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Mendeliome v0.6998 MCM10 Zornitza Stark edited their review of gene: MCM10: Added comment: PMID 33712616: second family reported, three affected sibs with restrictive cardiomyopathy and hypoplasia of the spleen and thymus. Functional data suggested that MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion.; Changed publications: 32865517, 33712616; Changed phenotypes: Susceptibility to CMV, Restrictive cardiomyopathy
Mendeliome v0.6998 CYBA Zornitza Stark Gene: cyba has been classified as Green List (High Evidence).
Mendeliome v0.6998 CYBA Zornitza Stark Phenotypes for gene: CYBA were changed from to Chronic granulomatous disease 4, autosomal recessive, MIM# 233690; MONDO:0009308
Mendeliome v0.6995 CYBA Zornitza Stark reviewed gene: CYBA: Rating: GREEN; Mode of pathogenicity: None; Publications: 2770793; Phenotypes: Chronic granulomatous disease 4, autosomal recessive, MIM# 233690, MONDO:0009308; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6995 NUP37 Zornitza Stark Phenotypes for gene: NUP37 were changed from Nephrotic syndrome to Nephrotic syndrome; Microcephaly 24, primary, autosomal recessive, MIM# 618179
Mendeliome v0.6994 NUP37 Zornitza Stark changed review comment from: Single family reported with nephrotic syndrome.
Sources: Literature; to: Single family reported with nephrotic syndrome and microcephaly.
Sources: Literature
Mendeliome v0.6994 NUP37 Zornitza Stark edited their review of gene: NUP37: Changed phenotypes: Nephrotic syndrome, Microcephaly 24, primary, autosomal recessive, MIM# 618179
Mendeliome v0.6994 COPB2 Zornitza Stark Gene: copb2 has been classified as Red List (Low Evidence).
Mendeliome v0.6994 COPB2 Zornitza Stark gene: COPB2 was added
gene: COPB2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COPB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB2 were set to 29036432
Phenotypes for gene: COPB2 were set to Microcephaly 19, primary, autosomal recessive, MIM# 617800
Review for gene: COPB2 was set to RED
Added comment: Two sibs with homozygous missense variant in this gene, mice homozygous for this variant had normal brain size however. Mice compound het for null allele and missense variant had some brain features, suggesting the missense variant is hypomorphic.
Sources: Expert list
Mendeliome v0.6993 WDR62 Zornitza Stark Gene: wdr62 has been classified as Green List (High Evidence).
Mendeliome v0.6993 WDR62 Zornitza Stark Phenotypes for gene: WDR62 were changed from to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317; MONDO:0011435
Mendeliome v0.6990 WDR62 Zornitza Stark reviewed gene: WDR62: Rating: GREEN; Mode of pathogenicity: None; Publications: 20890279, 20729831, 20890278, 21496009, 21834044, 22775483, 32677750, 31788460; Phenotypes: Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317, MONDO:0011435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6990 TRMT10A Zornitza Stark Gene: trmt10a has been classified as Green List (High Evidence).
Mendeliome v0.6987 TRAIP Zornitza Stark Gene: traip has been classified as Green List (High Evidence).
Mendeliome v0.6983 TOP3A Zornitza Stark Gene: top3a has been classified as Green List (High Evidence).
Mendeliome v0.6983 TOP3A Zornitza Stark Phenotypes for gene: TOP3A were changed from to Microcephaly, growth restriction, and increased sister chromatid exchange 2, MIM# 618097; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5, MIM#618098
Mendeliome v0.6980 TOP3A Zornitza Stark reviewed gene: TOP3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30057030, 33631320; Phenotypes: Microcephaly, growth restriction, and increased sister chromatid exchange 2, MIM# 618097, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5, MIM#618098; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6980 STIL Zornitza Stark Gene: stil has been classified as Green List (High Evidence).
Mendeliome v0.6980 STIL Zornitza Stark Phenotypes for gene: STIL were changed from to Microcephaly 7, primary, autosomal recessive, MIM# 612703; MONDO:0012989
Mendeliome v0.6977 STIL Zornitza Stark reviewed gene: STIL: Rating: GREEN; Mode of pathogenicity: None; Publications: 19215732, 22989186, 25218063, 33132204, 32677750, 29230157; Phenotypes: Microcephaly 7, primary, autosomal recessive, MIM# 612703, MONDO:0012989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6975 STAMBP Zornitza Stark Gene: stambp has been classified as Green List (High Evidence).
Mendeliome v0.6972 PCNT Zornitza Stark Gene: pcnt has been classified as Green List (High Evidence).
Mendeliome v0.6969 NHEJ1 Zornitza Stark Gene: nhej1 has been classified as Green List (High Evidence).
Mendeliome v0.6969 NHEJ1 Zornitza Stark Phenotypes for gene: NHEJ1 were changed from to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291; Cernunnos-XLF deficiency MONDO:0012650
Mendeliome v0.6966 NHEJ1 Zornitza Stark reviewed gene: NHEJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30898087, 30666249, 28741180, 25288157, 24511403, 21721379, 21535335; Phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291, Cernunnos-XLF deficiency MONDO:0012650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6966 NBN Zornitza Stark Gene: nbn has been classified as Green List (High Evidence).
Mendeliome v0.6963 MSMO1 Zornitza Stark Gene: msmo1 has been classified as Green List (High Evidence).
Mendeliome v0.6963 MSMO1 Zornitza Stark Phenotypes for gene: MSMO1 were changed from to Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834; MONDO:0014793; Disorders of the metabolism of sterols
Mendeliome v0.6960 MSMO1 Zornitza Stark reviewed gene: MSMO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21285510, 24144731, 28673550, 33161406; Phenotypes: Microcephaly, congenital cataract, and psoriasiform dermatitis, MIM# 616834, MONDO:0014793; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6960 MCPH1 Zornitza Stark Gene: mcph1 has been classified as Green List (High Evidence).
Mendeliome v0.6960 MCPH1 Zornitza Stark Phenotypes for gene: MCPH1 were changed from to Microcephaly 1, primary, autosomal recessive, MIM# 251200; MONDO:0009617
Mendeliome v0.6957 MCPH1 Zornitza Stark reviewed gene: MCPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12046007, 15199523, 16311745, 20978018, 32294449, 30351297, 29026105; Phenotypes: Microcephaly 1, primary, autosomal recessive, MIM# 251200, MONDO:0009617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6957 ATP1A3 Zornitza Stark Gene: atp1a3 has been classified as Green List (High Evidence).
Mendeliome v0.6953 LARP7 Zornitza Stark Gene: larp7 has been classified as Green List (High Evidence).
Mendeliome v0.6950 KNL1 Zornitza Stark Gene: knl1 has been classified as Green List (High Evidence).
Mendeliome v0.6950 KNL1 Zornitza Stark Phenotypes for gene: KNL1 were changed from to Microcephaly 4, primary, autosomal recessive, MIM# 604321; MONDO:0011437
Mendeliome v0.6947 KNL1 Zornitza Stark reviewed gene: KNL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22983954, 26626498, 27149178, 30304678, 27784895; Phenotypes: Microcephaly 4, primary, autosomal recessive, MIM# 604321, MONDO:0011437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6946 BAAT Zornitza Stark Gene: baat has been classified as Green List (High Evidence).
Mendeliome v0.6943 KIF11 Zornitza Stark Gene: kif11 has been classified as Green List (High Evidence).
Mendeliome v0.6940 IER3IP1 Zornitza Stark Gene: ier3ip1 has been classified as Green List (High Evidence).
Mendeliome v0.6937 EFTUD2 Zornitza Stark Gene: eftud2 has been classified as Green List (High Evidence).
Mendeliome v0.6937 EFTUD2 Zornitza Stark Phenotypes for gene: EFTUD2 were changed from to Mandibulofacial dysostosis, Guion-Almeida type, MIM# 610536; Mandibulofacial dysostosis-microcephaly syndrome MONDO:0012516
Mendeliome v0.6934 EFTUD2 Zornitza Stark reviewed gene: EFTUD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22305528, 23188108, 33601405, 33262786, 26507355; Phenotypes: Mandibulofacial dysostosis, Guion-Almeida type, MIM# 610536, Mandibulofacial dysostosis-microcephaly syndrome MONDO:0012516; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6934 CEP152 Zornitza Stark Gene: cep152 has been classified as Green List (High Evidence).
Mendeliome v0.6934 CEP152 Zornitza Stark Phenotypes for gene: CEP152 were changed from to Microcephaly 9, primary, autosomal recessive, MIM# 614852; MONDO:0013923; Seckel syndrome 5, MIM# 613823; MONDO:0013443
Mendeliome v0.6931 CEP152 Zornitza Stark reviewed gene: CEP152: Rating: GREEN; Mode of pathogenicity: None; Publications: 20598275, 22775483, 21131973, 23199753; Phenotypes: Microcephaly 9, primary, autosomal recessive, MIM# 614852, MONDO:0013923, Seckel syndrome 5, MIM# 613823, MONDO:0013443; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6931 GNPAT Zornitza Stark Gene: gnpat has been classified as Green List (High Evidence).
Mendeliome v0.6931 GNPAT Zornitza Stark Phenotypes for gene: GNPAT were changed from to Rhizomelic chondrodysplasia punctata, type 2, MIM# 222765; MONDO:0009112
Mendeliome v0.6928 GNPAT Zornitza Stark reviewed gene: GNPAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 9536089, 11152660, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 2, MIM# 222765, MONDO:0009112; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6927 CD4 Zornitza Stark Gene: cd4 has been classified as Green List (High Evidence).
Mendeliome v0.6927 CD4 Zornitza Stark Phenotypes for gene: CD4 were changed from to Immunodeficiency 79, MIM# 619238; Absence of CD4+ T cells; exuberant, relapsing, treatment-refractory warts
Mendeliome v0.6924 CD4 Zornitza Stark changed review comment from: Single individual reported, functional data, emerging gene.; to: Two individuals reported, functional data.
Mendeliome v0.6924 CD4 Zornitza Stark edited their review of gene: CD4: Changed rating: GREEN; Changed publications: 31781092, 33471124; Changed phenotypes: Immunodeficiency 79, MIM# 619238, Absence of CD4+ T cells, exuberant, relapsing, treatment-refractory warts
Mendeliome v0.6924 TMEM231 Zornitza Stark Gene: tmem231 has been classified as Green List (High Evidence).
Mendeliome v0.6921 TMEM216 Zornitza Stark Gene: tmem216 has been classified as Green List (High Evidence).
Mendeliome v0.6918 TMEM138 Zornitza Stark Gene: tmem138 has been classified as Green List (High Evidence).
Mendeliome v0.6915 TCTN2 Zornitza Stark Gene: tctn2 has been classified as Green List (High Evidence).
Mendeliome v0.6912 TCTN1 Zornitza Stark Gene: tctn1 has been classified as Green List (High Evidence).
Mendeliome v0.6908 SMCHD1 Zornitza Stark edited their review of gene: SMCHD1: Added comment: Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence. Choanal atresia is a feature. More than 30 unrelated individuals reported. Caused by gain of function missense variants with the extended ATPase domain.; Changed rating: GREEN; Changed mode of pathogenicity: Other; Changed publications: 28067909; Changed phenotypes: Bosma arhinia microphthalmia syndrome, MIM# 603457, Arhinia, choanal atresia, microphthalmia MONDO:0011323; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6908 SMCHD1 Zornitza Stark Phenotypes for gene: SMCHD1 were changed from Bosma arhinia microphthalmia syndrome, MIM 603457; Fascioscapulohumeral muscular dystrophy 2, digenic to Bosma arhinia microphthalmia syndrome, MIM 603457; Arhinia, choanal atresia, microphthalmia MONDO:0011323; Fascioscapulohumeral muscular dystrophy 2, digenic
Mendeliome v0.6906 TXNL4A Zornitza Stark Gene: txnl4a has been classified as Green List (High Evidence).
Mendeliome v0.6906 TXNL4A Zornitza Stark Phenotypes for gene: TXNL4A were changed from to Burn-McKeown syndrome, MIM# 608572; Choanal atresia - deafness - cardiac defects - dysmorphism syndrome, MONDO:0012064
Mendeliome v0.6903 TXNL4A Zornitza Stark reviewed gene: TXNL4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25434003; Phenotypes: Burn-McKeown syndrome, MIM# 608572, Choanal atresia - deafness - cardiac defects - dysmorphism syndrome, MONDO:0012064; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6901 SPINT2 Zornitza Stark changed review comment from: More than 15 unrelated families reported.; to: Well established gene-disease association. PMID 30445423 reviews 34 patients from 26 families: 13 different variants in SPINT2 were seen, including 3 premature termination codons, 2 start codon removals, and 3 canonical splice site variants, supporting loss of function as the pathogenic mechanism. The most commonly observed variant was Y163C, observed in 40 (59%) of 68 disease alleles. Seven unrelated patients with the Y163C mutation had a shared haplotype, suggesting that it is a founder mutation. Choanal atresia (20/34) and keratitis of infantile onset (26/34) were the most common findings. All patients presented with intractable diarrhoea, with onset typically in the first 2 weeks of life. Episodes of intestinal pseudoobstruction sometimes preceded the onset of diarrhoea. Characteristic epithelial tufts on intestinal histology were seen in 13 of the 34 patients.
Mendeliome v0.6901 FOXE1 Zornitza Stark Gene: foxe1 has been classified as Green List (High Evidence).
Mendeliome v0.6898 MIB1 Zornitza Stark Gene: mib1 has been classified as Green List (High Evidence).
Mendeliome v0.6897 ANO3 Zornitza Stark Gene: ano3 has been classified as Green List (High Evidence).
Mendeliome v0.6894 IPO8 Zornitza Stark Gene: ipo8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6894 IPO8 Zornitza Stark Classified gene: IPO8 as Amber List (moderate evidence)
Mendeliome v0.6894 IPO8 Zornitza Stark Gene: ipo8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6893 IPO8 Zornitza Stark gene: IPO8 was added
gene: IPO8 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IPO8 were set to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Review for gene: IPO8 was set to AMBER
Added comment: 12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression.
Sources: Expert Review
Mendeliome v0.6891 FAM20C Zornitza Stark Gene: fam20c has been classified as Green List (High Evidence).
Mendeliome v0.6886 ANKS6 Zornitza Stark Gene: anks6 has been classified as Green List (High Evidence).
Mendeliome v0.6886 ANKS6 Zornitza Stark Phenotypes for gene: ANKS6 were changed from to Nephronophthisis 16, MIM# 615382; MONDO:0014158
Mendeliome v0.6883 ANKS6 Zornitza Stark reviewed gene: ANKS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23793029, 31678577, 31635528, 26039630, 24610927; Phenotypes: Nephronophthisis 16, MIM# 615382, MONDO:0014158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6883 GLIS2 Zornitza Stark Phenotypes for gene: GLIS2 were changed from Nephronophthisis 7, OMIM#611498 to Nephronophthisis 7, OMIM#611498; MONDO:0012680
Mendeliome v0.6881 GLIS2 Zornitza Stark edited their review of gene: GLIS2: Changed publications: 17618285, 23559409, 31676329; Changed phenotypes: Nephronophthisis 7, OMIM#611498, MONDO:0012680
Mendeliome v0.6881 CLDN2 Zornitza Stark Phenotypes for gene: CLDN2 were changed from Susceptibility to pancreatitis to Susceptibility to pancreatitis; Azoospermia, obstructive, with nephrolithiasis, MIM# 301060
Mendeliome v0.6878 CLDN2 Zornitza Stark edited their review of gene: CLDN2: Added comment: Azoospermia: single multigenerational family reported.; Changed publications: 29884332, 31163246, 31320686; Changed phenotypes: Susceptibility to pancreatitis, Azoospermia, obstructive, with nephrolithiasis, MIM# 301060; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6877 FLII Zornitza Stark Classified gene: FLII as Green List (high evidence)
Mendeliome v0.6877 FLII Zornitza Stark Gene: flii has been classified as Green List (High Evidence).
Mendeliome v0.6876 POLR3A Elena Savva commented on gene: POLR3A: c.1909+22G>A is a recurring variant that results in a leaky splice site

Bi-allelic variants associated with Leukodystrophy and with Wiedemann-Rautenstrauch syndrome; note association between mono-allelic variants and susceptibility to severe VZV infection.

