Stark gene: RUNX1 was added
gene: RUNX1 was added to gNBS. Sources: ClinGen
for review, treatable, haematological tags were added to gene: RUNX1.
Mode of inheritance for gene: RUNX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RUNX1 were set to Platelet disorder, familial, with associated myeloid malignancy, MIM# 601399
Review for gene: RUNX1 was set to AMBER
Added comment: Assessed as 'moderate actionability' in paediatric patients by ClinGen.

HTHCPS is characterized by mild to moderate thrombocytopenia with normal platelet size, abnormal platelet functioning (defective release of delta granules and/or aggregation defects), and an increased risk of developing a haematologic malignancy.

Age of onset of bleeding can be highly variable, with some individuals presenting in early infancy and others not recognizing their symptoms until much later in life. Severe thrombocytopenia or profound platelet dysfunction can result in recognition during the perinatal or infancy period. Hematologic malignancies can occur in childhood or adulthood; the range of age of onset is wide with a median age of 33 years.

Use of clotting promotors (e.g., desmopressin, epsilon aminocaproic acid, tranexamic acid) can be used for surgeries, injuries, or dental treatments. Platelet transfusions may be used for severe bleeding or procedures with a high bleeding risk.

Though there is no specific treatment for HTHCPS, there are recommendations regarding the indications and timing of hematopoietic stem cell transplantation (HSCT) that vary. HSCT in pre-malignancy patients, particularly in the absence of any clonal progression, is debatable due to transplantation-associated risks and incomplete penetrance. Some suggested indications for HSCT include severe or symptomatic cytopenias, severe marrow dysplasia (particularly in the context of falling blood counts), complex or high-risk (e.g., monosomy 7) cytogenetic abnormalities (particularly if the clones are large or increasing in size) and increasing blasts >5%.

Consider use of a medical alert bracelet for thrombocytopenia, platelet dysfunction, or hematologic malignancy as indicated.
Sources: ClinGen
BabyScreen+ newborn screening v0.1771 DICER1 Zornitza Stark Marked gene: DICER1 as ready
BabyScreen+ newborn screening v0.1771 DICER1 Zornitza Stark Gene: dicer1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1771 DICER1 Zornitza Stark Classified gene: DICER1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1771 DICER1 Zornitza Stark Gene: dicer1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1770 DICER1 Zornitza Stark Tag for review tag was added to gene: DICER1.
Tag cancer tag was added to gene: DICER1.
Tag treatable tag was added to gene: DICER1.
BabyScreen+ newborn screening v0.1770 DICER1 Zornitza Stark gene: DICER1 was added
gene: DICER1 was added to gNBS. Sources: ClinGen
Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DICER1 were set to DICER1 syndrome, MONDO:0017288
Penetrance for gene: DICER1 were set to Incomplete
Review for gene: DICER1 was set to AMBER
Added comment: Rated as 'moderate actionability' in paediatric patients by ClinGen.

A multiple registry study examining neoplasm incidence in a cohort containing 102 non-probands with DICER1 pathogenic variants (3,344 person-years of observation in non-probands) found that by age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of non-probands had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of non-probands had developed a neoplasm (females, 26.5%; males, 10.2%).

Most individuals with pathogenic variants in DICER1 are healthy or have only minor DICER1-associaited conditions. The most severe manifestations tend to present in early childhood with adulthood characterized by good health. The majority of tumors in individuals with DICER1 pathogenic variants occur in individuals younger than 40. Many of these tumors typically only occur in childhood, including: PPB (before age 7), CN (before age 4), CBME typically occurs in young children, pituitary blastoma (before age 2), and childhood pineoblastoma (only one has been reported associated with a DICER1 mutation).

Surveillance recommendations:
In order to detect pulmonary cysts or PPB (one of the most important causes of DICER1-associated morbidity and mortality), chest x-rays are recommended every 6 months from birth to through age 7 years and then annually from 8-12 years. A chest computed tomography (CT) (with efforts to minimize radiation) should be obtained by 9 months of age, preferably between 3 and 6 months of age and repeated at approximately 2.5 years of age.

Abdominal ultrasound is recommended for the detection in infancy or at the time of the first chest CT then every 6-12 months until at least 8 years of age. Annual ultrasound may be considered until 12 years of age.

Beginning at ages 8-10 females should receive pelvic ultrasound performed in conjunction with abdominal ultrasound (every 6-12 months) until at least age 40 or as needed for signs and symptoms.

Individuals should undergo thyroid ultrasound with assessment for regional adenopathy every 2 to 3 years starting at age 8 or as needed for signs and symptoms.