Deep intronic variants commonly pathogenic

No clear gen-phen correlation
Mendeliome v0.6876 HSF2BP Zornitza Stark Gene: hsf2bp has been classified as Red List (Low Evidence).
Mendeliome v0.6876 HSF2BP Zornitza Stark gene: HSF2BP was added
gene: HSF2BP was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HSF2BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSF2BP were set to 32845237
Phenotypes for gene: HSF2BP were set to Premature ovarian failure, OMIM#619245
Review for gene: HSF2BP was set to RED
Added comment: Single family reported where homozygous missense variant segregated with POF in three sisters.
Sources: Expert list
Mendeliome v0.6875 COL4A6 Zornitza Stark Gene: col4a6 has been classified as Red List (Low Evidence).
Mendeliome v0.6872 COL4A6 Zornitza Stark Classified gene: COL4A6 as Red List (low evidence)
Mendeliome v0.6872 COL4A6 Zornitza Stark Gene: col4a6 has been classified as Red List (Low Evidence).
Mendeliome v0.6871 RNF6 Zornitza Stark Gene: rnf6 has been classified as Red List (Low Evidence).
Mendeliome v0.6871 RNF6 Zornitza Stark Classified gene: RNF6 as Red List (low evidence)
Mendeliome v0.6871 RNF6 Zornitza Stark Gene: rnf6 has been classified as Red List (Low Evidence).
Mendeliome v0.6870 MED12 Zornitza Stark Gene: med12 has been classified as Green List (High Evidence).
Mendeliome v0.6867 BMPR2 Zornitza Stark Gene: bmpr2 has been classified as Green List (High Evidence).
Mendeliome v0.6867 BMPR2 Zornitza Stark Phenotypes for gene: BMPR2 were changed from to Pulmonary venoocclusive disease 1 MIM#265450; Pulmonary hypertension, familial primary, 1, with or without HHT MIM#178600; Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated MIM#178600
Mendeliome v0.6863 BMPR2 Elena Savva reviewed gene: BMPR2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33380512; Phenotypes: Pulmonary venoocclusive disease 1 MIM#265450, Pulmonary hypertension, familial primary, 1, with or without HHT MIM#178600, Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated MIM#178600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6863 ZNF711 Zornitza Stark Gene: znf711 has been classified as Green List (High Evidence).
Mendeliome v0.6860 SLC35A2 Zornitza Stark Gene: slc35a2 has been classified as Green List (High Evidence).
Mendeliome v0.6860 SLC35A2 Zornitza Stark Phenotypes for gene: SLC35A2 were changed from to Congenital disorder of glycosylation, type IIm (MIM #300896) 30817854; Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)
Mendeliome v0.6857 SLC35A2 Zornitza Stark reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23561849, 24115232, 27743886, 25778940, 33407896; Phenotypes: Congenital disorder of glycosylation, type IIm (MIM #300896) 30817854, Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE); 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 v0.6856 MEF2A Zornitza Stark Gene: mef2a has been classified as Red List (Low Evidence).
Mendeliome v0.6855 MEF2A Zornitza Stark Classified gene: MEF2A as Red List (low evidence)
Mendeliome v0.6855 MEF2A Zornitza Stark Gene: mef2a has been classified as Red List (Low Evidence).
Mendeliome v0.6854 FN1 Zornitza Stark Gene: fn1 has been classified as Green List (High Evidence).
Mendeliome v0.6854 FN1 Zornitza Stark Phenotypes for gene: FN1 were changed from to Glomerulopathy with fibronectin deposits 2 (MIM#601894); Spondylometaphyseal dysplasia, corner fracture type (MIM#184255)
Mendeliome v0.6851 IL37 Zornitza Stark Gene: il37 has been classified as Red List (Low Evidence).
Mendeliome v0.6851 IL37 Zornitza Stark gene: IL37 was added
gene: IL37 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL37 were set to 33674380
Phenotypes for gene: IL37 were set to Infantile inflammatory bowel disease
Review for gene: IL37 was set to RED
Added comment: Single family reported with homozygous truncating variant this gene and infantile-onset of IBD, some functional data.
Sources: Literature
Mendeliome v0.6850 PEX10 Teresa Zhao reviewed gene: PEX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 30640048; Phenotypes: Peroxisome biogenesis disorder 6A (Zellweger) (MIM#614870), Peroxisome biogenesis disorder 6B (MIM#614871); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6850 FN1 Ain Roesley reviewed gene: FN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100092; Phenotypes: Glomerulopathy with fibronectin deposits 2 (MIM#601894), Spondylometaphyseal dysplasia, corner fracture type (MIM#184255); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6850 CHRDL1 Zornitza Stark Gene: chrdl1 has been classified as Green List (High Evidence).
Mendeliome v0.6847 HDL2 Bryony Thompson Str: hdl2 has been classified as Green List (High Evidence).
Mendeliome v0.6847 HDL2 Bryony Thompson Classified STR: HDL2 as Green List (high evidence)
Mendeliome v0.6847 HDL2 Bryony Thompson Str: hdl2 has been classified as Green List (High Evidence).
Mendeliome v0.6846 HDL2 Bryony Thompson STR: HDL2 was added
STR: HDL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: HDL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: HDL2 were set to 20301701
Phenotypes for STR: HDL2 were set to Huntington disease-like 2 MIM#606438
Review for STR: HDL2 was set to GREEN
STR: HDL2 was marked as clinically relevant
Added comment: NM_001271604.2:c.431CTG[X] or NM_020655.4:c.382+760CTG[X]
In an alternatively spliced exon, the repeat can be transcribed in both directions, leading to CUG (more common) or CAG (less common) repeat-containing transcripts. While a dominant RNA toxic effect may occur, the repeat expansion also reduces levels of the Junctophilin-3 protein
Normal: ≤28 repeats
Questionable significance: 29-39 repeats, mutable normal or reduced penetrance included
Full penetrance: ≥40 repeats
Sources: Expert list
Mendeliome v0.6845 JPH3 Bryony Thompson Classified gene: JPH3 as No list
Mendeliome v0.6845 JPH3 Bryony Thompson Added comment: Comment on list classification: See STRs for this panel
Mendeliome v0.6844 DM2 Bryony Thompson Str: dm2 has been classified as Green List (High Evidence).
Mendeliome v0.6844 DM2 Bryony Thompson Classified STR: DM2 as Green List (high evidence)
Mendeliome v0.6844 DM2 Bryony Thompson Str: dm2 has been classified as Green List (High Evidence).
Mendeliome v0.6843 DM2 Bryony Thompson STR: DM2 was added
STR: DM2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: DM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DM2 were set to 20301639; 29325606
Phenotypes for STR: DM2 were set to Myotonic dystrophy 2 MIM#602668
Review for STR: DM2 was set to GREEN
STR: DM2 was marked as clinically relevant
Added comment: HGVS nomenclature: NM_003418.4:c.-14-833_-14-830[X]
Toxic gain of function RNA expected mechanism of disease
Normal: ≤30 uninterrupted CCTG repeats, 11-26 CCTG repeats with any GCTC or TCTG interruptions
Unknown significance (normal vs. mutable): 27-29 CCTG repeats
Mutable normal (premutation) alleles. ~30-~54 CCTG repeats
Unknown significance (premutation vs pathogenic): ~55-74 CCTG repeats
Pathogenic: ~75-11,000 CCTG repeats
Sources: Expert list
Mendeliome v0.6842 CNBP Bryony Thompson Classified gene: CNBP as No list
Mendeliome v0.6842 CNBP Bryony Thompson Added comment: Comment on list classification: Condition is caused by a CCTG expansion in intron 1. No reported SNVs or indels reported in association with disease. Present under STRs on this panel
Mendeliome v0.6841 DM1 Bryony Thompson Str: dm1 has been classified as Green List (High Evidence).
Mendeliome v0.6841 DM1 Bryony Thompson Classified STR: DM1 as Green List (high evidence)
Mendeliome v0.6841 DM1 Bryony Thompson Str: dm1 has been classified as Green List (High Evidence).
Mendeliome v0.6840 DM1 Bryony Thompson STR: DM1 was added
STR: DM1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: DM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DM1 were set to 20301344; 29325606
Phenotypes for STR: DM1 were set to Myotonic dystrophy 1 MIM#160900
Review for STR: DM1 was set to GREEN
STR: DM1 was marked as clinically relevant
Added comment: HGVS nomenclature: NM_001081560.2:c.*224_*226CTG[X]
RNA toxic gain of function is mechanism of disease
Premutation: 35-49 repeats, no clinical signs
Mild: 50-~150 repeats, age of onset 20-70 yrs, clinical signs - cataracts, mild myotonia
Classic: ~100-~1,000 repeats, age of onset 10-30 yrs, clinical signs - weakness, myotonia, cataracts, balding, cardiac arrhythmia
Congenital: >1,000 repeats, age of onset birth-10 yrs , clinical signs - infantile hypotonia, respiratory deficits, intellectual disability, classic signs in adults
Sources: Expert list
Mendeliome v0.6839 DMPK Bryony Thompson Classified gene: DMPK as No list
Mendeliome v0.6839 DMPK Bryony Thompson Added comment: Comment on list classification: STR is the only cause of condition for this gene and is present in STRs for this panel.
Mendeliome v0.6838 SCA17 Bryony Thompson Str: sca17 has been classified as Green List (High Evidence).
Mendeliome v0.6838 SCA17 Bryony Thompson Classified STR: SCA17 as Green List (high evidence)
Mendeliome v0.6838 SCA17 Bryony Thompson Str: sca17 has been classified as Green List (High Evidence).
Mendeliome v0.6836 TBP Bryony Thompson Classified gene: TBP as No list
Mendeliome v0.6836 TBP Bryony Thompson Added comment: Comment on list classification: See STRs
Mendeliome v0.6835 SCA12 Bryony Thompson Str: sca12 has been classified as Green List (High Evidence).
Mendeliome v0.6835 SCA12 Bryony Thompson Classified STR: SCA12 as Green List (high evidence)
Mendeliome v0.6835 SCA12 Bryony Thompson Str: sca12 has been classified as Green List (High Evidence).
Mendeliome v0.6834 SCA12 Bryony Thompson STR: SCA12 was added
STR: SCA12 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA12 were set to 29325606; 20301381
Phenotypes for STR: SCA12 were set to Spinocerebellar ataxia 12 MIM#604326
Review for STR: SCA12 was set to GREEN
STR: SCA12 was marked as clinically relevant
Added comment: NM_181675.3:c.27CAG[X]
Uncertain if CAG repeat encodes polyglutamine or instead effects expression of specific splice variants of the encoded phosphatase
Normal: ≤32 repeats
Reduced penetrance: ~40-66 repeats
Full penetrance: ≥66 repeats
Sources: Expert list
Mendeliome v0.6833 PPP2R2B Bryony Thompson Classified gene: PPP2R2B as No list
Mendeliome v0.6832 SCA36 Bryony Thompson Str: sca36 has been classified as Green List (High Evidence).
Mendeliome v0.6832 SCA36 Bryony Thompson Classified STR: SCA36 as Green List (high evidence)
Mendeliome v0.6832 SCA36 Bryony Thompson Str: sca36 has been classified as Green List (High Evidence).
Mendeliome v0.6831 SCA36 Bryony Thompson STR: SCA36 was added
STR: SCA36 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA36 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA36 were set to 25101480
Phenotypes for STR: SCA36 were set to Spinocerebellar ataxia 36 MIM#614153
Review for STR: SCA36 was set to GREEN
STR: SCA36 was marked as clinically relevant
Added comment: NM_006392​.3:c.3+71GGCCTG[X]
Toxic RNA effect is suggested mechanism of disease
Normal: 3-14 repeats
Uncertain significance: 15-650 repeats
Pathogenic: ≥650 repeats
Sources: Expert list
Mendeliome v0.6830 NOP56 Bryony Thompson Classified gene: NOP56 as No list
Mendeliome v0.6830 NOP56 Bryony Thompson Added comment: Comment on list classification: A hexanucleotide (GGCCTG) repeat expansion in the first intron of the NOP56 gene is the only reported cause of disease. See STRS
Mendeliome v0.6829 SCA37 Bryony Thompson Str: sca37 has been classified as Green List (High Evidence).
Mendeliome v0.6829 SCA37 Bryony Thompson Classified STR: SCA37 as Green List (high evidence)
Mendeliome v0.6829 SCA37 Bryony Thompson Str: sca37 has been classified as Green List (High Evidence).
Mendeliome v0.6828 SCA37 Bryony Thompson STR: SCA37 was added
STR: SCA37 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA37 were set to 28686858; 31145571
Phenotypes for STR: SCA37 were set to Spinocerebellar ataxia 37 MIM#615945
Review for STR: SCA37 was set to GREEN
STR: SCA37 was marked as clinically relevant
Added comment: NC_000001.10:g.57832716_57832797ins[(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90]
Located in a 5'UTR intron, flanked by (ATTTT)n on both sides
Non-pathogenic allele: (ATTTT)7–400
Pathogenic allele: [(ATTTT)60–79(ATTTC)31–75(ATTTT)58–90]
Sources: Expert list
Mendeliome v0.6827 DAB1 Bryony Thompson Classified gene: DAB1 as No list
Mendeliome v0.6826 SCA31 Bryony Thompson Str: sca31 has been classified as Green List (High Evidence).
Mendeliome v0.6826 SCA31 Bryony Thompson Classified STR: SCA31 as Green List (high evidence)
Mendeliome v0.6826 SCA31 Bryony Thompson Str: sca31 has been classified as Green List (High Evidence).
Mendeliome v0.6825 SCA31 Bryony Thompson STR: SCA31 was added
STR: SCA31 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA31 were set to 19878914; 31755042
Phenotypes for STR: SCA31 were set to Spinocerebellar ataxia 31 MIM#117210
Review for STR: SCA31 was set to GREEN
STR: SCA31 was marked as clinically relevant
Added comment: Complex repeat insertion (TGGAA)n, (TAGAA)n, (TAAAA)n, (TAAAATAGAA)n, TGGAA is present only in affected cases. Sequencing showed that the insertion consisted of a preceding TCAC sequence, and 3 pentanucleotide repeat components (TGGAA)n, (TAGAA)n, and (TAAAA)n in all patients tested.
2.5-3.8 KB insertion is associated with disease and RNA toxicity expected to be mechanism of disease
Normal and pathogenic cut-offs are based on animal model experiments (PMID: 31755042)
Sources: Expert list
Mendeliome v0.6824 BEAN1 Bryony Thompson Classified gene: BEAN1 as No list
Mendeliome v0.6823 SCA7 Bryony Thompson Str: sca7 has been classified as Green List (High Evidence).
Mendeliome v0.6823 SCA7 Bryony Thompson Classified STR: SCA7 as Green List (high evidence)
Mendeliome v0.6823 SCA7 Bryony Thompson Str: sca7 has been classified as Green List (High Evidence).
Mendeliome v0.6821 ATXN7 Bryony Thompson Classified gene: ATXN7 as No list
Mendeliome v0.6820 SCA3 Bryony Thompson Str: sca3 has been classified as Green List (High Evidence).
Mendeliome v0.6820 SCA3 Bryony Thompson Classified STR: SCA3 as Green List (high evidence)
Mendeliome v0.6820 SCA3 Bryony Thompson Str: sca3 has been classified as Green List (High Evidence).
Mendeliome v0.6819 SCA3 Bryony Thompson STR: SCA3 was added
STR: SCA3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA3 were set to 20301375; 29325606
Phenotypes for STR: SCA3 were set to Machado-Joseph disease MIM#109150; Spinocerebellar ataxia type 3
Review for STR: SCA3 was set to GREEN
STR: SCA3 was marked as clinically relevant
Added comment: NM_004993​.5:c.886_888CAG[X]
Toxic aggregation and mislocalization in neurons is mechanism of disease
Normal: ≤44 repeats, mostly <31 repeats
Intermediate: 45-59 repeats, some intermediate alleles are not associated with classic clinical features of SCA3
Pathogenic (full penetrance): ≥60 repeats
Sources: Expert list
Mendeliome v0.6818 ATXN3 Bryony Thompson Classified gene: ATXN3 as No list
Mendeliome v0.6817 SCA2 Bryony Thompson Str: sca2 has been classified as Green List (High Evidence).
Mendeliome v0.6817 SCA2 Bryony Thompson Classified STR: SCA2 as Green List (high evidence)
Mendeliome v0.6817 SCA2 Bryony Thompson Str: sca2 has been classified as Green List (High Evidence).
Mendeliome v0.6816 SCA2 Bryony Thompson STR: SCA2 was added
STR: SCA2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA2 were set to 29325606; 20301452
Phenotypes for STR: SCA2 were set to Spinocerebellar ataxia 2 MIM#183090
Review for STR: SCA2 was set to GREEN
STR: SCA2 was marked as clinically relevant
Added comment: NM_002973​.3:c.496_498CAG[X]
Toxic protein aggregation is mechanism of disease
Benign: ≤31 repeats (homozygous 31/31 repeats reported for recessive SCA2)
Uncertain: 32 repeats
ALS risk allele: 30-32 repeats
Reduced penetrance: 33-34 repeats, may not develop symptoms or only very late in life
Full penetrance: ≥35 repeats
Interruption of a CAG expanded allele by a CAA repeat does not mitigate the pathogenicity of the repeat size, but may enhance the meiotic stability of the repeat
Sources: Expert list
Mendeliome v0.6815 ATXN2 Bryony Thompson Classified gene: ATXN2 as No list
Mendeliome v0.6814 SCA10 Bryony Thompson Str: sca10 has been classified as Green List (High Evidence).
Mendeliome v0.6814 SCA10 Bryony Thompson Classified STR: SCA10 as Green List (high evidence)
Mendeliome v0.6814 SCA10 Bryony Thompson Str: sca10 has been classified as Green List (High Evidence).
Mendeliome v0.6813 SCA10 Bryony Thompson STR: SCA10 was added
STR: SCA10 was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: SCA10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA10 were set to 20301354
Phenotypes for STR: SCA10 were set to Spinocerebellar ataxia 10 MIM#603516
Review for STR: SCA10 was set to GREEN
STR: SCA10 was marked as clinically relevant
Added comment: NM_013236​.2:c.1430+54822ATTCT[X]
Toxic RNA gain-of-function mechanism of disease
Normal alleles: 10-32 ATTCT repeats
Alleles of questionable significance: 33-280 ATTCT repeats
Reduced-penetrance alleles: 33-850 repeats
Full-penetrance alleles: 800-4,500 ATTCT repeats
Sources: Expert list
Mendeliome v0.6812 ATXN10 Bryony Thompson Classified gene: ATXN10 as No list
Mendeliome v0.6811 INPP4A Zornitza Stark Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6811 INPP4A Zornitza Stark Classified gene: INPP4A as Amber List (moderate evidence)
Mendeliome v0.6811 INPP4A Zornitza Stark Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6810 INPP4A Zornitza Stark gene: INPP4A was added
gene: INPP4A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 31978615; 31938306; 25338135; 20011524
Phenotypes for gene: INPP4A were set to Intellectual disability
Review for gene: INPP4A was set to AMBER
Added comment: Two families reported with bi-allelic variants and a neurological phenotype. Supportive mouse model and expression data.
Sources: Literature
Mendeliome v0.6808 SATB1 Zornitza Stark edited their review of gene: SATB1: Added comment: Kohlschutter-Tonz syndrome-like (KTZSL) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. This phenotype was reported in 28 patients (patients 13 to 40, PMID 33513338), including 9 patients from 3 families. Most variants were de novo, though some were inherited, suggestive of incomplete penetrance and variable expressivity.; Changed phenotypes: Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228, Kohlschutter-Tonz syndrome-like, MIM# 619229
Mendeliome v0.6808 SATB1 Zornitza Stark commented on gene: SATB1: Developmental delay with dysmorphic facies and dental anomalies (DEFDA) is characterized by generally mild global developmental delay with variably impaired intellectual development, walking by 2 to 3 years, and slow language acquisition. The severity of the disorder ranges from moderate cognitive deficits to mild learning difficulties or behavioral abnormalities. Most patients have dysmorphic facial features, often with abnormal dentition and nonspecific visual defects, such as myopia, astigmatism, and strabismus. Although rare, involvement of other systems, such as skeletal, cardiac, and gastrointestinal, may be present. 12 individuals from 11 families reported (one inherited variant, affected parent).
Mendeliome v0.6805 MKS1 Zornitza Stark Gene: mks1 has been classified as Green List (High Evidence).
Mendeliome v0.6802 FLII Zornitza Stark Gene: flii has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6802 FLII Zornitza Stark Classified gene: FLII as Amber List (moderate evidence)
Mendeliome v0.6802 FLII Zornitza Stark Gene: flii has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6800 RHBDF1 Zornitza Stark Gene: rhbdf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6800 RHBDF1 Zornitza Stark Classified gene: RHBDF1 as Amber List (moderate evidence)
Mendeliome v0.6800 RHBDF1 Zornitza Stark Gene: rhbdf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6798 MYLK3 Zornitza Stark Gene: mylk3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6798 MYLK3 Zornitza Stark Classified gene: MYLK3 as Amber List (moderate evidence)
Mendeliome v0.6798 MYLK3 Zornitza Stark Gene: mylk3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6797 MYLK3 Zornitza Stark gene: MYLK3 was added
gene: MYLK3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYLK3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709
Phenotypes for gene: MYLK3 were set to Dilated cardiomyopathy
Review for gene: MYLK3 was set to AMBER
Added comment: Two families reported with mono-allelic variants (one extension, one frameshift), and three consanguineous families reported with bi-allelic variants (two hmz frameshift, one hmz missense). Supportive mouse models.
Sources: Literature
Mendeliome v0.6796 NRAP Zornitza Stark Gene: nrap has been classified as Green List (High Evidence).
Mendeliome v0.6796 NRAP Zornitza Stark Classified gene: NRAP as Green List (high evidence)
Mendeliome v0.6796 NRAP Zornitza Stark Gene: nrap has been classified as Green List (High Evidence).
Mendeliome v0.6794 MPEG1 Zornitza Stark Gene: mpeg1 has been classified as Green List (High Evidence).
Mendeliome v0.6794 MPEG1 Zornitza Stark Classified gene: MPEG1 as Green List (high evidence)
Mendeliome v0.6794 MPEG1 Zornitza Stark Gene: mpeg1 has been classified as Green List (High Evidence).
Mendeliome v0.6793 MPEG1 Zornitza Stark gene: MPEG1 was added
gene: MPEG1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MPEG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MPEG1 were set to 33224153; 33692780; 28422754
Phenotypes for gene: MPEG1 were set to Immunodeficiency 77, MIM# 619223
Review for gene: MPEG1 was set to GREEN
Added comment: Immunodeficiency-77 (IMD77) is an immunologic disorder characterized by recurrent and persistent polymicrobial infections with multiple unusual organisms. Skin and pulmonary infections are the most common, consistent with increased susceptibility to epithelial cell infections. The age at onset is highly variable: some patients have recurrent infections from childhood, whereas others present in late adulthood. The limited number of reported patients are all female, suggesting incomplete penetrance or a possible sex-influenced trait. Patient cells, mainly macrophages, show impaired killing of intracellular bacteria and organisms, including nontubercular mycobacteria, although there is also impaired killing of other organisms, such as Pseudomonas, Candida, and Aspergillus.

Four individuals reported, functional data, including animal model.
Sources: Expert list
Mendeliome v0.6791 INPP5E Zornitza Stark Gene: inpp5e has been classified as Green List (High Evidence).
Mendeliome v0.6791 INPP5E Zornitza Stark Phenotypes for gene: INPP5E were changed from to Joubert syndrome 1, MIM# 213300; MONDO:0008944; Mental retardation, truncal obesity, retinal dystrophy, and micropenis, MIM# 610156; MONDO:0012423
Mendeliome v0.6788 INPP5E Zornitza Stark reviewed gene: INPP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: 19668216, 32139166, 29230161, 29052317, 27998989, 27401686; Phenotypes: Joubert syndrome 1, MIM# 213300, MONDO:0008944, Mental retardation, truncal obesity, retinal dystrophy, and micropenis, MIM# 610156, MONDO:0012423; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6788 CSPP1 Zornitza Stark Gene: cspp1 has been classified as Green List (High Evidence).
Mendeliome v0.6785 CSPP1 Zornitza Stark changed review comment from: More than 20 unrelated families reported.; to: More than 20 unrelated families reported. Classically associated with Joubert syndrome; however, note 4 individuals reported with features consistent with Jeune asphyxiating thoracic dystrophy, including short ribs, bell-shaped chest, and pulmonary hypoplasia.
Mendeliome v0.6785 CEP41 Zornitza Stark Gene: cep41 has been classified as Green List (High Evidence).
Mendeliome v0.6782 SCA1 Bryony Thompson Str: sca1 has been classified as Green List (High Evidence).
Mendeliome v0.6782 SCA1 Bryony Thompson Classified STR: SCA1 as Green List (high evidence)
Mendeliome v0.6782 SCA1 Bryony Thompson Str: sca1 has been classified as Green List (High Evidence).
Mendeliome v0.6780 ATXN1 Bryony Thompson Classified gene: ATXN1 as No list
Mendeliome v0.6779 RANBP2 Bryony Thompson Gene: ranbp2 has been classified as Green List (High Evidence).
Mendeliome v0.6779 NCSTN Bryony Thompson Gene: ncstn has been classified as Green List (High Evidence).
Mendeliome v0.6779 PSENEN Bryony Thompson Gene: psenen has been classified as Green List (High Evidence).
Mendeliome v0.6776 ALDH1L2 Zornitza Stark Gene: aldh1l2 has been classified as Red List (Low Evidence).
Mendeliome v0.6776 ALDH1L2 Zornitza Stark Classified gene: ALDH1L2 as Red List (low evidence)
Mendeliome v0.6776 ALDH1L2 Zornitza Stark Gene: aldh1l2 has been classified as Red List (Low Evidence).
Mendeliome v0.6775 ESCO2 Zornitza Stark Gene: esco2 has been classified as Green List (High Evidence).
Mendeliome v0.6771 RNF113A Bryony Thompson Classified gene: RNF113A as Green List (high evidence)
Mendeliome v0.6771 RNF113A Bryony Thompson Added comment: Comment on list classification: Additional cases published
Mendeliome v0.6771 RNF113A Bryony Thompson Gene: rnf113a has been classified as Green List (High Evidence).
Mendeliome v0.6769 ALDH1L2 Naomi Baker gene: ALDH1L2 was added
gene: ALDH1L2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALDH1L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH1L2 were set to PMID: 31341639; 33168096
Phenotypes for gene: ALDH1L2 were set to pruritic ichthyosis, severe diffuse hypomyelination seen on MRI, and abnormal lipid peaks
Review for gene: ALDH1L2 was set to RED
Added comment: Individual reported with bialleleic ALDH1L2 variants (non-canonical splice and a frameshift mutation), who also has a de novo hemizygous RPS6KA3 frameshift mutation. Authors state that not all features of the individual could be explained by the RPS6KA3 variant, and that consideration of Coffin-Lowry sysndrome was only made after identification of the RPS6KA3 variant. Therefore individual has there is a blended phenotype of Coffin–Lowry syndrome and Sjögren–Larsson syndrome. From functional studies authors propose that the ALDH1L2 loss induces mitochondrial dysfunction due to reduced NADPH and increased oxidative stress (PMID: 31341639). Knockout mouse model was viable and did not show an apparent phenotype, however metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Authors therefore postulate that the role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous disease.
Sources: Literature
Mendeliome v0.6769 FAM57B Zornitza Stark Gene: fam57b has been classified as Green List (High Evidence).
Mendeliome v0.6769 FAM57B Zornitza Stark Classified gene: FAM57B as Green List (high evidence)
Mendeliome v0.6769 FAM57B Zornitza Stark Gene: fam57b has been classified as Green List (High Evidence).
Mendeliome v0.6768 FAM57B Zornitza Stark gene: FAM57B was added
gene: FAM57B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM57B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM57B were set to 33077892
Phenotypes for gene: FAM57B were set to Cone–rod dystrophy; Maculopathy
Review for gene: FAM57B was set to GREEN
Added comment: 4 patients with cone-rod dystrophy or maculopathy from 3 families, with LOF pathogenic variants in TLCD3B (ceramide synthase gene). Ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. Variants segregated with disease. TLCD3B showed high expression in the adult retina with higher expression in the macular than in the peripheral region. Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina.
Sources: Literature
Mendeliome v0.6767 LRRC8A Bryony Thompson Gene: lrrc8a has been classified as Red List (Low Evidence).
Mendeliome v0.6767 LRRC8A Bryony Thompson Classified gene: LRRC8A as Red List (low evidence)
Mendeliome v0.6767 LRRC8A Bryony Thompson Gene: lrrc8a has been classified as Red List (Low Evidence).
Mendeliome v0.6766 LRRC8A Bryony Thompson changed review comment from: A single case reported with a reciprocal translocation, t(9;20)(q33.2;q12), and demonstrated truncation of the LRRC8A gene. No other supporting evidence; to: A single case reported with a reciprocal translocation, t(9;20)(q33.2;q12), and demonstrated truncation of the LRRC8A gene. No other supporting evidence could be identified.
Mendeliome v0.6766 SIAE Bryony Thompson Marked gene: SIAE as ready
Mendeliome v0.6766 SIAE Bryony Thompson Gene: siae has been classified as Red List (Low Evidence).
Mendeliome v0.6766 SIAE Bryony Thompson Classified gene: SIAE as Red List (low evidence)
Mendeliome v0.6766 SIAE Bryony Thompson Gene: siae has been classified as Red List (Low Evidence).
Mendeliome v0.6765 SIAE Bryony Thompson reviewed gene: SIAE: Rating: RED; Mode of pathogenicity: None; Publications: 20555325, 28900629, 22200769; Phenotypes: {Autoimmune disease, susceptibility to, 6} MIM#613551; Mode of inheritance: Unknown
Mendeliome v0.6765 TAOK2 Bryony Thompson Gene: taok2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6765 TAOK2 Bryony Thompson edited their review of gene: TAOK2: Changed phenotypes: Generalized verrucosis, abnormal T cell activation, autism
Mendeliome v0.6765 TAOK2 Bryony Thompson Phenotypes for gene: TAOK2 were changed from Generalized verrucosis; abnormal T cell activation to Generalized verrucosis; abnormal T cell activation; autism
Mendeliome v0.6764 TAOK2 Bryony Thompson Classified gene: TAOK2 as Amber List (moderate evidence)
Mendeliome v0.6764 TAOK2 Bryony Thompson Gene: taok2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6763 TAOK2 Bryony Thompson gene: TAOK2 was added
gene: TAOK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TAOK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TAOK2 were set to 28385331; 29467497
Phenotypes for gene: TAOK2 were set to Generalized verrucosis; abnormal T cell activation
Review for gene: TAOK2 was set to AMBER
Added comment: PMID: 28385331 - A single consanguineous family with generalized verrucosis and abnormal T cell activation, and a homozygous missense (p.R700C), with some assays on patient fibroblasts.
PMID: 29467497 - One of the several genes in the 16p11.2 microdeletion region associated with autism. Taok2 heterozygous and knockout mice had gene dosage-dependent impairments in cognition, anxiety, social interaction, brain size, and neural connectivity. 3 de novo variants and 3 predicted loss of function variants identified in 6 unrelated autism cases. 2 of the de novo variants have supporting functional assays, but 1 of them co-occurs in an individual with a CHD8 frameshift. 1 of the predicted loss of function variants was also identified in the unaffected father and sibling.
Sources: Literature
Mendeliome v0.6762 CC2D2A Zornitza Stark Gene: cc2d2a has been classified as Green List (High Evidence).
Mendeliome v0.6759 POLR3GL Zornitza Stark Phenotypes for gene: POLR3GL were changed from endosteal hyperostosis; oligodontia; growth retardation; facial dysmorphisms; lipodystrophy to Short stature, oligodontia, dysmorphic facies, and motor delay (SOFM), MIM#619234; endosteal hyperostosis; oligodontia; growth retardation; facial dysmorphisms; lipodystrophy
Mendeliome v0.6758 INVS Zornitza Stark Gene: invs has been classified as Green List (High Evidence).
Mendeliome v0.6758 INVS Zornitza Stark Phenotypes for gene: INVS were changed from to Nephronophthisis 2, infantile, (MIM#602088)
Mendeliome v0.6755 INVS Paul De Fazio reviewed gene: INVS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872123, 19177160; Phenotypes: Nephronophthisis 2, infantile, (MIM#602088); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.6755 ZCCHC8 Bryony Thompson Gene: zcchc8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6755 ZCCHC8 Bryony Thompson Classified gene: ZCCHC8 as Amber List (moderate evidence)
Mendeliome v0.6755 ZCCHC8 Bryony Thompson Gene: zcchc8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6754 ZCCHC8 Bryony Thompson gene: ZCCHC8 was added
gene: ZCCHC8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZCCHC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZCCHC8 were set to 31488579
Phenotypes for gene: ZCCHC8 were set to Pulmonary fibrosis
Review for gene: ZCCHC8 was set to AMBER
Added comment: A missense variant (P186L) segregates over 3 generations in a single family, and supporting in vitro assays and mouse model.
Sources: Literature
Mendeliome v0.6753 KDM5B Zornitza Stark reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal recessive 65 MIM#618109, Intellectual disability and/or autism, autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6753 KDM5B Zornitza Stark Gene: kdm5b has been classified as Green List (High Evidence).
Mendeliome v0.6753 KDM5B Zornitza Stark Phenotypes for gene: KDM5B were changed from to Mental retardation, autosomal recessive 65 MIM#618109; Intellectual disability and/or autism, autosomal dominant
Mendeliome v0.6750 TPP2 Zornitza Stark Gene: tpp2 has been classified as Green List (High Evidence).
Mendeliome v0.6747 DOCK7 Zornitza Stark Gene: dock7 has been classified as Green List (High Evidence).
Mendeliome v0.6742 UBAP1 Zornitza Stark changed review comment from: PMID 31696996: Five unrelated families reported with childhood-onset HSP. A recurrent two‐base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense‐mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant‐negative effect on the normal function of the endosome‐specific endosomal sorting complexes required for the transport‐I complex.; to: PMID 31696996: Five unrelated families reported with childhood-onset HSP. A recurrent two‐base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense‐mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant‐negative effect on the normal function of the endosome‐specific endosomal sorting complexes required for the transport‐I complex.