An annual routine dilated ophthalmologic exam with visual acuity screening is recommended from age 3 to at least age 10 for detection of CBME.
Sources: ClinGen
BabyScreen+ newborn screening v0.1769 BRCA1 Zornitza Stark Marked gene: BRCA1 as ready
BabyScreen+ newborn screening v0.1769 BRCA1 Zornitza Stark Gene: brca1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1769 BRCA1 Zornitza Stark Phenotypes for gene: BRCA1 were changed from Breast-ovarian cancer, familial, 1 to Fanconi anemia, complementation group S, MIM# 617883
BabyScreen+ newborn screening v0.1768 BRCA1 Zornitza Stark Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1767 BRCA1 Zornitza Stark Classified gene: BRCA1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1767 BRCA1 Zornitza Stark Gene: brca1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1766 BRCA1 Zornitza Stark Tag treatable tag was added to gene: BRCA1.
Tag haematological tag was added to gene: BRCA1.
BabyScreen+ newborn screening v0.1766 BRCA1 Zornitza Stark reviewed gene: BRCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi anemia, complementation group S, MIM# 617883; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1766 BRCA2 Zornitza Stark Marked gene: BRCA2 as ready
BabyScreen+ newborn screening v0.1766 BRCA2 Zornitza Stark Gene: brca2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1766 BRCA2 Zornitza Stark Phenotypes for gene: BRCA2 were changed from Fanconi anaemia, complementation group D, MIM#1 605724; Fanconi anemia, complementation group D1; Breast-ovarian cancer, familial, 2 to Fanconi anaemia, complementation group D1, MIM# 605724
BabyScreen+ newborn screening v0.1765 BRCA2 Zornitza Stark Mode of inheritance for gene: BRCA2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1764 BRCA2 Zornitza Stark Classified gene: BRCA2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1764 BRCA2 Zornitza Stark Gene: brca2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1763 BRCA2 Zornitza Stark Tag treatable tag was added to gene: BRCA2.
Tag haematological tag was added to gene: BRCA2.
BabyScreen+ newborn screening v0.1763 BRCA2 Zornitza Stark reviewed gene: BRCA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi anaemia, complementation group D1, MIM# 605724; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1763 KCNQ1 Zornitza Stark Marked gene: KCNQ1 as ready
BabyScreen+ newborn screening v0.1763 KCNQ1 Zornitza Stark Gene: kcnq1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1763 KCNQ1 Zornitza Stark Phenotypes for gene: KCNQ1 were changed from Short QT syndrome 2, MIM# 609621; Jervell and Lange-Nielsen syndrome; Long QT syndrome 1, MIM# 192500; Long QT syndrome-1; Jervell and Lange-Nielsen syndrome, MIM# 220400 to Long QT syndrome 1, MIM# 192500
BabyScreen+ newborn screening v0.1762 KCNQ1 Zornitza Stark Tag for review tag was added to gene: KCNQ1.
Tag cardiac tag was added to gene: KCNQ1.
Tag treatable tag was added to gene: KCNQ1.
BabyScreen+ newborn screening v0.1762 KCNQ1 Zornitza Stark reviewed gene: KCNQ1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 1, MIM# 192500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1762 KCNH2 Zornitza Stark Marked gene: KCNH2 as ready
BabyScreen+ newborn screening v0.1762 KCNH2 Zornitza Stark Gene: kcnh2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1762 KCNH2 Zornitza Stark Phenotypes for gene: KCNH2 were changed from Long QT syndrome-2 to Long QT syndrome 2, MIM# 613688
BabyScreen+ newborn screening v0.1761 KCNH2 Zornitza Stark Tag for review tag was added to gene: KCNH2.
Tag cardiac tag was added to gene: KCNH2.
Tag treatable tag was added to gene: KCNH2.
BabyScreen+ newborn screening v0.1761 KCNH2 Zornitza Stark reviewed gene: KCNH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 2, MIM# 613688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1761 TMEM43 Zornitza Stark Tag for review tag was added to gene: TMEM43.
Tag cardiac tag was added to gene: TMEM43.
Tag treatable tag was added to gene: TMEM43.
BabyScreen+ newborn screening v0.1761 TMEM43 Zornitza Stark reviewed gene: TMEM43: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Arrhythmogenic right ventricular dysplasia 5 MIM#604400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1761 PKP2 Zornitza Stark Marked gene: PKP2 as ready
BabyScreen+ newborn screening v0.1761 PKP2 Zornitza Stark Gene: pkp2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1761 PKP2 Zornitza Stark Phenotypes for gene: PKP2 were changed from Arrhythmogenic right ventricular dysplasia 9 to Arrhythmogenic right ventricular dysplasia 9, MIM# 609040
BabyScreen+ newborn screening v0.1760 PKP2 Zornitza Stark Tag for review tag was added to gene: PKP2.
Tag cardiac tag was added to gene: PKP2.
Tag treatable tag was added to gene: PKP2.
BabyScreen+ newborn screening v0.1760 PKP2 Zornitza Stark reviewed gene: PKP2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Arrhythmogenic right ventricular dysplasia 9, MIM# 609040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1760 DSP Zornitza Stark Marked gene: DSP as ready
BabyScreen+ newborn screening v0.1760 DSP Zornitza Stark Gene: dsp has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1760 DSP Zornitza Stark Phenotypes for gene: DSP were changed from Cardiomyopathy, dilated, with woolly hair and keratoderma, MIM# 605676; Epidermolysis bullosa, lethal acantholytic; Arrhythmogenic right ventricular dysplasia/cardiomyopathy; Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis , MIM#615821 to Arrhythmogenic right ventricular dysplasia 8, MIM# 607450
BabyScreen+ newborn screening v0.1759 DSP Zornitza Stark Mode of inheritance for gene: DSP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1758 DSP Zornitza Stark Tag for review tag was added to gene: DSP.
Tag cardiac tag was added to gene: DSP.
Tag treatable tag was added to gene: DSP.
BabyScreen+ newborn screening v0.1758 DSP Zornitza Stark reviewed gene: DSP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Arrhythmogenic right ventricular dysplasia 8, MIM# 607450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1758 DSG2 Zornitza Stark Marked gene: DSG2 as ready
BabyScreen+ newborn screening v0.1758 DSG2 Zornitza Stark Gene: dsg2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1758 DSG2 Zornitza Stark Phenotypes for gene: DSG2 were changed from Arrhythmogenic right ventricular cardiomyopathy to Arrhythmogenic right ventricular dysplasia 10, MIM# 610193
BabyScreen+ newborn screening v0.1757 DSG2 Zornitza Stark Tag for review tag was added to gene: DSG2.
Tag cardiac tag was added to gene: DSG2.
Tag treatable tag was added to gene: DSG2.
BabyScreen+ newborn screening v0.1757 DSG2 Zornitza Stark reviewed gene: DSG2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Arrhythmogenic right ventricular dysplasia 10, MIM# 610193; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1757 JUP Zornitza Stark Marked gene: JUP as ready
BabyScreen+ newborn screening v0.1757 JUP Zornitza Stark Gene: jup has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1757 JUP Zornitza Stark Phenotypes for gene: JUP were changed from Arrhythmogenic right ventricular dysplasia 12; Naxos disease to Arrhythmogenic right ventricular dysplasia 12 MIM# 611528; Naxos disease MIM# 601214
BabyScreen+ newborn screening v0.1756 JUP Zornitza Stark Tag for review tag was added to gene: JUP.
Tag cardiac tag was added to gene: JUP.
Tag treatable tag was added to gene: JUP.
BabyScreen+ newborn screening v0.1756 JUP Zornitza Stark reviewed gene: JUP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Arrhythmogenic right ventricular dysplasia 12 MIM# 611528, Naxos disease MIM# 601214; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1756 DSC2 Zornitza Stark Marked gene: DSC2 as ready
BabyScreen+ newborn screening v0.1756 DSC2 Zornitza Stark Gene: dsc2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1756 DSC2 Zornitza Stark Phenotypes for gene: DSC2 were changed from Arrhythmogenic right ventricular cardiomyopathy to Arrhythmogenic right ventricular dysplasia 11, MIM# 610476; Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair, MIM# 610476
BabyScreen+ newborn screening v0.1755 DSC2 Zornitza Stark Mode of inheritance for gene: DSC2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1754 DSC2 Zornitza Stark Tag for review tag was added to gene: DSC2.
Tag cardiac tag was added to gene: DSC2.
Tag treatable tag was added to gene: DSC2.
BabyScreen+ newborn screening v0.1754 DSC2 Zornitza Stark edited their review of gene: DSC2: Changed rating: AMBER
BabyScreen+ newborn screening v0.1754 DSC2 Zornitza Stark reviewed gene: DSC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Arrhythmogenic right ventricular dysplasia 11, MIM# 610476, Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair, MIM# 610476; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1754 OAT Zornitza Stark Marked gene: OAT as ready
BabyScreen+ newborn screening v0.1754 OAT Zornitza Stark Gene: oat has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1754 OAT Zornitza Stark Classified gene: OAT as Green List (high evidence)
BabyScreen+ newborn screening v0.1754 OAT Zornitza Stark Gene: oat has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1753 OAT Zornitza Stark gene: OAT was added
gene: OAT was added to gNBS. Sources: ClinGen
for review, treatable, metabolic tags were added to gene: OAT.
Mode of inheritance for gene: OAT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: OAT were set to Gyrate atrophy of choroid and retina with or without ornithinemia MIM#258870
Review for gene: OAT was set to GREEN
Added comment: Rated as 'moderate actionability' in paediatric patients by ClinGen.

GA due to deficiency of the enzyme ornithine aminotransferase (OAT) is characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. GA first presents as night blindness and constriction of the visual field caused by sharply demarcated circular areas of chorioretinal atrophy in the periphery. Atrophic areas progressively increase, coalesce, and spread towards the macula leading to central visual loss and blindness (vision less than 20/200).

Age at diagnosis ranges from 1 month to 44 years. The condition is characterized by the development of chorioretinal atrophic patches that start in the mid-peripheral retina in the first decade of life. Myopia, night blindness, changes in the macula (including cystic changes), and visual field affection usually start in the first or second decade. Most patients with GA have posterior subcapsular cataracts by the end of the second decade. Irreversible loss of vision and blindness generally occurs between 40 and 55 years of age but is highly variable.

Treatment of GA consists mainly of dietary modifications to help lower elevated systemic ornithine levels. Restriction of dietary arginine, a precursor of ornithine, appears to have therapeutic value. Pediatric patients undergoing arginine restriction should receive enough calories in their diet supplemented by essential amino acids, vitamins, and minerals to avoid malnutrition and excessive break down of endogenous proteins.

A long-term observational study of 27 patients with GA, 17 who complied with the arginine-restricted diet and 10 who were noncompliant, found that at 14 years follow-up the rates of vision loss were significantly slower in the compliant group for 3 of the 4 outcome measures, when adjusted for age.
Sources: ClinGen
BabyScreen+ newborn screening v0.1752 PCSK9 Zornitza Stark Marked gene: PCSK9 as ready
BabyScreen+ newborn screening v0.1752 PCSK9 Zornitza Stark Gene: pcsk9 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1752 PCSK9 Zornitza Stark Phenotypes for gene: PCSK9 were changed from Hypercholesterolemia to Hypercholesterolaemia, familial, 3, MIM# 603776
BabyScreen+ newborn screening v0.1751 PCSK9 Zornitza Stark Classified gene: PCSK9 as Green List (high evidence)
BabyScreen+ newborn screening v0.1751 PCSK9 Zornitza Stark Gene: pcsk9 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1750 PCSK9 Zornitza Stark Tag for review tag was added to gene: PCSK9.
Tag treatable tag was added to gene: PCSK9.
Tag metabolic tag was added to gene: PCSK9.
BabyScreen+ newborn screening v0.1750 PCSK9 Zornitza Stark reviewed gene: PCSK9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypercholesterolemia, familial, 3, MIM# 603776; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1750 PRKAR1A Zornitza Stark Phenotypes for gene: PRKAR1A were changed from Acrodysostosis 1, with or without hormone resistance, MIM# 101800; Carney complex, type 1, MIM# 160980; Myxoma, intracardiac, MIM# 255960; Pigmented nodular adrenocortical disease, primary, 1, MIM# 610489 to Carney complex, type 1, MIM# 160980
BabyScreen+ newborn screening v0.1749 PRKAR1A Zornitza Stark Classified gene: PRKAR1A as Green List (high evidence)
BabyScreen+ newborn screening v0.1749 PRKAR1A Zornitza Stark Gene: prkar1a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1748 PRKAR1A Zornitza Stark Tag for review tag was added to gene: PRKAR1A.
Tag cancer tag was added to gene: PRKAR1A.
Tag treatable tag was added to gene: PRKAR1A.
BabyScreen+ newborn screening v0.1748 PRKAR1A Zornitza Stark Deleted their comment
BabyScreen+ newborn screening v0.1748 PRKAR1A Zornitza Stark edited their review of gene: PRKAR1A: Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen, principally due to benefit from early detection of cardiac myxomas through surveillance.

CNC is associated with skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas.

Lentigines are the most common presenting feature of CNC and may be present at birth. Typically, they increase in number at puberty, fade after the fourth decade, but may still be evident in the eighth decade. Cutaneous myxomas appear between birth and the fourth decade. Cardiac myxomas may occur at a young age. Breast myxomas occur in females after puberty. Males and females may develop nipple myxomas at any age. In a minority of individuals, PPNAD presents in the first two to three years; in the majority, it presents in the second or third decade. LCCSCT often present in the first decade. Signs and symptoms of CNC may be present at birth, but the median age of diagnosis is 20 years. Most patients with CNC present with a mild increase in GH. However, clinically evident acromegaly is a relatively frequent manifestation of CNC, occurring in approximately 10% of adults at the time of presentation. Most individuals with CNC have a normal life span. However, because some die at an early age, the average life expectancy for individuals with CNC is 50 years. Causes of death include complications of cardiac myxoma (myxoma emboli, cardiomyopathy, cardiac arrhythmia, and surgical intervention), metastatic or intracranial PMS, thyroid carcinoma, and metastatic pancreatic and testicular tumors.

The only preventive measure in an asymptomatic individual is surgical removal of a heart tumor (cardiac myxoma) prior to the development of heart dysfunction, stroke, or other embolism. Cardiac myxomas should be diagnosed early through regular screening.

Development of metabolic abnormalities from Cushing syndrome or arthropathy and other complications from acromegaly may be prevented by medical or surgical treatment of the respective endocrine manifestations.

The overall penetrance of CNC in those with a PRKAR1A pathogenic variant is greater than 95% by age 50 years. 30-60% have cardiac myxomas.; Changed rating: GREEN; Changed phenotypes: Carney complex, type 1, MIM# 160980
BabyScreen+ newborn screening v0.1748 RPS10 Zornitza Stark Marked gene: RPS10 as ready
BabyScreen+ newborn screening v0.1748 RPS10 Zornitza Stark Gene: rps10 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1748 RPS10 Zornitza Stark Phenotypes for gene: RPS10 were changed from Diamond-Blackfan anaemia 9, MIM# 613308; Diamond-Blackfan anemia to Diamond-Blackfan anaemia 9, MIM# 613308
BabyScreen+ newborn screening v0.1747 RPS10 Zornitza Stark Classified gene: RPS10 as Green List (high evidence)
BabyScreen+ newborn screening v0.1747 RPS10 Zornitza Stark Gene: rps10 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1746 RPS10 Zornitza Stark Tag treatable tag was added to gene: RPS10.
Tag haematological tag was added to gene: RPS10.
BabyScreen+ newborn screening v0.1746 RPS10 Zornitza Stark reviewed gene: RPS10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond-Blackfan anaemia 9, MIM# 613308; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1746 MEN1 Zornitza Stark Tag treatable tag was added to gene: MEN1.
BabyScreen+ newborn screening v0.1746 MEN1 Zornitza Stark changed review comment from: For review re age of onset: surveillance starts age 5, disease onset generally later.; to: For review re age of onset: surveillance starts age 5, disease onset generally later.

Rated as 'strong actionability' in paediatric patients by ClinGen.

Parathyroid tumors, which cause PHPT, are the most common feature and the first clinical manifestation in 90% of individuals with MEN1 with onset typically between ages 20 and 25 years. Almost all (95-100%) individuals with MEN1 can expect to have PHPT by age 50 years. However, MEN1 affects all age groups, with a reported age range of 5 to 81 years; 17% of MEN1 tumors are diagnosed under age 21. Untreated patients with MEN1 have a decreased life expectancy with a 50% probability of death by age 50. The cause of death in 50-70% of cases is due to a malignant tumor process or sequelae of the disease, with malignancies accounting for 30% of all deaths.
BabyScreen+ newborn screening v0.1746 MEN1 Zornitza Stark Tag for review tag was added to gene: MEN1.
Tag cancer tag was added to gene: MEN1.
BabyScreen+ newborn screening v0.1746 SCN5A Zornitza Stark Marked gene: SCN5A as ready
BabyScreen+ newborn screening v0.1746 SCN5A Zornitza Stark Gene: scn5a has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1746 SCN5A Zornitza Stark Phenotypes for gene: SCN5A were changed from Sick sinus syndrome 1, MIM# 608567; Ventricular fibrillation, familial, 1, MIM# 603829; Brugada syndrome; Brugada syndrome 1, MIM# 601144; Long QT syndrome 3 (MIM#603830); Long QT syndrome; Heart block, progressive, type IA, MIM# 113900 to Long QT syndrome 3 (MIM#603830); Brugada syndrome 1, MIM# 601144
BabyScreen+ newborn screening v0.1745 SCN5A Zornitza Stark Tag for review tag was added to gene: SCN5A.
Tag cardiac tag was added to gene: SCN5A.
Tag treatable tag was added to gene: SCN5A.
BabyScreen+ newborn screening v0.1745 SCN5A Zornitza Stark reviewed gene: SCN5A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 3 (MIM#603830), Brugada syndrome 1, MIM# 601144; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1745 SLC26A4 Zornitza Stark Phenotypes for gene: SLC26A4 were changed from Pendred syndrome, MIM #274600 to Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 600791; Pendred syndrome 274600
BabyScreen+ newborn screening v0.1744 SLC26A4 Zornitza Stark Classified gene: SLC26A4 as Green List (high evidence)
BabyScreen+ newborn screening v0.1744 SLC26A4 Zornitza Stark Gene: slc26a4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1743 SLC26A4 Zornitza Stark Tag for review was removed from gene: SLC26A4.
Tag deafness tag was added to gene: SLC26A4.
BabyScreen+ newborn screening v0.1743 SLC26A4 Zornitza Stark reviewed gene: SLC26A4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 600791, Pendred syndrome 274600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1743 TGFB3 Zornitza Stark Marked gene: TGFB3 as ready
BabyScreen+ newborn screening v0.1743 TGFB3 Zornitza Stark Gene: tgfb3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1743 TGFB3 Zornitza Stark Phenotypes for gene: TGFB3 were changed from Arrhythmogenic right ventricular dysplasia to Loeys-Dietz syndrome 5 , MIM#615582
BabyScreen+ newborn screening v0.1742 TGFB3 Zornitza Stark Classified gene: TGFB3 as Green List (high evidence)
BabyScreen+ newborn screening v0.1742 TGFB3 Zornitza Stark Gene: tgfb3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1741 TGFB3 Zornitza Stark Tag for review tag was added to gene: TGFB3.
Tag cardiac tag was added to gene: TGFB3.
Tag treatable tag was added to gene: TGFB3.
BabyScreen+ newborn screening v0.1741 TGFB3 Zornitza Stark reviewed gene: TGFB3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Loeys-Dietz syndrome 5 , MIM#615582; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1741 TGFB2 Zornitza Stark Marked gene: TGFB2 as ready
BabyScreen+ newborn screening v0.1741 TGFB2 Zornitza Stark Gene: tgfb2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1741 TGFB2 Zornitza Stark Classified gene: TGFB2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1741 TGFB2 Zornitza Stark Gene: tgfb2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1740 TGFB2 Zornitza Stark Tag for review tag was added to gene: TGFB2.
Tag cardiac tag was added to gene: TGFB2.
Tag treatable tag was added to gene: TGFB2.
BabyScreen+ newborn screening v0.1740 TGFB2 Zornitza Stark gene: TGFB2 was added
gene: TGFB2 was added to gNBS. Sources: ClinGen
Mode of inheritance for gene: TGFB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TGFB2 were set to Loeys-Dietz syndrome 4, MIM# 614816
Review for gene: TGFB2 was set to GREEN
Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen.

Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms which are the major source of morbidity and mortality. Aortic growth can be faster than 10mm per year. Aortic dissection has been observed in early childhood, and the mean age of death is 26 years. Other life-threatening manifestations include spontaneous rupture of the spleen, bowel, and uterine rupture during pregnancy.

Prophylactic surgical repair is typically recommended at an aortic diameter of ≥ 4.2 cm.

Beta-blockers or other medications can be used to reduce hemodynamic stress.

Consider Medicalert bracelet.

Use of subacute bacterial endocarditis prophylaxis should be considered for individuals with connective tissue disorders and documented evidence of mitral and/or aortic regurgitation who are undergoing dental work or other procedures expected to contaminate the bloodstream with bacteria.