PMID 32934340: additional 7 families. Median age of onset 10yrs.
Mendeliome v0.6742 RTN2 Zornitza Stark Gene: rtn2 has been classified as Green List (High Evidence).
Mendeliome v0.6739 KDM5B Elena Savva reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29276005, 30217758, 30409806; Phenotypes: Mental retardation, autosomal recessive 65 MIM#618109, autosomal dominant autism spectrum disorder or intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6739 NIPA1 Zornitza Stark Gene: nipa1 has been classified as Green List (High Evidence).
Mendeliome v0.6736 DDHD1 Zornitza Stark Gene: ddhd1 has been classified as Green List (High Evidence).
Mendeliome v0.6736 DDHD1 Zornitza Stark Phenotypes for gene: DDHD1 were changed from to Spastic paraplegia 28, autosomal recessive, 609340; MONDO:0012256
Mendeliome v0.6733 DDHD1 Zornitza Stark reviewed gene: DDHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176821; Phenotypes: Spastic paraplegia 28, autosomal recessive, 609340, MONDO:0012256; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6730 CAPN1 Zornitza Stark Phenotypes for gene: CAPN1 were changed from Spastic paraplegia 76, autosomal recessive, MIM#616907 to Spastic paraplegia 76, autosomal recessive, MIM#616907; MONDO:0014827
Mendeliome v0.6729 AP5Z1 Zornitza Stark Gene: ap5z1 has been classified as Green List (High Evidence).
Mendeliome v0.6729 AP5Z1 Zornitza Stark Phenotypes for gene: AP5Z1 were changed from to Spastic paraplegia 48, autosomal recessive, MIM# 613647; MONDO:0013342
Mendeliome v0.6726 AP5Z1 Zornitza Stark reviewed gene: AP5Z1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26085577, 33543803, 27606357; Phenotypes: Spastic paraplegia 48, autosomal recessive, MIM# 613647, MONDO:0013342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6726 COPB1 Zornitza Stark Gene: copb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6726 COPB1 Zornitza Stark Classified gene: COPB1 as Amber List (moderate evidence)
Mendeliome v0.6726 COPB1 Zornitza Stark Gene: copb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6724 SLC1A4 Zornitza Stark Phenotypes for gene: SLC1A4 were changed from Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657 to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657; MONDO:0014725
Mendeliome v0.6723 SLC1A4 Zornitza Stark Gene: slc1a4 has been classified as Green List (High Evidence).
Mendeliome v0.6723 SLC1A4 Zornitza Stark Phenotypes for gene: SLC1A4 were changed from to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657
Mendeliome v0.6720 TFG Zornitza Stark Gene: tfg has been classified as Green List (High Evidence).
Mendeliome v0.6720 TFG Zornitza Stark Phenotypes for gene: TFG were changed from to Hereditary motor and sensory neuropathy, Okinawa type, MIM# 604484; Spastic paraplegia 57, autosomal recessive, MIM# 615658
Mendeliome v0.6718 TFG Zornitza Stark reviewed gene: TFG: Rating: GREEN; Mode of pathogenicity: None; Publications: 30467354, 30157421, 28124177, 27601211, 27492651, 23479643, 25098539, 23553329, 22883144, 31449671, 31111683; Phenotypes: Hereditary motor and sensory neuropathy, Okinawa type, MIM# 604484, Spastic paraplegia 57, autosomal recessive, MIM# 615658; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6718 WDR45B Zornitza Stark Gene: wdr45b has been classified as Green List (High Evidence).
Mendeliome v0.6715 REEP2 Zornitza Stark Gene: reep2 has been classified as Green List (High Evidence).
Mendeliome v0.6715 REEP2 Zornitza Stark Phenotypes for gene: REEP2 were changed from to Spastic paraplegia 72, dominant and recessive, MIM# 615625; MONDO:0014282
Mendeliome v0.6712 REEP2 Zornitza Stark reviewed gene: REEP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33526816, 28491902, 24388663; Phenotypes: Spastic paraplegia 72, dominant and recessive, MIM# 615625, MONDO:0014282; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6712 NT5C2 Zornitza Stark Gene: nt5c2 has been classified as Green List (High Evidence).
Mendeliome v0.6712 NT5C2 Zornitza Stark Phenotypes for gene: NT5C2 were changed from to Spastic paraplegia 45, autosomal recessive, MIM# 613162; MONDO:0013165
Mendeliome v0.6709 NT5C2 Zornitza Stark reviewed gene: NT5C2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 32153630, 29123918, 28884889, 28327087; Phenotypes: Spastic paraplegia 45, autosomal recessive, MIM# 613162, MONDO:0013165; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6709 HACE1 Zornitza Stark Gene: hace1 has been classified as Green List (High Evidence).
Mendeliome v0.6706 NKX6-2 Zornitza Stark Gene: nkx6-2 has been classified as Green List (High Evidence).
Mendeliome v0.6706 NKX6-2 Zornitza Stark Phenotypes for gene: NKX6-2 were changed from to Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, MIM# 617560; MONDO:0033043
Mendeliome v0.6703 NKX6-2 Zornitza Stark reviewed gene: NKX6-2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28575651, 15601927, 32246862, 32004679; Phenotypes: Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, MIM# 617560, MONDO:0033043; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6703 ARPC1B Zornitza Stark Gene: arpc1b has been classified as Green List (High Evidence).
Mendeliome v0.6703 ARPC1B Zornitza Stark Phenotypes for gene: ARPC1B were changed from to Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease 617718
Mendeliome v0.6700 ARPC1B Zornitza Stark reviewed gene: ARPC1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28368018, 33679784; Phenotypes: Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease 617718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6699 KDM5C Zornitza Stark changed review comment from: Progressive lower limb spasticity is a feature of this ID syndrome. More than 5 unrelated families reported.; to: Intellectual disability, progressive lower limb spasticity, epilepsy and a number of other more variable features. Affected females reported PMID 32279304.
Mendeliome v0.6699 KDM5C Zornitza Stark Gene: kdm5c has been classified as Green List (High Evidence).
Mendeliome v0.6696 ENTPD1 Zornitza Stark Gene: entpd1 has been classified as Green List (High Evidence).
Mendeliome v0.6696 ENTPD1 Zornitza Stark Phenotypes for gene: ENTPD1 were changed from to Spastic paraplegia 64, autosomal recessive MIM#615683
Mendeliome v0.6693 ENTPD1 Zornitza Stark reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 30652007; Phenotypes: Spastic paraplegia 64, autosomal recessive MIM#615683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6693 C12orf65 Zornitza Stark Gene: c12orf65 has been classified as Green List (High Evidence).
Mendeliome v0.6693 C12orf65 Zornitza Stark Phenotypes for gene: C12orf65 were changed from to Spastic paraplegia 55, autosomal recessive, MIM#615035; Combined oxidative phosphorylation deficiency 7, MIM# 613559
Mendeliome v0.6690 C12orf65 Zornitza Stark reviewed gene: C12orf65: Rating: GREEN; Mode of pathogenicity: None; Publications: 23188110, 24080142, 24198383, 20598281, 32808965, 32478789, 28804760; Phenotypes: Spastic paraplegia 55, autosomal recessive, MIM#615035, Combined oxidative phosphorylation deficiency 7, MIM# 613559; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6690 C19orf12 Zornitza Stark Gene: c19orf12 has been classified as Green List (High Evidence).
Mendeliome v0.6690 C19orf12 Zornitza Stark Phenotypes for gene: C19orf12 were changed from to Neurodegeneration with brain iron accumulation 4, MIM# 614298; Spastic paraplegia 43, autosomal recessive, MIM# 615043
Mendeliome v0.6687 C19orf12 Zornitza Stark reviewed gene: C19orf12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33688131, 21981780, 22508347, 23269600, 31804703, 30088953, 20039086; Phenotypes: Neurodegeneration with brain iron accumulation 4, MIM# 614298, Spastic paraplegia 43, autosomal recessive, MIM# 615043; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6687 CYP2U1 Zornitza Stark Gene: cyp2u1 has been classified as Green List (High Evidence).
Mendeliome v0.6687 CYP2U1 Zornitza Stark Phenotypes for gene: CYP2U1 were changed from to Spastic paraplegia 56, autosomal recessive, MIM#615030
Mendeliome v0.6684 CYP2U1 Zornitza Stark edited their review of gene: CYP2U1: Added comment: SPG56 is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive lower-limb spasticity resulting in walking difficulties. Upper limbs are often also affected, and some patients may have a subclinical axonal neuropathy. Onset is typically in the first decade. More than 5 unrelated families reported.; Changed rating: GREEN; Changed publications: 23176821, 32006740, 29034544
Mendeliome v0.6684 IFRD1 Zornitza Stark Gene: ifrd1 has been classified as Red List (Low Evidence).
Mendeliome v0.6684 IFRD1 Zornitza Stark gene: IFRD1 was added
gene: IFRD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IFRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFRD1 were set to 29362493
Phenotypes for gene: IFRD1 were set to Hereditary spastic paraplegia; peripheral neuropathy; ataxia
Review for gene: IFRD1 was set to RED
Added comment: A variant segregated with slowly progressing gait ataxia, pyramidal tract signs and peripheral neuropathy in three siblings from a single Chinese family. No functional analyses of the variant has been conducted. The variant (c.514 A>G, p.I172V) is too common (0.3%) for a dominant condition in the African population in gnomAD.
Sources: Expert Review
Mendeliome v0.6684 IFRD1 Zornitza Stark gene: IFRD1 was added
gene: IFRD1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IFRD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFRD1 were set to 29362493
Phenotypes for gene: IFRD1 were set to Hereditary spastic paraplegia; peripheral neuropathy; ataxia
Review for gene: IFRD1 was set to RED
Added comment: A variant segregated with slowly progressing gait ataxia, pyramidal tract signs and peripheral neuropathy in three siblings from a single Chinese family. No functional analyses of the variant has been conducted. The variant (c.514 A>G, p.I172V) is too common (0.3%) for a dominant condition in the African population in gnomAD.
Sources: Expert Review
Mendeliome v0.6683 KLC4 Zornitza Stark Gene: klc4 has been classified as Red List (Low Evidence).
Mendeliome v0.6683 KLC4 Zornitza Stark gene: KLC4 was added
gene: KLC4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KLC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KLC4 were set to 26423925
Phenotypes for gene: KLC4 were set to Complicated hereditary spastic paraplegia
Review for gene: KLC4 was set to RED
Added comment: Single family reported.
Sources: Expert Review
Mendeliome v0.6682 AP4M1 Zornitza Stark Gene: ap4m1 has been classified as Green List (High Evidence).
Mendeliome v0.6682 AP4M1 Zornitza Stark Phenotypes for gene: AP4M1 were changed from to Spastic paraplegia 50, autosomal recessive, MIM# 612936
Mendeliome v0.6679 AP4M1 Zornitza Stark reviewed gene: AP4M1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19559397, 21937992, 21937992, 32979048, 31915823, 29096665, 28464862, 25496299; Phenotypes: Spastic paraplegia 50, autosomal recessive, MIM# 612936; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6679 ADAMTS13 Zornitza Stark Gene: adamts13 has been classified as Green List (High Evidence).
Mendeliome v0.6676 AP4S1 Zornitza Stark Gene: ap4s1 has been classified as Green List (High Evidence).
Mendeliome v0.6676 AP4S1 Zornitza Stark Phenotypes for gene: AP4S1 were changed from to Spastic paraplegia 52, autosomal recessive, MIM# 614067
Mendeliome v0.6673 AP4S1 Zornitza Stark reviewed gene: AP4S1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21620353, 25552650, 32979048, 32216065, 31915823, 30283821, 27444738; Phenotypes: Spastic paraplegia 52, autosomal recessive, MIM# 614067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6673 AIMP1 Zornitza Stark Gene: aimp1 has been classified as Green List (High Evidence).
Mendeliome v0.6667 CC2D1A Zornitza Stark Gene: cc2d1a has been classified as Green List (High Evidence).
Mendeliome v0.6667 CC2D1A Zornitza Stark Phenotypes for gene: CC2D1A were changed from to Autosomal recessive mental retardation, (MIM#608443)
Mendeliome v0.6664 CC2D1A Zornitza Stark reviewed gene: CC2D1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25066123; Phenotypes: Autosomal recessive mental retardation, (MIM#608443); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6664 ZAP70 Zornitza Stark Gene: zap70 has been classified as Green List (High Evidence).
Mendeliome v0.6660 GDF5 Michelle Torres reviewed gene: GDF5: Rating: RED; Mode of pathogenicity: None; Publications: 8589725, 33333243; Phenotypes: ? Hunter-Thompson type acromesomelic dysplasia (MIM#201250) AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6660 CST3 Zornitza Stark Gene: cst3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6657 CST3 Zornitza Stark Classified gene: CST3 as Amber List (moderate evidence)
Mendeliome v0.6657 CST3 Zornitza Stark Gene: cst3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6656 NR3C1 Zornitza Stark Gene: nr3c1 has been classified as Green List (High Evidence).
Mendeliome v0.6656 NR3C1 Zornitza Stark Phenotypes for gene: NR3C1 were changed from to Glucocorticoid resistance, OMIM # 615962
Mendeliome v0.6653 NR3C1 Zornitza Stark reviewed gene: NR3C1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12754700, 1704018, 8445027, 31995340, 30158362; Phenotypes: Glucocorticoid resistance, OMIM # 615962; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6652 YY1AP1 Zornitza Stark commented on gene: YY1AP1: Grange syndrome: multiple arterial stenoses, severe early onset hypertension, fibromuscular dysplasia, variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Missense variant reported PMID: 31633303 with moyamoya like phenotype in adult case; fibroblasts suggest that the p.Pro360Leu variant decreases the stability of the YY1AP1 protein but most LOF. PMID: 30556293 non coding variants reported (intronic variants leading to aberrant splicing)
Mendeliome v0.6652 NOS3 Zornitza Stark Gene: nos3 has been classified as Red List (Low Evidence).
Mendeliome v0.6652 NOS3 Zornitza Stark Phenotypes for gene: NOS3 were changed from to {Hypertension, susceptibility to}, MIM#145500; {Ischemic stroke, susceptibility to}, MIM# 601367; {Hypertension, pregnancy-induced}, MIM# 189800
Mendeliome v0.6650 NOS3 Zornitza Stark Classified gene: NOS3 as Red List (low evidence)
Mendeliome v0.6650 NOS3 Zornitza Stark Gene: nos3 has been classified as Red List (Low Evidence).
Mendeliome v0.6649 NOS3 Zornitza Stark reviewed gene: NOS3: Rating: RED; Mode of pathogenicity: None; Publications: 24986538, 28084234, 33652340; Phenotypes: {Hypertension, susceptibility to}, MIM#145500, {Ischemic stroke, susceptibility to}, MIM# 601367, {Hypertension, pregnancy-induced}, MIM# 189800; Mode of inheritance: Unknown
Mendeliome v0.6649 CDT1 Zornitza Stark Gene: cdt1 has been classified as Green List (High Evidence).
Mendeliome v0.6646 CDK5RAP2 Zornitza Stark Gene: cdk5rap2 has been classified as Green List (High Evidence).
Mendeliome v0.6646 CDK5RAP2 Zornitza Stark Phenotypes for gene: CDK5RAP2 were changed from to Microcephaly 3, primary, autosomal recessive, MIM# 604804; MONDO:0011488
Mendeliome v0.6643 CDK5RAP2 Zornitza Stark reviewed gene: CDK5RAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15793586, 22887808, 23995685, 23726037, 27761245, 20460369, 32677750, 32015000; Phenotypes: Microcephaly 3, primary, autosomal recessive, MIM# 604804, MONDO:0011488; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6643 UGT2B17 Zornitza Stark Gene: ugt2b17 has been classified as Red List (Low Evidence).
Mendeliome v0.6643 UGT2B17 Zornitza Stark Classified gene: UGT2B17 as Red List (low evidence)
Mendeliome v0.6643 UGT2B17 Zornitza Stark Gene: ugt2b17 has been classified as Red List (Low Evidence).
Mendeliome v0.6640 PLD1 Zornitza Stark Classified gene: PLD1 as Green List (high evidence)
Mendeliome v0.6640 PLD1 Zornitza Stark Gene: pld1 has been classified as Green List (High Evidence).
Mendeliome v0.6639 DONSON Zornitza Stark Gene: donson has been classified as Green List (High Evidence).
Mendeliome v0.6636 SQOR Zornitza Stark Gene: sqor has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6635 SQOR Zornitza Stark Classified gene: SQOR as Amber List (moderate evidence)
Mendeliome v0.6635 SQOR Zornitza Stark Gene: sqor has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6633 PGK1 Zornitza Stark Gene: pgk1 has been classified as Green List (High Evidence).
Mendeliome v0.6630 PGM1 Zornitza Stark Gene: pgm1 has been classified as Green List (High Evidence).
Mendeliome v0.6626 PHKA1 Zornitza Stark Gene: phka1 has been classified as Green List (High Evidence).
Mendeliome v0.6626 PHKA1 Zornitza Stark Phenotypes for gene: PHKA1 were changed from to Muscle glycogenosis, MIM# 300559
Mendeliome v0.6623 PHKA1 Zornitza Stark reviewed gene: PHKA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 7874115, 12825073, 9731190; Phenotypes: Muscle glycogenosis, MIM# 300559; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6623 PHKB Zornitza Stark Gene: phkb has been classified as Green List (High Evidence).
Mendeliome v0.6623 PHKB Zornitza Stark Phenotypes for gene: PHKB were changed from to Phosphorylase kinase deficiency of liver and muscle, autosomal recessive 261750; Glycogen storage disease IXb, MONDO:0009868
Mendeliome v0.6620 PHKB Zornitza Stark reviewed gene: PHKB: Rating: GREEN; Mode of pathogenicity: None; Publications: 9215682, 25266922, 30659246; Phenotypes: Phosphorylase kinase deficiency of liver and muscle, autosomal recessive 261750, Glycogen storage disease IXb, MONDO:0009868; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6620 PHKG2 Zornitza Stark Gene: phkg2 has been classified as Green List (High Evidence).
Mendeliome v0.6617 PYGL Zornitza Stark Gene: pygl has been classified as Green List (High Evidence).
Mendeliome v0.6614 NHLRC1 Zornitza Stark Gene: nhlrc1 has been classified as Green List (High Evidence).
Mendeliome v0.6614 NHLRC1 Zornitza Stark Phenotypes for gene: NHLRC1 were changed from to Epilepsy, progressive myoclonic 2B (Lafora) 254780
Mendeliome v0.6611 NHLRC1 Zornitza Stark reviewed gene: NHLRC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21505799, 12958597; Phenotypes: Epilepsy, progressive myoclonic 2B (Lafora) 254780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6611 LDHA Zornitza Stark Gene: ldha has been classified as Green List (High Evidence).
Mendeliome v0.6608 SIAH1 Zornitza Stark Marked gene: SIAH1 as ready
Mendeliome v0.6608 SIAH1 Zornitza Stark Gene: siah1 has been classified as Green List (High Evidence).
Mendeliome v0.6608 SIAH1 Zornitza Stark Classified gene: SIAH1 as Green List (high evidence)
Mendeliome v0.6608 SIAH1 Zornitza Stark Gene: siah1 has been classified as Green List (High Evidence).
Mendeliome v0.6607 RPL18 Zornitza Stark Gene: rpl18 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6607 RPL18 Zornitza Stark Classified gene: RPL18 as Amber List (moderate evidence)
Mendeliome v0.6607 RPL18 Zornitza Stark Gene: rpl18 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6605 RPS15A Zornitza Stark Gene: rps15a has been classified as Red List (Low Evidence).
Mendeliome v0.6605 RPS15A Zornitza Stark gene: RPS15A was added
gene: RPS15A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RPS15A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS15A were set to 27909223
Phenotypes for gene: RPS15A were set to Diamond-Blackfan anemia 20, MIM# 618313
Review for gene: RPS15A was set to RED
Added comment: Single family reported.
Sources: Expert list
Mendeliome v0.6604 RPL35 Zornitza Stark Gene: rpl35 has been classified as Red List (Low Evidence).
Mendeliome v0.6604 RPL35 Zornitza Stark gene: RPL35 was added
gene: RPL35 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RPL35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL35 were set to 28280134
Phenotypes for gene: RPL35 were set to Diamond-Blackfan anemia 19, MIM# 618312
Review for gene: RPL35 was set to RED
Added comment: Single family reported.
Sources: Expert list
Mendeliome v0.6603 RPS7 Zornitza Stark Gene: rps7 has been classified as Green List (High Evidence).
Mendeliome v0.6600 RPS26 Zornitza Stark Gene: rps26 has been classified as Green List (High Evidence).
Mendeliome v0.6597 RPS24 Zornitza Stark Gene: rps24 has been classified as Green List (High Evidence).
Mendeliome v0.6593 RPS19 Zornitza Stark Gene: rps19 has been classified as Green List (High Evidence).
Mendeliome v0.6590 ACKR3 Zornitza Stark Phenotypes for gene: ACKR3 were changed from Oculomotor synkinesis; Ptosis to Oculomotor-abducens synkinesis, MIM# 619215
Mendeliome v0.6589 ACKR3 Zornitza Stark reviewed gene: ACKR3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Oculomotor-abducens synkinesis, MIM# 619215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6589 SIAH1 Arina Puzriakova gene: SIAH1 was added
gene: SIAH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIAH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SIAH1 were set to 32430360
Phenotypes for gene: SIAH1 were set to Developmental delay; Infantile hypotonia; Dysmorphic features; Laryngomalacia
Review for gene: SIAH1 was set to GREEN
Added comment: - PMID: 32430360 (2021) - Five unrelated individuals with shared features of developmental delay, infantile hypotonia, dysmorphic features and laryngomalacia. All had speech delay and where cognitive assessment was age appropriate individuals exhibited learning difficulties. Trio WES revealed distinct de novo variants in SIAH1. In vitro assays demonstrated that SIAH1 mutants induce loss of Wnt stimulatory activity.
Sources: Literature
Mendeliome v0.6589 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6589 SYCP2L Zornitza Stark Classified gene: SYCP2L as Amber List (moderate evidence)
Mendeliome v0.6589 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6588 RPL5 Zornitza Stark Gene: rpl5 has been classified as Green List (High Evidence).
Mendeliome v0.6585 RPL35A Zornitza Stark Gene: rpl35a has been classified as Green List (High Evidence).
Mendeliome v0.6582 SYCP2L Arina Puzriakova gene: SYCP2L was added
gene: SYCP2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SYCP2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCP2L were set to 32303603
Phenotypes for gene: SYCP2L were set to Premature ovarian insufficiency
Review for gene: SYCP2L was set to AMBER
Added comment: - PMID: 32303603 (2021) - Two unrelated individuals with premature ovarian insufficiency and homozygous variants (c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in SYCP2L.
In vitro assays revealed that mutant SYCP2L proteins induced mislocalisation and reduced expression. Sycp2l knockout mice exhibit accelerated reproductive ageing.
Sources: Literature
Mendeliome v0.6582 RPL27 Zornitza Stark Gene: rpl27 has been classified as Red List (Low Evidence).
Mendeliome v0.6579 RPL27 Zornitza Stark Classified gene: RPL27 as Red List (low evidence)
Mendeliome v0.6579 RPL27 Zornitza Stark Gene: rpl27 has been classified as Red List (Low Evidence).
Mendeliome v0.6578 RPL11 Zornitza Stark Gene: rpl11 has been classified as Green List (High Evidence).
Mendeliome v0.6572 CLCN4 Zornitza Stark Gene: clcn4 has been classified as Green List (High Evidence).
Mendeliome v0.6572 CLCN4 Zornitza Stark Phenotypes for gene: CLCN4 were changed from to Raynaud-Claes syndrome, MIM#300114; intellectual disability; epilepsy; autistic features; mood disorders; cerebral white matter changes; progressive appendicular spasticity
Mendeliome v0.6569 CLCN4 Zornitza Stark reviewed gene: CLCN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27550844; Phenotypes: Raynaud-Claes syndrome, MIM#300114, intellectual disability, epilepsy, autistic features, mood disorders, cerebral white matter changes, progressive appendicular spasticity; 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 v0.6569 KIRREL1 Zornitza Stark Phenotypes for gene: KIRREL1 were changed from Steroid-resistant nephrotic syndrome to Nephrotic syndrome, type 23, MIM# 619201
Mendeliome v0.6567 EN1 Zornitza Stark changed review comment from: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.
Sources: Literature; to: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.