Because of a high risk of cervical spine instability, a flexion and extension x-ray of the cervical spine should be performed prior to intubation or any other procedure involving manipulation of the neck.
Sources: ClinGen
BabyScreen+ newborn screening v0.1739 TRDN Zornitza Stark Marked gene: TRDN as ready
BabyScreen+ newborn screening v0.1739 TRDN Zornitza Stark Gene: trdn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1739 TRDN Zornitza Stark Phenotypes for gene: TRDN were changed from Catecholaminergic polymorphic ventricular tachycardia to Cardiac arrhythmia syndrome, with or without skeletal muscle weakness, MIM# 615441
BabyScreen+ newborn screening v0.1738 TRDN Zornitza Stark Classified gene: TRDN as Green List (high evidence)
BabyScreen+ newborn screening v0.1738 TRDN Zornitza Stark Gene: trdn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1737 TRDN Zornitza Stark Tag for review tag was added to gene: TRDN.
Tag cardiac tag was added to gene: TRDN.
Tag treatable tag was added to gene: TRDN.
BabyScreen+ newborn screening v0.1737 TRDN Zornitza Stark reviewed gene: TRDN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiac arrhythmia syndrome, with or without skeletal muscle weakness, MIM# 615441; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1737 TECRL Zornitza Stark Marked gene: TECRL as ready
BabyScreen+ newborn screening v0.1737 TECRL Zornitza Stark Gene: tecrl has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1737 TECRL Zornitza Stark Classified gene: TECRL as Green List (high evidence)
BabyScreen+ newborn screening v0.1737 TECRL Zornitza Stark Gene: tecrl has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1736 TECRL Zornitza Stark gene: TECRL was added
gene: TECRL was added to gNBS. Sources: ClinGen
for review, cardiac, treatable tags were added to gene: TECRL.
Mode of inheritance for gene: TECRL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TECRL were set to Ventricular tachycardia, catecholaminergic polymorphic, 3, MIM# 614021
Review for gene: TECRL was set to GREEN
Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen
BabyScreen+ newborn screening v0.1735 CALM3 Zornitza Stark Marked gene: CALM3 as ready
BabyScreen+ newborn screening v0.1735 CALM3 Zornitza Stark Gene: calm3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1735 CALM3 Zornitza Stark Classified gene: CALM3 as Green List (high evidence)
BabyScreen+ newborn screening v0.1735 CALM3 Zornitza Stark Gene: calm3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1734 CALM3 Zornitza Stark gene: CALM3 was added
gene: CALM3 was added to gNBS. Sources: ClinGen
for review, cardiac, treatable tags were added to gene: CALM3.
Mode of inheritance for gene: CALM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CALM3 were set to Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782
Penetrance for gene: CALM3 were set to Incomplete
Review for gene: CALM3 was set to GREEN
Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen
BabyScreen+ newborn screening v0.1733 CALM2 Zornitza Stark Marked gene: CALM2 as ready
BabyScreen+ newborn screening v0.1733 CALM2 Zornitza Stark Gene: calm2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1733 CALM2 Zornitza Stark Classified gene: CALM2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1733 CALM2 Zornitza Stark Gene: calm2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1732 CALM2 Zornitza Stark gene: CALM2 was added
gene: CALM2 was added to gNBS. Sources: ClinGen
for review, cardiac, treatable tags were added to gene: CALM2.
Mode of inheritance for gene: CALM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CALM2 were set to Catecholaminergic polymorphic ventricular tachycardia MONDO:0017990
Review for gene: CALM2 was set to GREEN
Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen
BabyScreen+ newborn screening v0.1731 CALM1 Zornitza Stark Marked gene: CALM1 as ready
BabyScreen+ newborn screening v0.1731 CALM1 Zornitza Stark Gene: calm1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1731 CALM1 Zornitza Stark Classified gene: CALM1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1731 CALM1 Zornitza Stark Gene: calm1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1730 CALM1 Zornitza Stark gene: CALM1 was added
gene: CALM1 was added to gNBS. Sources: ClinGen
for review, cardiac, treatable tags were added to gene: CALM1.
Mode of inheritance for gene: CALM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CALM1 were set to Ventricular tachycardia, catecholaminergic polymorphic, 4, MIM# 614916
Penetrance for gene: CALM1 were set to Incomplete
Review for gene: CALM1 was set to GREEN
Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen
BabyScreen+ newborn screening v0.1729 RPE65 Zornitza Stark Marked gene: RPE65 as ready
BabyScreen+ newborn screening v0.1729 RPE65 Zornitza Stark Gene: rpe65 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1729 RPE65 Zornitza Stark Classified gene: RPE65 as Green List (high evidence)
BabyScreen+ newborn screening v0.1729 RPE65 Zornitza Stark Gene: rpe65 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1728 RPE65 Zornitza Stark gene: RPE65 was added
gene: RPE65 was added to gNBS. Sources: ClinGen
for review, treatable, ophthalmological tags were added to gene: RPE65.
Mode of inheritance for gene: RPE65 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RPE65 were set to Leber congenital amaurosis 2 MIM#204100; Retinitis pigmentosa 20 MIM#613794
Review for gene: RPE65 was set to GREEN
Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen.

Biallelic RPE65 mutation-associated retinal dystrophy is a form of IRD caused by biallelic pathogenic variants in RPE65; it presents as a spectrum of disease with variable age of onset and progression of vision loss. Common clinical findings across the spectrum include night blindness, progressive loss of visual fields and loss of central vision.

In LCA, night blindness often occurs from birth. Characteristically, these patients have residual cone-mediated vision in the first to third decades with progressive visual field loss until complete blindness is observed, most often in mid- to late-adulthood. A range of age of onset has been described for night blindness in RP, but it typically onsets in later childhood.

In December 2017, the FDA approved LUXTURNA (voretigene neparvovec-rzyl) gene therapy for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The FDA’s conclusion of efficacy is based on improvement in a functional vision score over 1 year in a single open-label controlled Phase 3 study of 31 affected patients. The average age of the 31 randomized patients was 15 years (range 4 to 44 years), including 64% pediatric subjects (n=20, age from 4 to 17 years) and 36% adults (n=11). Functional vision was scored by a patient’s ability to navigate a course in various luminance levels. Using both treated eyes of the 21 subjects in the LUXTURNA treatment group, 11 (52%) had a clinically meaningful score improvement, while only one of the ten (10%) subjects in the control group had a clinically meaningful score improvement. Using the first treated eye only, 15/21 (71%) had a clinically meaningful score improvement, while no comparable score improvement was observed in controls. Other secondary clinical outcomes were also examined. Analysis of white light full-field light sensitivity threshold testing showed statistically significant improvement at 1 year in the LUXTURNA treatment group compared to the control group. The change in visual acuity was not significantly different between the LUXTURNA and control groups.

LUXTURNA is administered subretinally by injection. Per the FDA package insert, the most common adverse reactions (incidence ≥ 5%) in the clinical trials for LUXTURNA included conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), and macular hole. Several other ocular adverse effects were also reported, including risk of endophthalmitis. Safety data was included on the basis of 41 patients (81 eyes).

For review: availability of therapy?
Sources: ClinGen
BabyScreen+ newborn screening v0.1727 CP Zornitza Stark Marked gene: CP as ready
BabyScreen+ newborn screening v0.1727 CP Zornitza Stark Gene: cp has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1727 CP Zornitza Stark Phenotypes for gene: CP were changed from Aceruloplasminaemia to Aceruloplasminaemia, MIM#604290
BabyScreen+ newborn screening v0.1726 CP Zornitza Stark Tag treatable tag was added to gene: CP.
Tag metabolic tag was added to gene: CP.
BabyScreen+ newborn screening v0.1726 CP Zornitza Stark reviewed gene: CP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Aceruloplasminaemia, MIM#604290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1726 WT1 Zornitza Stark Marked gene: WT1 as ready
BabyScreen+ newborn screening v0.1726 WT1 Zornitza Stark Gene: wt1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1726 WT1 Zornitza Stark Phenotypes for gene: WT1 were changed from Denys-Drash syndrome; Wilms tumor, type 1; Frasier syndrome to Wilms tumor, type 1, MIM#194070
BabyScreen+ newborn screening v0.1725 WT1 Zornitza Stark Tag for review tag was added to gene: WT1.
Tag cancer tag was added to gene: WT1.
Tag treatable tag was added to gene: WT1.
BabyScreen+ newborn screening v0.1725 WT1 Zornitza Stark reviewed gene: WT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Wilms tumor, type 1, MIM#194070; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1725 ITGB3 Zornitza Stark Marked gene: ITGB3 as ready
BabyScreen+ newborn screening v0.1725 ITGB3 Zornitza Stark Gene: itgb3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1725 ITGB3 Zornitza Stark Classified gene: ITGB3 as Green List (high evidence)
BabyScreen+ newborn screening v0.1725 ITGB3 Zornitza Stark Gene: itgb3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1724 ITGB3 Zornitza Stark gene: ITGB3 was added
gene: ITGB3 was added to gNBS. Sources: ClinGen
treatable, haematological tags were added to gene: ITGB3.
Mode of inheritance for gene: ITGB3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ITGB3 were set to Glanzmann thrombasthenia 2, MIM# 619267
Review for gene: ITGB3 was set to GREEN
Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen.

GT can present soon after birth with episodic mucocutaneous bleeding, purpura, petechiae, unprovoked bruising, and excessive bleeding from the umbilical stump or post-circumcision. Major bleeding complications during the neonatal period, such as ICH following delivery are rare. The clinical severity of GT tends to diminish with age, although the bleeding manifestations persist and are life-long.