An additional fourth individual had cerebellar hypoplasia in addition to the skeletal phenotype, and a bi-allelic LoF variant.
Sources: Literature
Mendeliome v0.6567 EN1 Zornitza Stark Gene: en1 has been classified as Green List (High Evidence).
Mendeliome v0.6567 EN1 Zornitza Stark Classified gene: EN1 as Green List (high evidence)
Mendeliome v0.6567 EN1 Zornitza Stark Gene: en1 has been classified as Green List (High Evidence).
Mendeliome v0.6566 EN1 Zornitza Stark gene: EN1 was added
gene: EN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EN1 were set to 33568816
Phenotypes for gene: EN1 were set to ENDOVE syndrome, limb-only type, MIM# 619217
Review for gene: EN1 was set to GREEN
Added comment: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype.
Sources: Literature
Mendeliome v0.6560 EEF2 Zornitza Stark Classified gene: EEF2 as Green List (high evidence)
Mendeliome v0.6560 EEF2 Zornitza Stark Gene: eef2 has been classified as Green List (High Evidence).
Mendeliome v0.6559 MKRN3 Zornitza Stark Gene: mkrn3 has been classified as Green List (High Evidence).
Mendeliome v0.6556 ACSL5 Zornitza Stark Gene: acsl5 has been classified as Red List (Low Evidence).
Mendeliome v0.6556 ACSL5 Zornitza Stark gene: ACSL5 was added
gene: ACSL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACSL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACSL5 were set to 33191500
Phenotypes for gene: ACSL5 were set to severe FTT (no OMIM #)
Review for gene: ACSL5 was set to RED
Added comment: 6 individuals of a large consanguineous family presented in the neonatal period with recurrent vomiting and diarrhea, leading to severe FTT. Autozygosity mapping and WES identified homozygous variant (c.1358C>A:p.(Thr453Lys) in ACSL5. Segregated with affected individuals. Functional in vitro analysis of the ACSL5 variant by immunofluorescence, western blotting and enzyme assay suggested that Thr453Lys is a loss‐of‐function mutation without any remaining activity. Affected individuals were treated with total parenteral nutrition or medium‐chain triglyceride‐based formula restricted in long‐chain triglycerides. They responded well and follow up suggests that treatment is only required during early life.
Sources: Literature
Mendeliome v0.6555 GDF5 Zornitza Stark Gene: gdf5 has been classified as Green List (High Evidence).
Mendeliome v0.6555 GDF5 Zornitza Stark Phenotypes for gene: GDF5 were changed from to Type A1C brachydactyly (MIM#615072); Type A2 brachydactyly, (MIM#112600); Type C brachydactyly (MIM#113100); Grebe type chondrodysplasia (MIM#200700); Du Pan syndrome (MIM#228900); Multiple synostoses syndrome 2 (MIM#610017); Proximal Symphalangism 1B (MIM#615298)
Mendeliome v0.6554 GDF5 Zornitza Stark reviewed gene: GDF5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Type A1C brachydactyly (MIM#615072), Type A2 brachydactyly, (MIM#112600), Type C brachydactyly (MIM#113100), Grebe type chondrodysplasia (MIM#200700), Du Pan syndrome (MIM#228900), Multiple synostoses syndrome 2 (MIM#610017), Proximal Symphalangism 1B (MIM#615298); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6552 KIDINS220 Zornitza Stark Gene: kidins220 has been classified as Green List (High Evidence).
Mendeliome v0.6552 KIDINS220 Zornitza Stark Phenotypes for gene: KIDINS220 were changed from to Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296; cerebral ventriculomegaly; limb contractures
Mendeliome v0.6549 KIDINS220 Zornitza Stark reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: None; Publications: 27005418; Phenotypes: Spastic paraplegia, intellectual disability, nystagmus, and obesity, MIM# 617296; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6549 MYO15A Zornitza Stark Phenotypes for gene: MYO15A were changed from Deafness, autosomal recessive 3, MIM# 600316 to Deafness, autosomal recessive 3, MIM# 600316; autosomal recessive nonsyndromic deafness 3 MONDO:0010860
Mendeliome v0.6547 MYO3A Zornitza Stark Phenotypes for gene: MYO3A were changed from to Deafness, autosomal recessive 30 OMIM:607101; autosomal recessive nonsyndromic deafness 30 MONDO:0011774; dominant deafness
Mendeliome v0.6544 MYO3A Zornitza Stark reviewed gene: MYO3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 21165622, 26754646, 23990876; Phenotypes: Deafness, autosomal recessive 30, MIM# 607101; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6544 COL9A3 Zornitza Stark Gene: col9a3 has been classified as Green List (High Evidence).
Mendeliome v0.6544 COL9A3 Zornitza Stark Phenotypes for gene: COL9A3 were changed from to Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969; Stickler syndrome; Deafness
Mendeliome v0.6541 COL9A3 Zornitza Stark reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30450842, 31090205, 24273071, 10090888, 15551337; Phenotypes: Epiphyseal dysplasia, multiple, 3, with or without myopathy, MIM# 600969, Stickler syndrome, Deafness; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6541 DLK1 Zornitza Stark Gene: dlk1 has been classified as Green List (High Evidence).
Mendeliome v0.6541 DLK1 Zornitza Stark Classified gene: DLK1 as Green List (high evidence)
Mendeliome v0.6541 DLK1 Zornitza Stark Gene: dlk1 has been classified as Green List (High Evidence).
Mendeliome v0.6540 DLK1 Zornitza Stark gene: DLK1 was added
gene: DLK1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: DLK1 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: DLK1 were set to 28324015; 30462238
Phenotypes for gene: DLK1 were set to central precocious puberty
Review for gene: DLK1 was set to GREEN
Added comment: PMID: 30462238 "three frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Val271Cysfs*14, and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1". PMID: 28324015 single large family, only affected females, central precocious puberty all carrying paternally inherited LOF variant (del/dup of 5'UTR and exon 1) absent DLK1 expression in all affected. Unclear if males affected as none reported to date.
Sources: Expert Review
Mendeliome v0.6539 GDF5 Ain Roesley reviewed gene: GDF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33333243; Phenotypes: Type A1C brachydactyly (MIM#615072), Type A2 brachydactyly, (MIM#112600), Type C brachydactyly (MIM#113100), Grebe type chondrodysplasia (MIM#200700), Du Pan syndrome (MIM#228900), Multiple synostoses syndrome 2 (MIM#610017), Proximal Symphalangism 1B (MIM#615298); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6539 MYO15A Eleanor Williams reviewed gene: MYO15A: Rating: ; Mode of pathogenicity: None; Publications: 33078831; Phenotypes: Deafness, autosomal recessive 3 OMIM:600316, autosomal recessive nonsyndromic deafness 3 MONDO:0010860; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6539 MYO3A Eleanor Williams reviewed gene: MYO3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33078831, 26841241, 29880844; Phenotypes: Deafness, autosomal recessive 30 OMIM:607101, autosomal recessive nonsyndromic deafness 30 MONDO:0011774; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6539 COL9A3 Eleanor Williams reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33078831, 15917166; Phenotypes: autosomal recessive non-syndromic hearing impairment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6539 EIF5A Zornitza Stark Gene: eif5a has been classified as Green List (High Evidence).
Mendeliome v0.6539 EIF5A Zornitza Stark Classified gene: EIF5A as Green List (high evidence)
Mendeliome v0.6539 EIF5A Zornitza Stark Gene: eif5a has been classified as Green List (High Evidence).
Mendeliome v0.6537 POLRMT Zornitza Stark Gene: polrmt has been classified as Green List (High Evidence).
Mendeliome v0.6537 POLRMT Zornitza Stark Classified gene: POLRMT as Green List (high evidence)
Mendeliome v0.6537 POLRMT Zornitza Stark Gene: polrmt has been classified as Green List (High Evidence).
Mendeliome v0.6536 POLRMT Zornitza Stark gene: POLRMT was added
gene: POLRMT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLRMT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POLRMT were set to 33602924
Phenotypes for gene: POLRMT were set to Mitochondrial disorder; intellectual disability; hypotonia
Review for gene: POLRMT was set to GREEN
Added comment: 8 individuals from 7 families reported. 5 families with bi-allelic variants and 2 with heterozygous variants. Affected individuals presented with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype.
Sources: Literature
Mendeliome v0.6535 PERP Zornitza Stark Phenotypes for gene: PERP were changed from Erythrokeratoderma, no OMIM # yet to Olmsted syndrome 2, MIM# 619208; Erythrokeratodermia variabilis et progressiva 7, MIM# 619209
Mendeliome v0.6532 PERP Zornitza Stark Classified gene: PERP as Green List (high evidence)
Mendeliome v0.6532 PERP Zornitza Stark Gene: perp has been classified as Green List (High Evidence).
Mendeliome v0.6531 PERP Zornitza Stark edited their review of gene: PERP: Added comment: Four families reported with heterozygous variants and Olmsted syndrome-2 (OLMS2), which is characterised by mutilating hyperkeratotic skin lesions, primarily on the palms and soles, but also extending onto dorsal surfaces of the hands and feet and distal extremities. The lesions are progressive, becoming thicker with verrucous fissures on the palms and soles over time. In addition, affected individuals exhibit perioral hyperkeratosis, and may have lesions around other orifices as well, such as the nostrils, perineum, and anus. Most patients also have hyperkeratotic nails and light-colored woolly hair.

Two families reported with bi-allelic variants and Erythrokeratodermia variabilis et progressiva-7 (EKVP7), which is characterised by palmoplantar keratoderma that extends to the dorsal surface of the hands and feet (transgrediens), as well as erythematous annular skin lesions. Pruritis, woolly hair, and dystrophic nails may also be present.; Changed rating: GREEN; Changed publications: 31898316, 30321533, 31361044; Changed phenotypes: Olmsted syndrome 2, MIM# 619208, Erythrokeratodermia variabilis et progressiva 7, MIM# 619209; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6531 KARS Zornitza Stark edited their review of gene: KARS: Changed phenotypes: Leukoencephalopathy with or without deafness (LEPID), MIM#619147, Deafness, autosomal recessive 89, MIM# 613916, Congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE), MIM#619196
Mendeliome v0.6531 KARS Zornitza Stark Phenotypes for gene: KARS were changed from Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Deafness, autosomal recessive 89, MIM# 613916 to Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Deafness, autosomal recessive 89, MIM# 613916; Congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE), MIM#619196
Mendeliome v0.6530 KARS Zornitza Stark Gene: kars has been classified as Green List (High Evidence).
Mendeliome v0.6530 KARS Zornitza Stark Phenotypes for gene: KARS were changed from to Leukoencephalopathy with or without deafness (LEPID), MIM#619147; Deafness, autosomal recessive 89, MIM# 613916
Mendeliome v0.6527 KARS Zornitza Stark reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 26741492, 31618474, 28887846, 25330800, 29615062, 30252186, 28496994, 23768514, 14975237; Phenotypes: Leukoencephalopathy with or without deafness (LEPID), MIM#619147, Deafness, autosomal recessive 89, MIM# 613916; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6527 APOO Zornitza Stark reviewed gene: APOO: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, Lactic acidosis, Muscle weakness, Hypotonia, Repetitive infections, Cognitive impairment, Autistic behaviour; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.6527 APOO Zornitza Stark Gene: apoo has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6527 APOO Zornitza Stark Classified gene: APOO as Amber List (moderate evidence)
Mendeliome v0.6527 APOO Zornitza Stark Gene: apoo has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6526 APOO Arina Puzriakova gene: APOO was added
gene: APOO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: APOO 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: APOO were set to 32439808
Phenotypes for gene: APOO were set to Developmental delay; Lactic acidosis; Muscle weakness; Hypotonia; Repetitive infections; Cognitive impairment; Autistic behaviour
Review for gene: APOO was set to RED
Added comment: - PMID: 32439808 (2021) - Three generation family with c.350T>C variant in APOO, encoding a component of the MICOS complex which plays a role in maintaining inner mitochondrial membrane architecture.
Phenotypes include fatigue and muscle weakness (6/8), learning difficulties and cognitive impairment (4/8), and increased blood lactate (2/8). Four individuals were asymptomatic carriers, including one male (authors indicate variability in female carriers was due to skewed X-inactivation, although skewing studies were inconclusive in some cases). Variability in clinical presentation suggests reduced penetrance or possible contribution of additional factors.
Functional studies showed altered MICOS assembly and abnormalities in mitochondria ultrastructure in patient-derived fibroblasts. Knockdown studies in Drosophila and yeast demonstrated mitochondrial structural and functional deficiencies.
Sources: Literature
Mendeliome v0.6526 ECE1 Zornitza Stark Gene: ece1 has been classified as Red List (Low Evidence).
Mendeliome v0.6523 ECE1 Zornitza Stark Classified gene: ECE1 as Red List (low evidence)
Mendeliome v0.6523 ECE1 Zornitza Stark Gene: ece1 has been classified as Red List (Low Evidence).
Mendeliome v0.6522 AMH Seb Lunke Gene: amh has been classified as Green List (High Evidence).
Mendeliome v0.6522 AMH Seb Lunke Phenotypes for gene: AMH were changed from to Persistent Mullerian duct syndrome, type I (MIM#261550)
Mendeliome v0.6519 AMH Seb Lunke reviewed gene: AMH: Rating: GREEN; Mode of pathogenicity: None; Publications: 32172781; Phenotypes: Persistent Mullerian duct syndrome, type I (MIM#261550); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6519 PAX4 Zornitza Stark Gene: pax4 has been classified as Green List (High Evidence).
Mendeliome v0.6516 PCBD1 Zornitza Stark Gene: pcbd1 has been classified as Green List (High Evidence).
Mendeliome v0.6513 SPTAN1 Zornitza Stark Gene: sptan1 has been classified as Green List (High Evidence).
Mendeliome v0.6510 PSAP Zornitza Stark changed review comment from: Well established gene-disease association. Phenotype expansion with early-onset PD reported.; to: Well established gene-disease association for bi-allelic variants. Early-onset PD reported with mono-allelic variants.
Mendeliome v0.6508 PSAP Zornitza Stark changed review comment from: Well established gene-disease association. Phenotype expansion reported with early-onset PD reported.; to: Well established gene-disease association. Phenotype expansion with early-onset PD reported.
Mendeliome v0.6508 ACTL9 Zornitza Stark Gene: actl9 has been classified as Green List (High Evidence).
Mendeliome v0.6505 IRF4 Bryony Thompson Gene: irf4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6502 IRF4 Bryony Thompson Classified gene: IRF4 as Amber List (moderate evidence)
Mendeliome v0.6502 IRF4 Bryony Thompson Added comment: Comment on list classification: Single case and mouse model for recessive combined immunodeficiency
Mendeliome v0.6502 IRF4 Bryony Thompson Gene: irf4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6501 PCBD1 Michelle Torres edited their review of gene: PCBD1: Added comment: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes.

PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; Changed phenotypes: MODY, Hyperphenylalaninemia, BH4-deficient, D 264070
Mendeliome v0.6501 SPEN Alison Yeung Classified gene: SPEN as Green List (high evidence)
Mendeliome v0.6501 SPEN Alison Yeung Gene: spen has been classified as Green List (High Evidence).
Mendeliome v0.6500 SPTAN1 Alison Yeung Added comment: Comment on mode of inheritance: phenotype expansion
Mendeliome v0.6499 PSAP Seb Lunke Gene: psap has been classified as Green List (High Evidence).
Mendeliome v0.6497 ACTL9 Alison Yeung Classified gene: ACTL9 as Green List (high evidence)
Mendeliome v0.6497 ACTL9 Alison Yeung Gene: actl9 has been classified as Green List (High Evidence).
Mendeliome v0.6496 MAST2 Seb Lunke Gene: mast2 has been classified as Red List (Low Evidence).
Mendeliome v0.6496 MAST2 Seb Lunke Classified gene: MAST2 as Red List (low evidence)
Mendeliome v0.6496 MAST2 Seb Lunke Gene: mast2 has been classified as Red List (Low Evidence).
Mendeliome v0.6495 SPEN Chern Lim reviewed gene: SPEN: Rating: GREEN; Mode of pathogenicity: None; Publications: 33596411; Phenotypes: Developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.6495 ANGPTL6 Alison Yeung Classified gene: ANGPTL6 as Green List (high evidence)
Mendeliome v0.6495 ANGPTL6 Alison Yeung Gene: angptl6 has been classified as Green List (High Evidence).
Mendeliome v0.6494 PCBD1 Michelle Torres changed review comment from: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes.

PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; to: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes.

PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY
Mendeliome v0.6494 EPAS1 Seb Lunke Gene: epas1 has been classified as Green List (High Evidence).
Mendeliome v0.6494 EPAS1 Seb Lunke Phenotypes for gene: EPAS1 were changed from to Familial erythrocytosis (MIM#4611783), AD
Mendeliome v0.6492 NLRP3 Alison Yeung Classified gene: NLRP3 as Green List (high evidence)
Mendeliome v0.6492 NLRP3 Alison Yeung Gene: nlrp3 has been classified as Green List (High Evidence).
Mendeliome v0.6490 PCBD1 Michelle Torres changed review comment from: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes.

PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY; to: PMID: 24848070: one consanguineous family with early-onset nonautoimmune diabetes. The individual with early onset is biallelic, and 3 other carriers had later onset diabetes. In addition, 3 other patients with mild neonatal hyperphenylalaninemia with features similar to dominantly inherited HNF1A-diabetes.

PMID: 24204001: 2 out 3 patients with hypomagnesemia and renal magnesium wasting associated to biallelic PCBD1 variants developed MODY
Mendeliome v0.6487 NLRP3 Alison Yeung Gene: nlrp3 has been classified as Green List (High Evidence).
Mendeliome v0.6487 MED27 Alison Yeung Gene: med27 has been classified as Green List (High Evidence).
Mendeliome v0.6487 MED27 Alison Yeung Classified gene: MED27 as Green List (high evidence)
Mendeliome v0.6487 MED27 Alison Yeung Gene: med27 has been classified as Green List (High Evidence).
Mendeliome v0.6486 MED27 Alison Yeung gene: MED27 was added
gene: MED27 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; cerebellar hypoplasia; dystonia
Review for gene: MED27 was set to GREEN
gene: MED27 was marked as current diagnostic
Added comment: 16 patients from 11 families with balletic variants
Sources: Literature
Mendeliome v0.6485 ACTL9 Elena Savva gene: ACTL9 was added
gene: ACTL9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACTL9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACTL9 were set to PMID: 33626338
Phenotypes for gene: ACTL9 were set to Fertilization failure; male infertility
Review for gene: ACTL9 was set to GREEN
Added comment: Three families with homozygous pathogenic variants (two missense, one PTC). Single affected in each family. Functional analysis from patients shows all sperm had morphological defects, protein had reduced binding to ACTL7A
All variants very rare in gnomAD.
Sources: Literature
Mendeliome v0.6485 MAST2 Elena Savva gene: MAST2 was added
gene: MAST2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAST2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAST2 were set to PMID: 33465109
Phenotypes for gene: MAST2 were set to Thrombophilia; venous thrombosis
Review for gene: MAST2 was set to RED
Added comment: Single missense identified in a family with venous thrombosis and thrombophilia. Missense variant reviewed by in silicos only. Shown to affect regulation of TFP1 and SERPINE1 gene expression.

RNAi of MAST2 followed by RNAseq showed expression changes in many downstream targets
Sources: Literature
Mendeliome v0.6485 EPAS1 Teresa Zhao reviewed gene: EPAS1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27292716, 19208626; Phenotypes: Familial erythrocytosis (MIM#4611783), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6485 AGPS Zornitza Stark Gene: agps has been classified as Green List (High Evidence).
Mendeliome v0.6485 AGPS Zornitza Stark Phenotypes for gene: AGPS were changed from to Rhizomelic chondrodysplasia punctata, type 3, MIM# 600121
Mendeliome v0.6482 AGPS Zornitza Stark reviewed gene: AGPS: Rating: GREEN; Mode of pathogenicity: None; Publications: 9553082, 8611652, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 3, MIM# 600121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6482 BANF1 Zornitza Stark Gene: banf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6479 BANF1 Zornitza Stark Classified gene: BANF1 as Amber List (moderate evidence)
Mendeliome v0.6479 BANF1 Zornitza Stark Gene: banf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6478 FOXP2 Zornitza Stark Gene: foxp2 has been classified as Green List (High Evidence).
Mendeliome v0.6475 GLI3 Zornitza Stark Gene: gli3 has been classified as Green List (High Evidence).
Mendeliome v0.6472 KIF22 Zornitza Stark Gene: kif22 has been classified as Green List (High Evidence).
Mendeliome v0.6471 KIF22 Zornitza Stark reviewed gene: KIF22: Rating: GREEN; Mode of pathogenicity: None; Publications: 25256152; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2, MIM# 603546; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6471 KIF22 Zornitza Stark Phenotypes for gene: KIF22 were changed from to Spondyloepimetaphyseal dysplasia with joint laxity, type 2 MIM#603546
Mendeliome v0.6468 ANKZF1 Bryony Thompson Gene: ankzf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6468 ANKZF1 Bryony Thompson Classified gene: ANKZF1 as Amber List (moderate evidence)
Mendeliome v0.6468 ANKZF1 Bryony Thompson Gene: ankzf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6466 ANGPT1 Bryony Thompson Classified gene: ANGPT1 as Amber List (moderate evidence)
Mendeliome v0.6466 ANGPT1 Bryony Thompson Gene: angpt1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6465 ANGPT1 Bryony Thompson gene: ANGPT1 was added
gene: ANGPT1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: ANGPT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANGPT1 were set to 28601681; 24852101; 30689269; 10617467; 8980224
Phenotypes for gene: ANGPT1 were set to Hereditary angioedema
Review for gene: ANGPT1 was set to AMBER
Added comment: A missense variant (A119S) identified in 4 affected individuals in a single family. Supportive data in patient cells, functional assays of the variant, and animal models (both overexpression and null) for the gene.
Sources: Other
Mendeliome v0.6464 CLTCL1 Bryony Thompson Gene: cltcl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6464 CLTCL1 Bryony Thompson Classified gene: CLTCL1 as Amber List (moderate evidence)
Mendeliome v0.6464 CLTCL1 Bryony Thompson Added comment: Comment on list classification: A single family, but also some compelling functional data for an association with insensitivity to pain.
Mendeliome v0.6464 CLTCL1 Bryony Thompson Gene: cltcl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6463 CLTCL1 Bryony Thompson changed review comment from: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons.

PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system

Other reports of associations with limited evidence:
PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided.

PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively.
Sources: Literature; to: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons.

PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system.

Other reports of associations with limited evidence:
PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided.

PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively.
Sources: Literature
Mendeliome v0.6463 CLTCL1 Bryony Thompson gene: CLTCL1 was added
gene: CLTCL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLTCL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLTCL1 were set to 26068709; 29402896; 22511880; 31354784
Phenotypes for gene: CLTCL1 were set to Congenital insensitivity to pain
Review for gene: CLTCL1 was set to AMBER
Added comment: PMID: 26068709 - Three siblings in a single consanguineous family with congenital insensitivity to pain, inability to feel touch, and cognitive delay and a homozygous rare missense variant (Glu330Lys - no homozygotes in gnomAD v2.1). In vitro functional assays of the variant suggested a deleterious effect on the protein. Additionally cellular assays suggested a role for the gene in neural crest development and in the genesis of pain and touch sensing neurons.

PMID: 29402896 - more in depth functional assays and proteomic analyses suggesting a role for the protein in regulating sensory neuron differentiation in the human peripheral system

Other reports of associations with limited evidence:
PMID: 22511880 - Identified as a candidate gene in an autism study, but the homozygous variant (reported as R125C, but actually R1165C) has 40 homozygotes in gnomAD v2.1. And many of the other compound heterozygous candidate variants in the study are too common in gnomAD v2.1, with many homozygotes present. The missense reported in the pain insensitivity family Glu330Lys was reported with another rare missense variant (Glu1310Lys) in one of the autism cases, but no other phenotype information was provided.