Recombinant activated factor VII (rFVIIa) may be considered for patients with: moderate to severe acute bleeding; for treatment of refractory minor bleeds; for prophylaxis in patients with frequent severe bleeds; treatment during minor and major surgery; and in patients who are refractory to platelet transfusion. Some guidelines suggest utilizing rFVIIa as a first line therapy and saving platelet transfusion for more severe or non-responsive bleeds. High doses have been successful, particularly if used early and upfront. rFVIIa in a dose of =80 µg/kg at intervals of 2.5 h or less were observed to be safe and effective in nonsurgical bleeds, minor and major procedures in patients with or without antibodies, and/or refractoriness.

The International Glanzmann Thrombasthenia Registry (GTR), published in 2015, studied 184 patients with 829 bleeding episodes and 96 patients with 206 surgical interventions. rFVIIa alone was used in 124/829 bleeds and the proportion of successful treatment to stop bleeding was 91%. In patients without antibodies/refractoriness, rFVIIa, either alone or with antifibrinolytics, and platelets±antifibrinolytics were rated 100% effective for 24 minor and 4 major procedures. The lowest effectiveness of rFVIIa treatment alone was 88.9% (16/18 effective minor procedures) in refractory patients with platelet antibodies.

Desmopressin (DDAVP) may be considered as an additional treatment for mild bleeding episodes. DDAVP has been shown to be effective in many bleeding disorders, including inherited platelet function disorders. However, DDAVP efficacy among GT patients has not been established and guideline recommendations are conflicting.
Sources: ClinGen
BabyScreen+ newborn screening v0.1723 ITGA2B Zornitza Stark Marked gene: ITGA2B as ready
BabyScreen+ newborn screening v0.1723 ITGA2B Zornitza Stark Gene: itga2b has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1723 ITGA2B Zornitza Stark Classified gene: ITGA2B as Green List (high evidence)
BabyScreen+ newborn screening v0.1723 ITGA2B Zornitza Stark Gene: itga2b has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1722 ITGA2B Zornitza Stark gene: ITGA2B was added
gene: ITGA2B was added to gNBS. Sources: ClinGen
treatable, haematological tags were added to gene: ITGA2B.
Mode of inheritance for gene: ITGA2B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ITGA2B were set to Glanzmann thrombasthaenia 1, MIM# 273800
Review for gene: ITGA2B was set to GREEN
Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen.

GT can present soon after birth with episodic mucocutaneous bleeding, purpura, petechiae, unprovoked bruising, and excessive bleeding from the umbilical stump or post-circumcision. Major bleeding complications during the neonatal period, such as ICH following delivery are rare. The clinical severity of GT tends to diminish with age, although the bleeding manifestations persist and are life-long.

Recombinant activated factor VII (rFVIIa) may be considered for patients with: moderate to severe acute bleeding; for treatment of refractory minor bleeds; for prophylaxis in patients with frequent severe bleeds; treatment during minor and major surgery; and in patients who are refractory to platelet transfusion. Some guidelines suggest utilizing rFVIIa as a first line therapy and saving platelet transfusion for more severe or non-responsive bleeds. High doses have been successful, particularly if used early and upfront. rFVIIa in a dose of =80 µg/kg at intervals of 2.5 h or less were observed to be safe and effective in nonsurgical bleeds, minor and major procedures in patients with or without antibodies, and/or refractoriness.

The International Glanzmann Thrombasthenia Registry (GTR), published in 2015, studied 184 patients with 829 bleeding episodes and 96 patients with 206 surgical interventions. rFVIIa alone was used in 124/829 bleeds and the proportion of successful treatment to stop bleeding was 91%. In patients without antibodies/refractoriness, rFVIIa, either alone or with antifibrinolytics, and platelets±antifibrinolytics were rated 100% effective for 24 minor and 4 major procedures. The lowest effectiveness of rFVIIa treatment alone was 88.9% (16/18 effective minor procedures) in refractory patients with platelet antibodies.

Desmopressin (DDAVP) may be considered as an additional treatment for mild bleeding episodes. DDAVP has been shown to be effective in many bleeding disorders, including inherited platelet function disorders. However, DDAVP efficacy among GT patients has not been established and guideline recommendations are conflicting.
Sources: ClinGen
BabyScreen+ newborn screening v0.1721 F7 Zornitza Stark Tag for review was removed from gene: F7.
BabyScreen+ newborn screening v0.1721 F7 Zornitza Stark changed review comment from: Well established gene-disease association.

Variable severity.

Treatment: Recombinant coagulation Factor VIIa

Non-genetic confirmatory testing: factor VII level; to: Well established gene-disease association.

Variable severity.

Treatment: Recombinant coagulation Factor VIIa

Non-genetic confirmatory testing: factor VII level

Rated as 'strong actionability' in paediatric patients by ClinGen.

Clinical expression of factor VII deficiency is highly variable, and no consistent relationship has been found between the severity of the hemorrhagic syndrome and the residual levels of FVII activity. Individuals can be completely asymptomatic despite a very low FVII level. A bleeding history appears more predictive of further bleeding than the factor VII level. Factor VII levels increase during pregnancy, but levels usually remain insufficient for hemostasis in severely affected cases. Individuals with no history of bleeding do not appear to be at increased risk of PPH. Heterozygotes often have approximately half-normal levels of coagulation factors and are often asymptomatic. However, up to 2% of patients with severe bleeding phenotype are heterozygotes.

Consider prophylaxis using rFVIIa in certain circumstances. Long term prophylaxis should be considered for cases with a personal or family history of severe bleeding or with FVII activity <0.01 IU/ml using rFVIIa, adjusting to maintain clinical response. Short term prophylaxis should be considered for cases for neonates without a personal or family history of severe bleeding but who have FVII activity 0.01-0.05 IU/ml up to 6-12 months of age.
BabyScreen+ newborn screening v0.1721 ABCC8 Zornitza Stark Marked gene: ABCC8 as ready
BabyScreen+ newborn screening v0.1721 ABCC8 Zornitza Stark Gene: abcc8 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1721 ABCC8 Zornitza Stark Tag treatable tag was added to gene: ABCC8.
Tag endocrine tag was added to gene: ABCC8.
BabyScreen+ newborn screening v0.1721 ABCC8 Zornitza Stark reviewed gene: ABCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes mellitus, permanent neonatal 3, with or without neurologic features, MIM 618857; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1721 COL9A2 Zornitza Stark Tag treatable tag was added to gene: COL9A2.
Tag ophthalmological tag was added to gene: COL9A2.
BabyScreen+ newborn screening v0.1721 COL9A2 Zornitza Stark edited their review of gene: COL9A2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1721 COL9A2 Zornitza Stark reviewed gene: COL9A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21671392, 31090205, 33356723; Phenotypes: Stickler syndrome, type V, MIM 614284; Mode of inheritance: None
BabyScreen+ newborn screening v0.1721 COL9A1 Zornitza Stark Marked gene: COL9A1 as ready
BabyScreen+ newborn screening v0.1721 COL9A1 Zornitza Stark Gene: col9a1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1721 COL9A1 Zornitza Stark Tag treatable tag was added to gene: COL9A1.
Tag ophthalmological tag was added to gene: COL9A1.
BabyScreen+ newborn screening v0.1721 TFAP2B Zornitza Stark Marked gene: TFAP2B as ready
BabyScreen+ newborn screening v0.1721 TFAP2B Zornitza Stark Gene: tfap2b has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1721 TFAP2B Zornitza Stark Phenotypes for gene: TFAP2B were changed from Char syndrome to Char syndrome, MIM 169100
BabyScreen+ newborn screening v0.1720 TFAP2B Zornitza Stark Classified gene: TFAP2B as Red List (low evidence)
BabyScreen+ newborn screening v0.1720 TFAP2B Zornitza Stark Gene: tfap2b has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1719 TFAP2B Zornitza Stark reviewed gene: TFAP2B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Char syndrome, MIM 169100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1719 TFAP2A Zornitza Stark Marked gene: TFAP2A as ready
BabyScreen+ newborn screening v0.1719 TFAP2A Zornitza Stark Gene: tfap2a has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1719 TFAP2A Zornitza Stark Phenotypes for gene: TFAP2A were changed from Branchiooculofacial syndrome to Branchiooculofacial syndrome, MIM 107580
BabyScreen+ newborn screening v0.1718 TFAP2A Zornitza Stark Classified gene: TFAP2A as Red List (low evidence)
BabyScreen+ newborn screening v0.1718 TFAP2A Zornitza Stark Gene: tfap2a has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1717 TFAP2A Zornitza Stark reviewed gene: TFAP2A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Branchiooculofacial syndrome, MIM 107580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1717 TECTA Zornitza Stark Marked gene: TECTA as ready
BabyScreen+ newborn screening v0.1717 TECTA Zornitza Stark Gene: tecta has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1717 TECTA Zornitza Stark Phenotypes for gene: TECTA were changed from Deafness to Deafness, autosomal recessive 21 603629; Deafness, autosomal dominant 8/12 601543
BabyScreen+ newborn screening v0.1716 TECTA Zornitza Stark Mode of inheritance for gene: TECTA was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1715 TECTA Zornitza Stark Tag deafness tag was added to gene: TECTA.
BabyScreen+ newborn screening v0.1715 TCN2 Zornitza Stark Publications for gene: TCN2 were set to
BabyScreen+ newborn screening v0.1714 TCN2 Zornitza Stark Tag treatable tag was added to gene: TCN2.
Tag metabolic tag was added to gene: TCN2.
BabyScreen+ newborn screening v0.1714 TCIRG1 Zornitza Stark Tag treatable tag was added to gene: TCIRG1.
Tag skeletal tag was added to gene: TCIRG1.
BabyScreen+ newborn screening v0.1714 TCF3 Zornitza Stark Tag treatable tag was added to gene: TCF3.
Tag immunological tag was added to gene: TCF3.
BabyScreen+ newborn screening v0.1714 TAT Zornitza Stark Tag metabolic tag was added to gene: TAT.
BabyScreen+ newborn screening v0.1714 STXBP2 Zornitza Stark Tag treatable tag was added to gene: STXBP2.
Tag immunological tag was added to gene: STXBP2.
BabyScreen+ newborn screening v0.1714 STX11 Zornitza Stark Tag treatable tag was added to gene: STX11.
Tag immunological tag was added to gene: STX11.
BabyScreen+ newborn screening v0.1714 STAT3 Zornitza Stark Tag treatable tag was added to gene: STAT3.
Tag immunological tag was added to gene: STAT3.
BabyScreen+ newborn screening v0.1714 STAR Zornitza Stark Tag treatable tag was added to gene: STAR.
Tag endocrine tag was added to gene: STAR.
BabyScreen+ newborn screening v0.1714 SRP54 Zornitza Stark Tag treatable tag was added to gene: SRP54.
Tag immunological tag was added to gene: SRP54.
BabyScreen+ newborn screening v0.1714 SPR Zornitza Stark Tag treatable tag was added to gene: SPR.
Tag neurological tag was added to gene: SPR.
BabyScreen+ newborn screening v0.1714 SP110 Zornitza Stark Tag treatable tag was added to gene: SP110.
Tag immunological tag was added to gene: SP110.
BabyScreen+ newborn screening v0.1714 SMPD1 Zornitza Stark Tag treatable tag was added to gene: SMPD1.
Tag metabolic tag was added to gene: SMPD1.
BabyScreen+ newborn screening v0.1714 SMN1 Zornitza Stark Tag neurological tag was added to gene: SMN1.
BabyScreen+ newborn screening v0.1714 SLC5A7 Zornitza Stark Tag treatable tag was added to gene: SLC5A7.
Tag neurological tag was added to gene: SLC5A7.
BabyScreen+ newborn screening v0.1714 SLC34A3 Zornitza Stark Tag skeletal tag was added to gene: SLC34A3.
BabyScreen+ newborn screening v0.1714 SLC26A3 Zornitza Stark Tag treatable tag was added to gene: SLC26A3.
Tag gastrointestinal tag was added to gene: SLC26A3.
BabyScreen+ newborn screening v0.1714 SLC25A15 Zornitza Stark Tag treatable tag was added to gene: SLC25A15.
Tag metabolic tag was added to gene: SLC25A15.
BabyScreen+ newborn screening v0.1712 SLC22A5 Zornitza Stark Tag metabolic tag was added to gene: SLC22A5.
BabyScreen+ newborn screening v0.1712 SLC19A3 Zornitza Stark Tag metabolic tag was added to gene: SLC19A3.
BabyScreen+ newborn screening v0.1712 SLC19A2 Zornitza Stark Tag metabolic tag was added to gene: SLC19A2.
BabyScreen+ newborn screening v0.1712 SLC18A3 Zornitza Stark Tag treatable tag was added to gene: SLC18A3.
Tag neurological tag was added to gene: SLC18A3.
BabyScreen+ newborn screening v0.1712 SLC12A1 Zornitza Stark Tag treatable tag was added to gene: SLC12A1.
Tag renal tag was added to gene: SLC12A1.
BabyScreen+ newborn screening v0.1712 SI Zornitza Stark Tag treatable tag was added to gene: SI.
Tag gastrointestinal tag was added to gene: SI.
BabyScreen+ newborn screening v0.1712 SH2D1A Zornitza Stark Tag treatable tag was added to gene: SH2D1A.
Tag immunological tag was added to gene: SH2D1A.
BabyScreen+ newborn screening v0.1712 SCNN1B Zornitza Stark Tag treatable tag was added to gene: SCNN1B.
Tag endocrine tag was added to gene: SCNN1B.
BabyScreen+ newborn screening v0.1712 SCNN1A Zornitza Stark Tag endocrine tag was added to gene: SCNN1A.
BabyScreen+ newborn screening v0.1712 SBDS Zornitza Stark Tag haematological tag was added to gene: SBDS.
Tag gastrointestinal tag was added to gene: SBDS.
BabyScreen+ newborn screening v0.1712 SAMHD1 Zornitza Stark Tag for review tag was added to gene: SAMHD1.
Tag neurological tag was added to gene: SAMHD1.
BabyScreen+ newborn screening v0.1712 RET Zornitza Stark Marked gene: RET as ready
BabyScreen+ newborn screening v0.1712 RET Zornitza Stark Gene: ret has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1712 RDX Zornitza Stark Tag deafness tag was added to gene: RDX.
BabyScreen+ newborn screening v0.1712 QDPR Zornitza Stark Tag metabolic tag was added to gene: QDPR.
BabyScreen+ newborn screening v0.1712 PTS Zornitza Stark Tag metabolic tag was added to gene: PTS.
BabyScreen+ newborn screening v0.1712 PSPH Zornitza Stark Marked gene: PSPH as ready
BabyScreen+ newborn screening v0.1712 PSPH Zornitza Stark Gene: psph has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1712 PSPH Zornitza Stark Publications for gene: PSPH were set to
BabyScreen+ newborn screening v0.1711 PSPH Zornitza Stark Classified gene: PSPH as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1711 PSPH Zornitza Stark Gene: psph has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1710 PSPH Zornitza Stark edited their review of gene: PSPH: Changed publications: 16763900, 26589312
BabyScreen+ newborn screening v0.1710 PSPH Zornitza Stark Tag for review tag was added to gene: PSPH.
BabyScreen+ newborn screening v0.1710 PSPH Zornitza Stark reviewed gene: PSPH: Rating: AMBER; Mode of pathogenicity: None; Publications: 26589312; Phenotypes: Phosphoserine phosphatase deficiency MIM#614023; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1710 PKLR Zornitza Stark Tag treatable tag was added to gene: PKLR.
Tag metabolic tag was added to gene: PKLR.
BabyScreen+ newborn screening v0.1710 PHKG2 Zornitza Stark Tag metabolic tag was added to gene: PHKG2.
BabyScreen+ newborn screening v0.1710 PHKB Zornitza Stark Tag treatable tag was added to gene: PHKB.
Tag metabolic tag was added to gene: PHKB.
BabyScreen+ newborn screening v0.1710 PHKA2 Zornitza Stark Tag treatable tag was added to gene: PHKA2.
Tag metabolic tag was added to gene: PHKA2.
BabyScreen+ newborn screening v0.1710 PHGDH Zornitza Stark Tag metabolic tag was added to gene: PHGDH.
BabyScreen+ newborn screening v0.1710 PGM1 Zornitza Stark Tag metabolic tag was added to gene: PGM1.
BabyScreen+ newborn screening v0.1710 PDZD7 Zornitza Stark Tag deafness tag was added to gene: PDZD7.
BabyScreen+ newborn screening v0.1710 PDX1 Zornitza Stark Tag treatable tag was added to gene: PDX1.
Tag endocrine tag was added to gene: PDX1.
BabyScreen+ newborn screening v0.1710 PDHX Zornitza Stark Tag treatable tag was added to gene: PDHX.
Tag metabolic tag was added to gene: PDHX.
BabyScreen+ newborn screening v0.1710 PDHA1 Zornitza Stark Tag treatable tag was added to gene: PDHA1.
Tag metabolic tag was added to gene: PDHA1.
BabyScreen+ newborn screening v0.1710 PCDH15 Zornitza Stark Tag deafness tag was added to gene: PCDH15.
BabyScreen+ newborn screening v0.1710 PCCB Zornitza Stark Tag metabolic tag was added to gene: PCCB.
BabyScreen+ newborn screening v0.1710 PCCA Zornitza Stark Tag metabolic tag was added to gene: PCCA.
BabyScreen+ newborn screening v0.1710 PCBD1 Zornitza Stark Tag treatable tag was added to gene: PCBD1.
Tag metabolic tag was added to gene: PCBD1.
BabyScreen+ newborn screening v0.1710 PC Zornitza Stark Tag treatable tag was added to gene: PC.
Tag metabolic tag was added to gene: PC.
BabyScreen+ newborn screening v0.1710 PAX8 Zornitza Stark Tag treatable tag was added to gene: PAX8.
Tag endocrine tag was added to gene: PAX8.
BabyScreen+ newborn screening v0.1710 PAX3 Zornitza Stark Tag deafness tag was added to gene: PAX3.
BabyScreen+ newborn screening v0.1710 PALB2 Zornitza Stark Tag treatable tag was added to gene: PALB2.
Tag haematological tag was added to gene: PALB2.
BabyScreen+ newborn screening v0.1710 PAH Zornitza Stark Tag metabolic tag was added to gene: PAH.
BabyScreen+ newborn screening v0.1710 OXCT1 Zornitza Stark Tag metabolic tag was added to gene: OXCT1.
BabyScreen+ newborn screening v0.1710 OTOGL Zornitza Stark Tag deafness tag was added to gene: OTOGL.
BabyScreen+ newborn screening v0.1710 OTOF Zornitza Stark Tag deafness tag was added to gene: OTOF.
BabyScreen+ newborn screening v0.1710 OTOA Zornitza Stark Tag deafness tag was added to gene: OTOA.
BabyScreen+ newborn screening v0.1710 OTC Zornitza Stark Tag metabolic tag was added to gene: OTC.
BabyScreen+ newborn screening v0.1710 NR5A1 Zornitza Stark Tag endocrine tag was added to gene: NR5A1.
BabyScreen+ newborn screening v0.1710 NR3C2 Zornitza Stark Tag treatable tag was added to gene: NR3C2.
Tag endocrine tag was added to gene: NR3C2.
BabyScreen+ newborn screening v0.1710 NR0B1 Zornitza Stark Tag endocrine tag was added to gene: NR0B1.
BabyScreen+ newborn screening v0.1710 NPC2 Zornitza Stark Tag treatable tag was added to gene: NPC2.
Tag metabolic tag was added to gene: NPC2.
BabyScreen+ newborn screening v0.1710 NPC1 Zornitza Stark Tag treatable tag was added to gene: NPC1.
Tag metabolic tag was added to gene: NPC1.
BabyScreen+ newborn screening v0.1710 NNT Zornitza Stark Tag endocrine tag was added to gene: NNT.
BabyScreen+ newborn screening v0.1710 NKX2-1 Zornitza Stark Tag treatable tag was added to gene: NKX2-1.
Tag endocrine tag was added to gene: NKX2-1.
BabyScreen+ newborn screening v0.1710 NIPAL4 Zornitza Stark Tag for review tag was added to gene: NIPAL4.
BabyScreen+ newborn screening v0.1710 NIPAL4 Zornitza Stark commented on gene: NIPAL4: For review: treatment available?
BabyScreen+ newborn screening v0.1710 NHEJ1 Zornitza Stark Tag immunological tag was added to gene: NHEJ1.
BabyScreen+ newborn screening v0.1710 NF1 Zornitza Stark Tag for review tag was added to gene: NF1.
BabyScreen+ newborn screening v0.1710 NEUROG3 Zornitza Stark Tag gastrointestinal tag was added to gene: NEUROG3.
BabyScreen+ newborn screening v0.1710 NCF2 Zornitza Stark Tag immunological tag was added to gene: NCF2.
BabyScreen+ newborn screening v0.1710 NCF1 Zornitza Stark Tag immunological tag was added to gene: NCF1.
BabyScreen+ newborn screening v0.1710 NAGS Zornitza Stark Tag metabolic tag was added to gene: NAGS.
BabyScreen+ newborn screening v0.1710 NAGLU Zornitza Stark Tag metabolic tag was added to gene: NAGLU.
BabyScreen+ newborn screening v0.1710 MYSM1 Zornitza Stark Tag haematological tag was added to gene: MYSM1.
BabyScreen+ newborn screening v0.1710 MYO7A Zornitza Stark Tag deafness tag was added to gene: MYO7A.
BabyScreen+ newborn screening v0.1710 MYO6 Zornitza Stark Tag deafness tag was added to gene: MYO6.
BabyScreen+ newborn screening v0.1710 MYO15A Zornitza Stark Tag deafness tag was added to gene: MYO15A.
BabyScreen+ newborn screening v0.1710 MVK Zornitza Stark Tag metabolic tag was added to gene: MVK.
BabyScreen+ newborn screening v0.1710 MUT Zornitza Stark Tag metabolic tag was added to gene: MUT.
BabyScreen+ newborn screening v0.1710 MUSK Zornitza Stark Tag neurological tag was added to gene: MUSK.
BabyScreen+ newborn screening v0.1710 MTTP Zornitza Stark Tag metabolic tag was added to gene: MTTP.
BabyScreen+ newborn screening v0.1710 MTRR Zornitza Stark Tag treatable tag was added to gene: MTRR.
Tag metabolic tag was added to gene: MTRR.
BabyScreen+ newborn screening v0.1710 MTR Zornitza Stark Tag treatable tag was added to gene: MTR.
Tag haematological tag was added to gene: MTR.
BabyScreen+ newborn screening v0.1710 MRAP Zornitza Stark Tag endocrine tag was added to gene: MRAP.
BabyScreen+ newborn screening v0.1710 MPL Zornitza Stark Tag haematological tag was added to gene: MPL.
BabyScreen+ newborn screening v0.1710 MPI Zornitza Stark Tag metabolic tag was added to gene: MPI.
BabyScreen+ newborn screening v0.1710 MOCS1 Zornitza Stark Tag metabolic tag was added to gene: MOCS1.
BabyScreen+ newborn screening v0.1710 MMADHC Zornitza Stark Marked gene: MMADHC as ready
BabyScreen+ newborn screening v0.1710 MMADHC Zornitza Stark Gene: mmadhc has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1710 MMADHC Zornitza Stark Tag metabolic tag was added to gene: MMADHC.
BabyScreen+ newborn screening v0.1710 MMACHC Zornitza Stark Tag metabolic tag was added to gene: MMACHC.
BabyScreen+ newborn screening v0.1710 MMAB Zornitza Stark Tag metabolic tag was added to gene: MMAB.
BabyScreen+ newborn screening v0.1710 MMAA Zornitza Stark Tag metabolic tag was added to gene: MMAA.
BabyScreen+ newborn screening v0.1710 MLYCD Zornitza Stark Tag metabolic tag was added to gene: MLYCD.
BabyScreen+ newborn screening v0.1710 MITF Zornitza Stark Tag deafness tag was added to gene: MITF.
BabyScreen+ newborn screening v0.1710 MEFV Zornitza Stark Tag haematological tag was added to gene: MEFV.
BabyScreen+ newborn screening v0.1710 MCFD2 Zornitza Stark Tag haematological tag was added to gene: MCFD2.
BabyScreen+ newborn screening v0.1710 MC2R Zornitza Stark Tag endocrine tag was added to gene: MC2R.
BabyScreen+ newborn screening v0.1710 MARVELD2 Zornitza Stark Tag deafness tag was added to gene: MARVELD2.
BabyScreen+ newborn screening v0.1710 MAN2B1 Zornitza Stark Tag metabolic tag was added to gene: MAN2B1.
BabyScreen+ newborn screening v0.1710 TFAP2B David Amor reviewed gene: TFAP2B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: MIM 169100 Char syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1710 TFAP2A David Amor reviewed gene: TFAP2A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: MIM 107580 Branchiooculofacial syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1710 COL9A1 David Amor changed review comment from: Gene-disease association: strong but rare, prbably <1% of Sticller syndrome; Van Camp et al. (2006) described a consanguineous Moroccan family in which 4 of 10 sibs had features characteristic of Stickler syndrome, including moderate to severe sensorineural hearing loss, moderate to high myopia with vitreoretinopathy, and epiphyseal dysplasia. Nikopoulos et al. (2011) reported 2 sisters in a Turkish family and 1 boy in a Moroccan family with features of autosomal recessive Stickler syndrome. All 3 individuals had myopia, vitreous changes, sensorineural hearing loss, and epiphyseal dysplasia. They also had exudative rhegmatogenous retinal detachment.

Severity: moderate-severe

Age of onset: congenital

Non-molecular confirmatory testing: Affected individuals have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, cataracts, and epiphyseal dysplasia

Treatment: as per other Stickler syndrome; to: Gene-disease association: strong but rare, prbably <1% of Sticller syndrome; Van Camp et al. (2006) described a consanguineous Moroccan family in which 4 of 10 sibs had features characteristic of Stickler syndrome, including moderate to severe sensorineural hearing loss, moderate to high myopia with vitreoretinopathy, and epiphyseal dysplasia. Nikopoulos et al. (2011) reported 2 sisters in a Turkish family and 1 boy in a Moroccan family with features of autosomal recessive Stickler syndrome. All 3 individuals had myopia, vitreous changes, sensorineural hearing loss, and epiphyseal dysplasia. They also had exudative rhegmatogenous retinal detachment.

Severity: moderate-severe

Age of onset: congenital

Non-molecular confirmatory testing: Affected individuals have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, cataracts, and epiphyseal dysplasia

Treatment: as per other Stickler syndrome
BabyScreen+ newborn screening v0.1710 COL9A2 David Amor reviewed gene: COL9A2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: MIM 614284 ?Stickler syndrome, type V; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1710 COL9A1 David Amor reviewed gene: COL9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: MIM 120210 Stickler syndrome, type IV; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor reviewed gene: ABCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: MIM 256450 Hyperinsulinemic hypoglycemia, familial, 1, MIM 618857 Diabetes mellitus, permanent neonatal 3, with or without neurologic features; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor Deleted their review
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor Deleted their comment
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor Deleted their comment
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor commented on gene: ABCC8: Gene-disease association: strong. Note sporadic cases of Familial hyperinsulinemic hypoglycemiawith focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele.

ABCC8 associated permanent neonatal diabetes mellitus typically due to GoF missense variants. Fathers are at increased risk of T2DM also.

Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide, oral pancreatic enzymes
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor edited their review of gene: ABCC8: Changed phenotypes: MIM 256450 Hyperinsulinemic hypoglycemia, familial, 1, MIM 618857 Diabetes mellitus, permanent neonatal 3, with or without neurologic features
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor Deleted their comment
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor commented on gene: ABCC8: Gene-disease association: strong. Note sporadic cases of Familial hyperinsulinemic hypoglycemiawith focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele.

ABCC8 associated permanent neonatal diabetes mellitus typically due to GoF missense variants. Fathers are at increased risk of T2DM also.

Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide, oral pancreatic enzymes
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor changed review comment from: Gene-disease association: strong. Note sporadic cases of Familial hyperinsulinemic hypoglycemiawith focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele.

ABCC8 associated permanent neonatal diabetes mellitus typically due to GoF missense variants. Fathers are at increased risk of T2DM also.



Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide, oral pancreatic enzymes
; to: Gene-disease association: strong. Note sporadic cases of Familial hyperinsulinemic hypoglycemiawith focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele.

ABCC8 associated permanent neonatal diabetes mellitus typically due to GoF missense variants. Fathers are at increased risk of T2DM also.

Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide, oral pancreatic enzymes
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor changed review comment from: Gene-disease association: strong. Note sporadic cases with focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele

Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes, glucose, insulin, free fatty acid levels

Treatment: as per rx-genes, Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus; to: Gene-disease association: strong. Note sporadic cases of Familial hyperinsulinemic hypoglycemiawith focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele.

ABCC8 associated permanent neonatal diabetes mellitus typically due to GoF missense variants. Fathers are at increased risk of T2DM also.



Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide, oral pancreatic enzymes
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor reviewed gene: ABCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: MIM 256450 Hyperinsulinemic hypoglycemia, familial, 1; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1710 TECTA David Amor reviewed gene: TECTA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 21, Deafness, autosomal dominant 8/12; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1710 LYST Zornitza Stark Tag immunological tag was added to gene: LYST.
BabyScreen+ newborn screening v0.1710 LRTOMT Zornitza Stark Tag deafness tag was added to gene: LRTOMT.
BabyScreen+ newborn screening v0.1710 LRP5 Zornitza Stark Tag treatable tag was added to gene: LRP5.
Tag skeletal tag was added to gene: LRP5.
BabyScreen+ newborn screening v0.1710 LOXHD1 Zornitza Stark Tag deafness tag was added to gene: LOXHD1.
BabyScreen+ newborn screening v0.1710 LMBRD1 Zornitza Stark Tag metabolic tag was added to gene: LMBRD1.
BabyScreen+ newborn screening v0.1710 LIPA Zornitza Stark Tag metabolic tag was added to gene: LIPA.
BabyScreen+ newborn screening v0.1710 LIG4 Zornitza Stark Tag treatable tag was added to gene: LIG4.
Tag immunological tag was added to gene: LIG4.
BabyScreen+ newborn screening v0.1710 LHX4 Zornitza Stark Tag endocrine tag was added to gene: LHX4.
BabyScreen+ newborn screening v0.1710 LHX3 Zornitza Stark Tag endocrine tag was added to gene: LHX3.
BabyScreen+ newborn screening v0.1710 LHFPL5 Zornitza Stark Tag deafness tag was added to gene: LHFPL5.
BabyScreen+ newborn screening v0.1710 LEPR Zornitza Stark Tag endocrine tag was added to gene: LEPR.
BabyScreen+ newborn screening v0.1710 LDLR Zornitza Stark Tag for review was removed from gene: LDLR.
Tag treatable tag was added to gene: LDLR.
Tag metabolic tag was added to gene: LDLR.
Combined Immunodeficiency v1.31 LCP2 Peter McNaughton gene: LCP2 was added
gene: LCP2 was added to Combined Immunodeficiency. Sources: Literature
Mode of inheritance for gene: LCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LCP2 were set to PMID: 36474126; PMID: 33231617
Review for gene: LCP2 was set to GREEN
Added comment: 3-year-old child who was born to first-cousins parents and presented with recurrent infections, failure to thrive, and severe EBV-related infection and lymphoproliferation.
Functional testing linking gene with impaired t cell signalling.
Previous unrelated patient reported in PMID: 33231617 with SCID phenotype.
Sources: Literature
BabyScreen+ newborn screening v0.1710 L1CAM Zornitza Stark Marked gene: L1CAM as ready
BabyScreen+ newborn screening v0.1710 L1CAM Zornitza Stark Gene: l1cam has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1710 L1CAM Zornitza Stark Phenotypes for gene: L1CAM were changed from X-linked hydrocephalus syndrome to Hydrocephalus due to aqueductal stenosis, MIM# 307000
BabyScreen+ newborn screening v0.1709 L1CAM Zornitza Stark Classified gene: L1CAM as Red List (low evidence)
BabyScreen+ newborn screening v0.1709 L1CAM Zornitza Stark Gene: l1cam has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1708 KCNJ11 Zornitza Stark changed review comment from: Association with hyperinsulinism is well established.

Onset is congenital.

Treatment: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

Association with neonatal diabetes is also well established.

Treatment: Insulin, glibenclamide, oral pancreatic enzymes.

Phenotypes are expected to be distinguishable clinically.; to: Association with hyperinsulinism is well established, mono-allelic variants.

Onset is congenital.

Treatment: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

Association with neonatal diabetes is also well established, bi-allelic variants.

Treatment: Insulin, glibenclamide, oral pancreatic enzymes.

Phenotypes are expected to be distinguishable clinically.
BabyScreen+ newborn screening v0.1708 KCNJ11 Zornitza Stark Marked gene: KCNJ11 as ready
BabyScreen+ newborn screening v0.1708 KCNJ11 Zornitza Stark Gene: kcnj11 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1708 KCNJ11 Zornitza Stark Phenotypes for gene: KCNJ11 were changed from Hyperinsulinemic hypoglycemia, familial, MIM#601820 to Diabetes mellitus, transient neonatal, 3 610582; Diabetes, permanent neonatal, with or without neurologic features 606176; Hyperinsulinemic hypoglycemia, familial, 2 601820
BabyScreen+ newborn screening v0.1707 KCNJ11 Zornitza Stark Mode of inheritance for gene: KCNJ11 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1706 KCNJ11 Zornitza Stark Tag treatable tag was added to gene: KCNJ11.
Tag endocrine tag was added to gene: KCNJ11.
BabyScreen+ newborn screening v0.1706 KCNJ11 Zornitza Stark reviewed gene: KCNJ11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes mellitus, transient neonatal, 3 610582, Diabetes, permanent neonatal, with or without neurologic features 606176, Hyperinsulinemic hypoglycemia, familial, 2 601820; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1706 KCNJ1 Zornitza Stark Tag treatable tag was added to gene: KCNJ1.
Tag renal tag was added to gene: KCNJ1.
BabyScreen+ newborn screening v0.1706 IVD Zornitza Stark Tag metabolic tag was added to gene: IVD.
BabyScreen+ newborn screening v0.1706 ILDR1 Zornitza Stark Tag deafness tag was added to gene: ILDR1.
BabyScreen+ newborn screening v0.1706 HMGCL Zornitza Stark Tag metabolic tag was added to gene: HMGCL.
BabyScreen+ newborn screening v0.1706 HLCS Zornitza Stark Tag metabolic tag was added to gene: HLCS.
BabyScreen+ newborn screening v0.1706 HK1 Zornitza Stark Tag treatable tag was added to gene: HK1.
Tag endocrine tag was added to gene: HK1.
BabyScreen+ newborn screening v0.1706 HGF Zornitza Stark Tag deafness tag was added to gene: HGF.
BabyScreen+ newborn screening v0.1706 HADHB Zornitza Stark Tag metabolic tag was added to gene: HADHB.
BabyScreen+ newborn screening v0.1706 HADHA Zornitza Stark Tag metabolic tag was added to gene: HADHA.
BabyScreen+ newborn screening v0.1706 GRXCR1 Zornitza Stark Tag deafness tag was added to gene: GRXCR1.