PMID: 31354784 - a single case with infantile spasm reported with compound het missense (Met1316Val & Arg1165Cys), but both are very common in gnomAD v2.1 with 33,000 and 40 homozygotes, respectively.
Sources: Literature
Mendeliome v0.6462 KIF22 Elena Savva reviewed gene: KIF22: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22152677, 22152678; Phenotypes: Spondyloepimetaphyseal dysplasia with joint laxity, type 2 MIM#603546; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v0.6461 SLC7A6OS Zornitza Stark Phenotypes for gene: SLC7A6OS were changed from Progressive myoclonus epilepsy to Epilepsy, progressive myoclonic, 12, MIM# 619191
Mendeliome v0.6460 SLC7A6OS Zornitza Stark edited their review of gene: SLC7A6OS: Changed phenotypes: Epilepsy, progressive myoclonic, 12, MIM# 619191
Mendeliome v0.6460 G6PC Zornitza Stark Gene: g6pc has been classified as Green List (High Evidence).
Mendeliome v0.6457 ALPI Zornitza Stark Classified gene: ALPI as Amber List (moderate evidence)
Mendeliome v0.6457 ALPI Zornitza Stark Gene: alpi has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6456 NMNAT2 Bryony Thompson Gene: nmnat2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6456 NMNAT2 Bryony Thompson Gene: nmnat2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6456 NMNAT2 Bryony Thompson Classified gene: NMNAT2 as Amber List (moderate evidence)
Mendeliome v0.6456 NMNAT2 Bryony Thompson Gene: nmnat2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6455 NMNAT2 Bryony Thompson gene: NMNAT2 was added
gene: NMNAT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NMNAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NMNAT2 were set to 31132363; 25271157; 20126265
Phenotypes for gene: NMNAT2 were set to polyneuropathy; erythromelalgia
Review for gene: NMNAT2 was set to AMBER
Added comment: A single family with siblings with a homozygous variant that confers a partial loss of function. Strong supporting functional evidence that the gene plays a key role in axonal survival.
Sources: Literature
Mendeliome v0.6451 USF1 Bryony Thompson Gene: usf1 has been classified as Red List (Low Evidence).
Mendeliome v0.6451 USF1 Bryony Thompson Classified gene: USF1 as Red List (low evidence)
Mendeliome v0.6451 USF1 Bryony Thompson Gene: usf1 has been classified as Red List (Low Evidence).
Mendeliome v0.6449 PDXK Bryony Thompson Classified gene: PDXK as Green List (high evidence)
Mendeliome v0.6449 PDXK Bryony Thompson Added comment: Comment on list classification: Additional family published in 2020
Mendeliome v0.6449 PDXK Bryony Thompson Gene: pdxk has been classified as Green List (High Evidence).
Mendeliome v0.6447 LIPI Bryony Thompson Gene: lipi has been classified as Red List (Low Evidence).
Mendeliome v0.6447 LIPI Bryony Thompson Classified gene: LIPI as Red List (low evidence)
Mendeliome v0.6447 LIPI Bryony Thompson Gene: lipi has been classified as Red List (Low Evidence).
Mendeliome v0.6446 GALNT12 Bryony Thompson Gene: galnt12 has been classified as Red List (Low Evidence).
Mendeliome v0.6446 GALNT12 Bryony Thompson Classified gene: GALNT12 as Red List (low evidence)
Mendeliome v0.6446 GALNT12 Bryony Thompson Gene: galnt12 has been classified as Red List (Low Evidence).
Mendeliome v0.6445 ABCG2 Bryony Thompson Gene: abcg2 has been classified as Red List (Low Evidence).
Mendeliome v0.6445 ABCG2 Bryony Thompson Classified gene: ABCG2 as Red List (low evidence)
Mendeliome v0.6445 ABCG2 Bryony Thompson Gene: abcg2 has been classified as Red List (Low Evidence).
Mendeliome v0.6444 SAT1 Bryony Thompson Gene: sat1 has been classified as Red List (Low Evidence).
Mendeliome v0.6444 SAT1 Bryony Thompson Classified gene: SAT1 as Red List (low evidence)
Mendeliome v0.6444 SAT1 Bryony Thompson Gene: sat1 has been classified as Red List (Low Evidence).
Mendeliome v0.6443 SAT1 Bryony Thompson reviewed gene: SAT1: Rating: RED; Mode of pathogenicity: None; Publications: 12215835, 20672378, 9228047; Phenotypes: Keratosis follicularis spinulosa decalvans; 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 v0.6442 ALPI Zornitza Stark Classified gene: ALPI as Green List (high evidence)
Mendeliome v0.6442 ALPI Zornitza Stark Gene: alpi has been classified as Green List (High Evidence).
Mendeliome v0.6441 MIR5004 Bryony Thompson Gene: mir5004 has been classified as Red List (Low Evidence).
Mendeliome v0.6441 MIR5004 Bryony Thompson Classified gene: MIR5004 as Red List (low evidence)
Mendeliome v0.6441 MIR5004 Bryony Thompson Gene: mir5004 has been classified as Red List (Low Evidence).
Mendeliome v0.6440 TOGARAM1 Zornitza Stark Phenotypes for gene: TOGARAM1 were changed from Cleft of the lip and palate; Microphthalmia; Cerebral dysgenesis; Hydrocephalus to Joubert syndrome 37, MIM# 619185
Mendeliome v0.6438 TOGARAM1 Zornitza Stark Classified gene: TOGARAM1 as Green List (high evidence)
Mendeliome v0.6438 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Green List (High Evidence).
Mendeliome v0.6437 ALDOA Zornitza Stark Gene: aldoa has been classified as Green List (High Evidence).
Mendeliome v0.6434 RDH5 Zornitza Stark Gene: rdh5 has been classified as Green List (High Evidence).
Mendeliome v0.6431 RPGRIP1 Zornitza Stark Gene: rpgrip1 has been classified as Green List (High Evidence).
Mendeliome v0.6431 RPGRIP1 Zornitza Stark Phenotypes for gene: RPGRIP1 were changed from to Cone-rod dystrophy 13 (MIM#608194) , Leber congenital amaurosis (MIM#61382)
Mendeliome v0.6428 RPGRIP1 Ain Roesley reviewed gene: RPGRIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33308271, 31666973; Phenotypes: Cone-rod dystrophy 13 (MIM#608194) , Leber congenital amaurosis (MIM#61382); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6428 IRX4 Zornitza Stark Gene: irx4 has been classified as Red List (Low Evidence).
Mendeliome v0.6425 IRX4 Zornitza Stark Classified gene: IRX4 as Red List (low evidence)
Mendeliome v0.6425 IRX4 Zornitza Stark Gene: irx4 has been classified as Red List (Low Evidence).
Mendeliome v0.6424 AKAP6 Zornitza Stark Gene: akap6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6421 AKAP6 Zornitza Stark Classified gene: AKAP6 as Amber List (moderate evidence)
Mendeliome v0.6421 AKAP6 Zornitza Stark Gene: akap6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6420 ASCC3 Bryony Thompson Gene: ascc3 has been classified as Green List (High Evidence).
Mendeliome v0.6420 ASCC3 Bryony Thompson Classified gene: ASCC3 as Green List (high evidence)
Mendeliome v0.6420 ASCC3 Bryony Thompson Gene: ascc3 has been classified as Green List (High Evidence).
Mendeliome v0.6418 HS2ST1 Zornitza Stark Phenotypes for gene: HS2ST1 were changed from Intellectual disability; dysmorphic features; congenital anomalies to Neurofacioskeletal syndrome with or without renal agenesis, MIM#619194; Intellectual disability; dysmorphic features; congenital anomalies
Mendeliome v0.6417 HS2ST1 Zornitza Stark reviewed gene: HS2ST1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurofacioskeletal syndrome with or without renal agenesis, MIM#619194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6414 ARSG Bryony Thompson Classified gene: ARSG as Green List (high evidence)
Mendeliome v0.6414 ARSG Bryony Thompson Added comment: Comment on list classification: 2 additional families reported, upgraded to green
Mendeliome v0.6414 ARSG Bryony Thompson Gene: arsg has been classified as Green List (High Evidence).
Mendeliome v0.6412 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500 to Microcephaly 26, primary, autosomal dominant, MIM# 619179; Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500
Mendeliome v0.6411 LMNB1 Zornitza Stark edited their review of gene: LMNB1: Changed phenotypes: Microcephaly 26, primary, autosomal dominant, MIM# 619179, Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis, Leukodystrophy, adult-onset, autosomal dominant, MIM#169500
Mendeliome v0.6410 CRYM Zornitza Stark Gene: crym has been classified as Green List (High Evidence).
Mendeliome v0.6407 HARS Zornitza Stark Gene: hars has been classified as Green List (High Evidence).
Mendeliome v0.6401 PMVK Zornitza Stark Gene: pmvk has been classified as Green List (High Evidence).
Mendeliome v0.6401 PMVK Zornitza Stark Classified gene: PMVK as Green List (high evidence)
Mendeliome v0.6401 PMVK Zornitza Stark Gene: pmvk has been classified as Green List (High Evidence).
Mendeliome v0.6400 PMVK Zornitza Stark gene: PMVK was added
gene: PMVK was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: PMVK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMVK were set to 26202976
Phenotypes for gene: PMVK were set to Porokeratosis 1, multiple types, MIM# 175800
Review for gene: PMVK was set to GREEN
Added comment: At least 9 individuals reported.
Sources: Expert Review
Mendeliome v0.6399 MVD Zornitza Stark Gene: mvd has been classified as Green List (High Evidence).
Mendeliome v0.6399 MVD Zornitza Stark Classified gene: MVD as Green List (high evidence)
Mendeliome v0.6399 MVD Zornitza Stark Gene: mvd has been classified as Green List (High Evidence).
Mendeliome v0.6398 MVD Zornitza Stark gene: MVD was added
gene: MVD was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MVD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MVD were set to 30942823; 33491095
Phenotypes for gene: MVD were set to Porokeratosis 7, multiple types, MIM# 614714
Review for gene: MVD was set to GREEN
Added comment: Porokeratoses are a heterogeneous group of keratinization disorders. For linear porokeratosis and disseminated superficial actinic porokeratosis, a heterozygous pathogenic germline variant in a mevalonate pathway gene and a postzygotic second hit mutation present in affected skin have been shown to be the patho-genetic mechanism for the development of the lesions. At least 5 individuals reported.
Sources: Expert list
Mendeliome v0.6396 UNC45B Zornitza Stark Phenotypes for gene: UNC45B were changed from Progressive Myopathy with Eccentric Cores to Myofibrillar myopathy 11, MIM# 619178; Progressive Myopathy with Eccentric Cores
Mendeliome v0.6395 SHROOM3 Zornitza Stark Gene: shroom3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6395 SHROOM3 Zornitza Stark Classified gene: SHROOM3 as Amber List (moderate evidence)
Mendeliome v0.6395 SHROOM3 Zornitza Stark Gene: shroom3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6394 SHROOM3 Zornitza Stark gene: SHROOM3 was added
gene: SHROOM3 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SHROOM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHROOM3 were set to 32621286
Phenotypes for gene: SHROOM3 were set to Anencephaly; cleft lip and palate
Review for gene: SHROOM3 was set to AMBER
Added comment: Animal model and other functional data link SHROOM3 to neural tube development. Single family reported with bi-allelic LoF in a fetus with anencephaly and CL/P.
Sources: Expert Review
Mendeliome v0.6393 FLT3 Zornitza Stark Gene: flt3 has been classified as Red List (Low Evidence).
Mendeliome v0.6393 FLT3 Zornitza Stark Classified gene: FLT3 as Red List (low evidence)
Mendeliome v0.6393 FLT3 Zornitza Stark Gene: flt3 has been classified as Red List (Low Evidence).
Mendeliome v0.6392 MSL3 Zornitza Stark Gene: msl3 has been classified as Green List (High Evidence).
Mendeliome v0.6392 MSL3 Zornitza Stark Phenotypes for gene: MSL3 were changed from to Basilicata-Akhtar syndrome, OMIM # 301032
Mendeliome v0.6389 MSL3 Zornitza Stark reviewed gene: MSL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33173220; Phenotypes: Basilicata-Akhtar syndrome, OMIM # 301032; 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 v0.6389 TOE1 Zornitza Stark Gene: toe1 has been classified as Green List (High Evidence).
Mendeliome v0.6389 TOE1 Zornitza Stark Phenotypes for gene: TOE1 were changed from to Pontocerebellar hypoplasia, type 7, MIM# 614969
Mendeliome v0.6386 TOE1 Zornitza Stark reviewed gene: TOE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28092684; Phenotypes: Pontocerebellar hypoplasia, type 7, MIM# 614969; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6386 VRK1 Zornitza Stark Gene: vrk1 has been classified as Green List (High Evidence).
Mendeliome v0.6386 VRK1 Zornitza Stark Phenotypes for gene: VRK1 were changed from to Pontocerebellar hypoplasia type 1A, MIM# 607596; SMA
Mendeliome v0.6383 VRK1 Zornitza Stark edited their review of gene: VRK1: Changed rating: GREEN; Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, SMA
Mendeliome v0.6383 SPTBN2 Zornitza Stark Gene: sptbn2 has been classified as Green List (High Evidence).
Mendeliome v0.6383 SPTBN2 Zornitza Stark Phenotypes for gene: SPTBN2 were changed from to Spinocerebellar ataxia, autosomal recessive 14, MIM# 615386; Spinocerebellar ataxia 5, MIM# 600224
Mendeliome v0.6380 SEPSECS Zornitza Stark Gene: sepsecs has been classified as Green List (High Evidence).
Mendeliome v0.6380 SEPSECS Zornitza Stark Phenotypes for gene: SEPSECS were changed from to Pontocerebellar hypoplasia type 2D, 613811; cerebellar ataxia and cognitive impairment
Mendeliome v0.6377 SEPSECS Zornitza Stark reviewed gene: SEPSECS: Rating: GREEN; Mode of pathogenicity: None; Publications: 20920667, 25044680, 31748115, 29464431; Phenotypes: Pontocerebellar hypoplasia type 2D, MIM# 613811; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6377 ITPR1 Zornitza Stark changed review comment from: Gillespie syndrome is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild. Multiple families reported with bi-allelic or de novo heterozygous variants.; to: Gillespie syndrome: usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild. Multiple families reported with bi-allelic or de novo heterozygous variants.
Mendeliome v0.6377 ITPR1 Zornitza Stark Gene: itpr1 has been classified as Green List (High Evidence).
Mendeliome v0.6377 ITPR1 Zornitza Stark Phenotypes for gene: ITPR1 were changed from to Gillespie syndrome, MIM# 206700; Spinocerebellar ataxia 15 MIM#606658; Spinocerebellar ataxia 29, congenital nonprogressive MIM#117360
Mendeliome v0.6374 EXOSC8 Zornitza Stark Gene: exosc8 has been classified as Green List (High Evidence).
Mendeliome v0.6374 EXOSC8 Zornitza Stark Phenotypes for gene: EXOSC8 were changed from to Pontocerebellar hypoplasia, type 1C, MIM# 616081
Mendeliome v0.6371 EXOSC8 Zornitza Stark reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24989451; Phenotypes: Pontocerebellar hypoplasia, type 1C, MIM# 616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6371 EXOSC3 Zornitza Stark Gene: exosc3 has been classified as Green List (High Evidence).
Mendeliome v0.6371 EXOSC3 Zornitza Stark Phenotypes for gene: EXOSC3 were changed from to Pontocerebellar hypoplasia, type 1B, MIM# 614678
Mendeliome v0.6368 EXOSC3 Zornitza Stark reviewed gene: EXOSC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22544365, 23284067, 24524299; Phenotypes: Pontocerebellar hypoplasia, type 1B, MIM# 614678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6368 CLP1 Zornitza Stark Gene: clp1 has been classified as Green List (High Evidence).
Mendeliome v0.6368 CLP1 Zornitza Stark Phenotypes for gene: CLP1 were changed from to Pontocerebellar hypoplasia type 10, MIM# 615803
Mendeliome v0.6365 CLP1 Zornitza Stark reviewed gene: CLP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24766809, 29307788; Phenotypes: Pontocerebellar hypoplasia type 10, MIM# 615803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6365 CHMP1A Zornitza Stark Gene: chmp1a has been classified as Green List (High Evidence).
Mendeliome v0.6365 CHMP1A Zornitza Stark Phenotypes for gene: CHMP1A were changed from to Pontocerebellar hypoplasia, type 8, MIM# 614961
Mendeliome v0.6362 CHMP1A Zornitza Stark reviewed gene: CHMP1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23023333; Phenotypes: Pontocerebellar hypoplasia, type 8, MIM# 614961; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6362 BRF1 Zornitza Stark Gene: brf1 has been classified as Green List (High Evidence).
Mendeliome v0.6359 DHODH Zornitza Stark Gene: dhodh has been classified as Green List (High Evidence).
Mendeliome v0.6356 ITGB4 Zornitza Stark Gene: itgb4 has been classified as Green List (High Evidence).
Mendeliome v0.6356 ITGB4 Zornitza Stark Phenotypes for gene: ITGB4 were changed from to Epidermolysis bullosa of hands and feet, MIM# 131800; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Epidermolysis bullosa, junctional, with pyloric atresia, MIM# 226730
Mendeliome v0.6353 ITGB4 Zornitza Stark reviewed gene: ITGB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11328943, 9670011, 33225458, 30079450, 29380424, 29198538, 28557647; Phenotypes: Epidermolysis bullosa of hands and feet, MIM# 131800, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650, Epidermolysis bullosa, junctional, with pyloric atresia, MIM# 226730; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.6353 LAMA3 Zornitza Stark Gene: lama3 has been classified as Green List (High Evidence).
Mendeliome v0.6353 LAMA3 Zornitza Stark Phenotypes for gene: LAMA3 were changed from to Epidermolysis bullosa, generalized atrophic benign, MIM# 226650; Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700
Mendeliome v0.6350 LAMA3 Zornitza Stark reviewed gene: LAMA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 7633458, 8530087, 11810295, 10366601; Phenotypes: Epidermolysis bullosa, generalized atrophic benign, MIM# 226650, Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6350 LAMB3 Zornitza Stark Gene: lamb3 has been classified as Green List (High Evidence).
Mendeliome v0.6350 LAMB3 Zornitza Stark Phenotypes for gene: LAMB3 were changed from to Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650
Mendeliome v0.6347 LAMB3 Zornitza Stark reviewed gene: LAMB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 11023379, 7706760; Phenotypes: Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6347 LAMC2 Zornitza Stark Gene: lamc2 has been classified as Green List (High Evidence).
Mendeliome v0.6347 LAMC2 Zornitza Stark Phenotypes for gene: LAMC2 were changed from to Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700; Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650
Mendeliome v0.6344 LAMC2 Zornitza Stark reviewed gene: LAMC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11810295, 25888738, 24533970; Phenotypes: Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700, Epidermolysis bullosa, junctional, non-Herlitz type, MIM# 226650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6344 KRT5 Zornitza Stark Gene: krt5 has been classified as Green List (High Evidence).
Mendeliome v0.6344 KRT5 Zornitza Stark Phenotypes for gene: KRT5 were changed from to Dowling-Degos disease 1, MIM# 179850; Epidermolysis bullosa simplex-MCR, MIM# 609352; Epidermolysis bullosa simplex-MP 131960; Epidermolysis bullosa simplex, Dowling-Meara type, MIM# 131760; Epidermolysis bullosa simplex, Koebner type, MIM# 131900; Epidermolysis bullosa simplex, recessive 1, MIM# 601001; Epidermolysis bullosa simplex, Weber-Cockayne type, MIM# 131800
Mendeliome v0.6342 KRT5 Zornitza Stark reviewed gene: KRT5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dowling-Degos disease 1, MIM# 179850, Epidermolysis bullosa simplex-MCR, MIM# 609352, Epidermolysis bullosa simplex-MP 131960, Epidermolysis bullosa simplex, Dowling-Meara type, MIM# 131760, Epidermolysis bullosa simplex, Koebner type, MIM# 131900, Epidermolysis bullosa simplex, recessive 1, MIM# 601001, Epidermolysis bullosa simplex, Weber-Cockayne type, MIM# 131800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6340 ITGA6 Zornitza Stark Gene: itga6 has been classified as Green List (High Evidence).
Mendeliome v0.6340 ITGA6 Zornitza Stark Phenotypes for gene: ITGA6 were changed from to Epidermolysis bullosa, junctional, with pyloric stenosis, MIM# 226730
Mendeliome v0.6337 ITGA6 Zornitza Stark reviewed gene: ITGA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31502654, 27607025, 9158140; Phenotypes: Epidermolysis bullosa, junctional, with pyloric stenosis, MIM# 226730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6337 ITGA3 Zornitza Stark Gene: itga3 has been classified as Green List (High Evidence).
Mendeliome v0.6337 ITGA3 Zornitza Stark Phenotypes for gene: ITGA3 were changed from to Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital, MIM# 614748
Mendeliome v0.6334 ITGA3 Zornitza Stark reviewed gene: ITGA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22512483, 25810266, 27717396, 32198874, 26854491; Phenotypes: Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital, MIM# 614748; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6334 FERMT1 Zornitza Stark Gene: fermt1 has been classified as Green List (High Evidence).
Mendeliome v0.6331 EXPH5 Zornitza Stark Gene: exph5 has been classified as Green List (High Evidence).
Mendeliome v0.6331 EXPH5 Zornitza Stark Phenotypes for gene: EXPH5 were changed from to Epidermolysis bullosa, nonspecific, autosomal recessive, MIM# 615028
Mendeliome v0.6328 EXPH5 Zornitza Stark reviewed gene: EXPH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176819, 32176379, 27730671, 27384765; Phenotypes: Epidermolysis bullosa, nonspecific, autosomal recessive, MIM# 615028; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6328 COL7A1 Zornitza Stark Gene: col7a1 has been classified as Green List (High Evidence).
Mendeliome v0.6328 COL7A1 Zornitza Stark Phenotypes for gene: COL7A1 were changed from to EBD inversa, MIM# 226600; EBD, Bart type MIM# 132000; EBD, localisata variant; Epidermolysis bullosa dystrophica, MIM# 131750; Epidermolysis bullosa dystrophica, 226600; Epidermolysis bullosa pruriginosa 604129; Epidermolysis bullosa, pretibial, MIM# 131850; Transient bullous of the newborn 131705
Mendeliome v0.6326 COL7A1 Zornitza Stark reviewed gene: COL7A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: EBD inversa, MIM# 226600, EBD, Bart type MIM# 132000, EBD, localisata variant, Epidermolysis bullosa dystrophica, MIM# 131750, Epidermolysis bullosa dystrophica, 226600, Epidermolysis bullosa pruriginosa 604129, Epidermolysis bullosa, pretibial, MIM# 131850, Transient bullous of the newborn 131705; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6326 IGSF1 Zornitza Stark Gene: igsf1 has been classified as Green List (High Evidence).
Mendeliome v0.6323 FSTL5 Zornitza Stark Gene: fstl5 has been classified as Red List (Low Evidence).
Mendeliome v0.6323 FSTL5 Zornitza Stark Classified gene: FSTL5 as Red List (low evidence)
Mendeliome v0.6323 FSTL5 Zornitza Stark Gene: fstl5 has been classified as Red List (Low Evidence).
Mendeliome v0.6322 NCOA3 Zornitza Stark Gene: ncoa3 has been classified as Red List (Low Evidence).
Mendeliome v0.6322 NCOA3 Zornitza Stark Classified gene: NCOA3 as Red List (low evidence)
Mendeliome v0.6322 NCOA3 Zornitza Stark Gene: ncoa3 has been classified as Red List (Low Evidence).
Mendeliome v0.6321 FCHO1 Zornitza Stark Phenotypes for gene: FCHO1 were changed from Combined immunodeficiency; T cells: low, poor proliferation; B cells: normal number; Recurrent infections (viral, mycobacteria, bacterial, fungal); lymphoproliferation; Failure to thrive; Increased activation-induced T-cell death; Defective clathrin-mediated endocytosis to Immunodeficiency 76, MIM# 619164; Combined immunodeficiency; T cells: low, poor proliferation; B cells: normal number; Recurrent infections (viral, mycobacteria, bacterial, fungal); lymphoproliferation; Failure to thrive; Increased activation-induced T-cell death; Defective clathrin-mediated endocytosis
Mendeliome v0.6320 FCHO1 Zornitza Stark edited their review of gene: FCHO1: Changed phenotypes: Immunodeficiency 76, MIM# 619164, Combined immunodeficiency, T cells: low, poor proliferation, B cells: normal number, Recurrent infections (viral, mycobacteria, bacterial, fungal), lymphoproliferation, Failure to thrive, Increased activation-induced T-cell death, Defective clathrin-mediated endocytosis
Mendeliome v0.6320 FSTL5 Eleanor Williams gene: FSTL5 was added
gene: FSTL5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FSTL5 was set to Unknown
Publications for gene: FSTL5 were set to 33105483
Phenotypes for gene: FSTL5 were set to isolated club-foot; iTEV; Talipes equinovarus
Review for gene: FSTL5 was set to RED
Added comment: PMID: 33105483 - Khanshour et al 20201 - GWAS study of isolated Talipes equinovarus (clubfoot, iTEV) identified an associated locus within FSTL5. They show that Fstl5 is expressed in the embryonic hindlimb in bats, chicks and mice. However, Fstl5 was expressed more highly in neural tissues in mice, and rats lacking Fstl5 showed no gross developmental malformations. Conditional overexpression of Fstl5 in osteochondroprogenitors resulted in sexually dimorphic differences in skeletal development in mice.
Sources: Literature
Mendeliome v0.6320 NCOA3 Eleanor Williams gene: NCOA3 was added
gene: NCOA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NCOA3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NCOA3 were set to 33326993
Phenotypes for gene: NCOA3 were set to non-syndromic hearing loss
Review for gene: NCOA3 was set to RED
Added comment: PMID: 33326993 - Salazar da Silva et al 2020 - report a 5 generation Brazilian family with 15 individuals with non-syndromic, bilateral and progressive hearing loss. Using linkage analysis and then exome sequencing they identified a heterozygous variant in NCOA3 (NM_181659, c.2810C > G; p.Ser937Cys) that was found in the 7 analysed affected individuals. It was also found in 4 unaffected individuals but they are within the range of onset of hearing loss observed in the family. Expression of nco3 was found in the inner ear of mice and zebrafish. ncoa3-/- zebrafish showed subtle alterations in cartilage, mineral density and abnormal adult swimming behaviour, which may suggest the mechanism of pathogenicity.
Sources: Literature
Mendeliome v0.6320 CFHR3 Zornitza Stark Gene: cfhr3 has been classified as Green List (High Evidence).
Mendeliome v0.6317 CFHR1 Zornitza Stark Gene: cfhr1 has been classified as Green List (High Evidence).
Mendeliome v0.6312 OTUD5 Zornitza Stark Classified gene: OTUD5 as Green List (high evidence)
Mendeliome v0.6312 OTUD5 Zornitza Stark Gene: otud5 has been classified as Green List (High Evidence).
Mendeliome v0.6311 OTUD5 Zornitza Stark edited their review of gene: OTUD5: Added comment: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; Changed rating: GREEN; Changed publications: 33131077, 33523931; Changed phenotypes: Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, MIM# 301056
Mendeliome v0.6311 SCARB1 Bryony Thompson Gene: scarb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6311 SCARB1 Bryony Thompson Phenotypes for gene: SCARB1 were changed from to High density lipoprotein cholesterol level QTL6 MIM#610762; Scavenger receptor class B type I deficiency; Inherited hypolipidaemias
Mendeliome v0.6308 SCARB1 Bryony Thompson Classified gene: SCARB1 as Amber List (moderate evidence)
Mendeliome v0.6308 SCARB1 Bryony Thompson Added comment: Comment on list classification: Benign clinical phenotype
Mendeliome v0.6308 SCARB1 Bryony Thompson Gene: scarb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6307 SCARB1 Bryony Thompson reviewed gene: SCARB1: Rating: ; Mode of pathogenicity: None; Publications: 21226579, 30720493, 21480869, 26965621, 27604308; Phenotypes: High density lipoprotein cholesterol level QTL6 MIM#610762, Scavenger receptor class B type I deficiency, Inherited hypolipidaemias; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6307 CETP Bryony Thompson Gene: cetp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6307 CETP Bryony Thompson Phenotypes for gene: CETP were changed from to Hyperalphalipoproteinemia MIM#143470; Disorders of high density lipoprotein metabolism
Mendeliome v0.6304 CETP Bryony Thompson Classified gene: CETP as Amber List (moderate evidence)
Mendeliome v0.6304 CETP Bryony Thompson Added comment: Comment on list classification: Benign metabolic condition
Mendeliome v0.6304 CETP Bryony Thompson Gene: cetp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6303 CETP Bryony Thompson reviewed gene: CETP: Rating: ; Mode of pathogenicity: None; Publications: 12070157, 2586614, 27604308, 2215607, 2390095; Phenotypes: Hyperalphalipoproteinemia MIM#143470, Disorders of high density lipoprotein metabolism; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6302 DMGDH Bryony Thompson Classified gene: DMGDH as Amber List (moderate evidence)
Mendeliome v0.6302 DMGDH Bryony Thompson Gene: dmgdh has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6301 CD320 Bryony Thompson Gene: cd320 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6301 CD320 Bryony Thompson Phenotypes for gene: CD320 were changed from to Methylmalonic aciduria, transient, due to transcobalamin receptor defect MIM#613646; Disorders of cobalamin absorption, transport and metabolism
Mendeliome v0.6299 CD320 Bryony Thompson Classified gene: CD320 as Amber List (moderate evidence)
Mendeliome v0.6299 CD320 Bryony Thompson Added comment: Comment on list classification: Benign clinical condition
Mendeliome v0.6299 CD320 Bryony Thompson Gene: cd320 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6298 CD320 Bryony Thompson reviewed gene: CD320: Rating: ; Mode of pathogenicity: None; Publications: 29663633, 27604308, 30303736; Phenotypes: Methylmalonic aciduria, transient, due to transcobalamin receptor defect MIM#613646, Disorders of cobalamin absorption, transport and metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6298 SHPK Bryony Thompson Gene: shpk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6298 SHPK Bryony Thompson Classified gene: SHPK as Amber List (moderate evidence)
Mendeliome v0.6298 SHPK Bryony Thompson Added comment: Comment on list classification: Likely benign disorder
Mendeliome v0.6298 SHPK Bryony Thompson Gene: shpk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6297 SHPK Bryony Thompson gene: SHPK was added
gene: SHPK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHPK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHPK were set to 25647543; 27604308
Phenotypes for gene: SHPK were set to Sedoheptulokinase deficiency MIM#617213
Review for gene: SHPK was set to AMBER
Added comment: 2 unrelated cases reported, with elevated excretion of erythritol and sedoheptulose, and each had a homozygous nonsense variant. The first patient presented with neonatal cholestasis, hypoglycemia, and anemia, while the second patient presented with congenital arthrogryposis multiplex, multiple contractures, and dysmorphisms. Due to inconsistency in phenotypes, likely SHPK deficiency is a benign disorder.
Sources: Literature
Mendeliome v0.6296 PNLIP Bryony Thompson Gene: pnlip has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6296 PNLIP Bryony Thompson Classified gene: PNLIP as Amber List (moderate evidence)
Mendeliome v0.6296 PNLIP Bryony Thompson Added comment: Comment on list classification: Appears to be a clinically benign metabolic condition
Mendeliome v0.6296 PNLIP Bryony Thompson Gene: pnlip has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6294 TDO2 Zornitza Stark Gene: tdo2 has been classified as Red List (Low Evidence).
Mendeliome v0.6294 TDO2 Zornitza Stark gene: TDO2 was added
gene: TDO2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TDO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDO2 were set to 28285122; 27604308
Phenotypes for gene: TDO2 were set to Hypertryptophanemia MIM#600627; Disorders of histidine, tryptophan or lysine metabolism
Review for gene: TDO2 was set to RED
Added comment: Single case reported, biochemical phenotype of hypertryptophanemia and hyperserotoninemia does not appear to have significant clinical consequences
Sources: Expert list
Mendeliome v0.6293 SUGCT Zornitza Stark Gene: sugct has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6290 SUGCT Zornitza Stark Classified gene: SUGCT as Amber List (moderate evidence)
Mendeliome v0.6290 SUGCT Zornitza Stark Gene: sugct has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6289 SLC36A2 Zornitza Stark Gene: slc36a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6286 SLC36A2 Zornitza Stark Classified gene: SLC36A2 as Amber List (moderate evidence)
Mendeliome v0.6286 SLC36A2 Zornitza Stark Gene: slc36a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6285 SARDH Zornitza Stark Gene: sardh has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6285 SARDH Zornitza Stark Phenotypes for gene: SARDH were changed from to Sarcosinemia MIM#268900; Disorders of serine, glycine or glycerate metabolism
Mendeliome v0.6282 SARDH Zornitza Stark Classified gene: SARDH as Amber List (moderate evidence)
Mendeliome v0.6282 SARDH Zornitza Stark Gene: sardh has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6281 SARDH Zornitza Stark reviewed gene: SARDH: Rating: AMBER; Mode of pathogenicity: None; Publications: 22825317, 27604308; Phenotypes: Sarcosinemia MIM#268900, Disorders of serine, glycine or glycerate metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6281 OPLAH Zornitza Stark Gene: oplah has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6278 OPLAH Zornitza Stark Classified gene: OPLAH as Amber List (moderate evidence)
Mendeliome v0.6278 OPLAH Zornitza Stark Gene: oplah has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6277 KHK Zornitza Stark Gene: khk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6274 KHK Zornitza Stark Classified gene: KHK as Amber List (moderate evidence)
Mendeliome v0.6274 KHK Zornitza Stark Gene: khk has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6273 HAL Zornitza Stark Gene: hal has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6273 HAL Zornitza Stark Phenotypes for gene: HAL were changed from to Histidinemia MIM#235800; Disorders of histidine, tryptophan or lysine metabolism
Mendeliome v0.6270 HAL Zornitza Stark Classified gene: HAL as Amber List (moderate evidence)
Mendeliome v0.6270 HAL Zornitza Stark Gene: hal has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6269 HAL Zornitza Stark reviewed gene: HAL: Rating: AMBER; Mode of pathogenicity: None; Publications: 27604308, 15806399, 20156889; Phenotypes: Histidinemia MIM#235800, Disorders of histidine, tryptophan or lysine metabolism; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6268 GGT1 Zornitza Stark Classified gene: GGT1 as Amber List (moderate evidence)
Mendeliome v0.6268 GGT1 Zornitza Stark Gene: ggt1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6267 DCXR Zornitza Stark Gene: dcxr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6267 DCXR Zornitza Stark Classified gene: DCXR as Amber List (moderate evidence)
Mendeliome v0.6267 DCXR Zornitza Stark Gene: dcxr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6265 CTH Zornitza Stark Gene: cth has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6262 CTH Zornitza Stark Classified gene: CTH as Amber List (moderate evidence)
Mendeliome v0.6262 CTH Zornitza Stark Gene: cth has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6261 ACSF3 Zornitza Stark Gene: acsf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6258 ACSF3 Zornitza Stark Classified gene: ACSF3 as Amber List (moderate evidence)
Mendeliome v0.6258 ACSF3 Zornitza Stark Gene: acsf3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6257 PHGDH Zornitza Stark Gene: phgdh has been classified as Green List (High Evidence).
Mendeliome v0.6253 PNP Zornitza Stark Gene: pnp has been classified as Green List (High Evidence).
Mendeliome v0.6253 PNP Zornitza Stark Phenotypes for gene: PNP were changed from to Immunodeficiency due to purine nucleoside phosphorylase deficiency, MIM# 613179
Mendeliome v0.6250 PNP Zornitza Stark reviewed gene: PNP: Rating: GREEN; Mode of pathogenicity: None; Publications: 3029074, 1384322, 11453975, 32695102, 32514656; Phenotypes: Immunodeficiency due to purine nucleoside phosphorylase deficiency, MIM# 613179; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6250 PNPLA2 Zornitza Stark Gene: pnpla2 has been classified as Green List (High Evidence).
Mendeliome v0.6247 ESRP2 Zornitza Stark Gene: esrp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6244 ESRP2 Zornitza Stark Classified gene: ESRP2 as Amber List (moderate evidence)
Mendeliome v0.6244 ESRP2 Zornitza Stark Gene: esrp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6243 ACBD5 Zornitza Stark Gene: acbd5 has been classified as Green List (High Evidence).
Mendeliome v0.6240 SAR1B Zornitza Stark Gene: sar1b has been classified as Green List (High Evidence).
Mendeliome v0.6237 SC5D Zornitza Stark Gene: sc5d has been classified as Green List (High Evidence).
Mendeliome v0.6237 SC5D Zornitza Stark Phenotypes for gene: SC5D were changed from to Lathosterolosis, MIM# 607330
Mendeliome v0.6234 SC5D Zornitza Stark reviewed gene: SC5D: Rating: GREEN; Mode of pathogenicity: None; Publications: 17853487, 12189593, 12812989, 24142275; Phenotypes: Lathosterolosis, MIM# 607330; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6234 SLC39A14 Zornitza Stark Gene: slc39a14 has been classified as Green List (High Evidence).
Mendeliome v0.6231 SLC46A1 Zornitza Stark Gene: slc46a1 has been classified as Green List (High Evidence).
Mendeliome v0.6228 SLC46A1 Zornitza Stark changed review comment from: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system. More than 5 unrelated families reported.; to: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhoea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system. More than 5 unrelated families reported.
Mendeliome v0.6228 ST3GAL3 Zornitza Stark Gene: st3gal3 has been classified as Green List (High Evidence).
Mendeliome v0.6228 ST3GAL3 Zornitza Stark Phenotypes for gene: ST3GAL3 were changed from to Mental retardation, autosomal recessive 12 MIM# 611090
Mendeliome v0.6225 ST3GAL3 Zornitza Stark reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23252400, 21907012, 31584066; Phenotypes: Mental retardation, autosomal recessive 12 MIM# 611090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6221 DDX58 Zornitza Stark edited their review of gene: DDX58: Added comment: Prasov et al. 2021 (PMID: 33495304) - A heterozygous DDX58 variant (c.1529A>T) was identified in 5 individuals from 2 unrelated families from different ethnic backgrounds. Phenotypes varied with some being severely affected by systemic features and others solely with glaucoma.Functional analysis demonstrated the variant confers a dominant gain-of-function effect on interferon activity.; Changed mode of pathogenicity: Other; Changed publications: 25620203, 33495304
Mendeliome v0.6221 KL Bryony Thompson Gene: kl has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6220 KL Bryony Thompson Phenotypes for gene: KL were changed from to Tumoral calcinosis, hyperphosphatemic, familial, 3 MIM#617994; Hyperphosphatemia
Mendeliome v0.6219 KL Bryony Thompson Classified gene: KL as Amber List (moderate evidence)
Mendeliome v0.6219 KL Bryony Thompson Gene: kl has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6218 KL Bryony Thompson reviewed gene: KL: Rating: AMBER; Mode of pathogenicity: None; Publications: 17710231, 31013726, 9363890; Phenotypes: Tumoral calcinosis, hyperphosphatemic, familial, 3 MIM#617994, Hyperphosphatemia; Mode of inheritance: None
Mendeliome v0.6218 GLRX2 Bryony Thompson Gene: glrx2 has been classified as Red List (Low Evidence).
Mendeliome v0.6218 GLRX2 Bryony Thompson Classified gene: GLRX2 as Red List (low evidence)
Mendeliome v0.6218 GLRX2 Bryony Thompson Gene: glrx2 has been classified as Red List (Low Evidence).
Mendeliome v0.6217 GLRX3 Bryony Thompson Classified gene: GLRX3 as Red List (low evidence)
Mendeliome v0.6217 GLRX3 Bryony Thompson Gene: glrx3 has been classified as Red List (Low Evidence).
Mendeliome v0.6216 GSTO2 Bryony Thompson Gene: gsto2 has been classified as Red List (Low Evidence).
Mendeliome v0.6216 GSTO2 Bryony Thompson Classified gene: GSTO2 as Red List (low evidence)
Mendeliome v0.6216 GSTO2 Bryony Thompson Gene: gsto2 has been classified as Red List (Low Evidence).
Mendeliome v0.6215 SIX1 Zornitza Stark changed review comment from: DEFINITIVE by ClinGen. Variable expressivity, some families reported with isolated deafness, however this likely represents a spectrum rather than a separate disorder.; to: Deafness/BOS: DEFINITIVE by ClinGen. Variable expressivity, some families reported with isolated deafness, however this likely represents a spectrum rather than a separate disorder.
Mendeliome v0.6215 SIX1 Zornitza Stark Phenotypes for gene: SIX1 were changed from Deafness, autosomal dominant 23, MIM# 605192; Branchiootic syndrome 3, MIM# 608389 to Deafness, autosomal dominant 23, MIM# 605192; Branchiootic syndrome 3, MIM# 608389; Sagittal synostosis; Multi-suture synostosis
Mendeliome v0.6214 SIX1 Zornitza Stark Publications for gene: SIX1 were set to 15141091; 18330911; 21254961; 17637804; 29500469; 21700001; 24164807
Mendeliome v0.6213 BMP7 Zornitza Stark Phenotypes for gene: BMP7 were changed from Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract to Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract; Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS)
Mendeliome v0.6211 BMP7 Zornitza Stark changed review comment from: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis

CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT.
Sources: Literature; to: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis

CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT.
Sources: Literature

PMID 33434492: Two individuals with likely deleterious variants identified in a cohort of individuals with MRKHS.
Mendeliome v0.6211 BMP7 Zornitza Stark edited their review of gene: BMP7: Changed phenotypes: Non-syndromic metopic craniosynostosis, Congenital abnormalities of the kidneys and urinary tract, Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS)
Mendeliome v0.6211 BMP7 Zornitza Stark Phenotypes for gene: BMP7 were changed from Non-syndromic metopic craniosynostosis to Non-syndromic metopic craniosynostosis; Congenital abnormalities of the kidneys and urinary tract
Mendeliome v0.6210 BMP7 Zornitza Stark edited their review of gene: BMP7: Changed phenotypes: Non-syndromic metopic craniosynostosis, Congenital abnormalities of the kidneys and urinary tract
Mendeliome v0.6210 SIX1 Arina Puzriakova reviewed gene: SIX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33436522; Phenotypes: Sagittal synostosis, Multi-suture synostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6210 WBP11 Zornitza Stark Gene: wbp11 has been classified as Green List (High Evidence).
Mendeliome v0.6210 WBP11 Zornitza Stark Classified gene: WBP11 as Green List (high evidence)
Mendeliome v0.6210 WBP11 Zornitza Stark Gene: wbp11 has been classified as Green List (High Evidence).
Mendeliome v0.6208 CLRN2 Zornitza Stark Gene: clrn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6208 CLRN2 Zornitza Stark Phenotypes for gene: CLRN2 were changed from Non-syndromic hearing loss to Non-syndromic hearing loss; Deafness, autosomal recessive 117, MIM# 619174
Mendeliome v0.6207 WBP11 Eleanor Williams gene: WBP11 was added
gene: WBP11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WBP11 were set to 33276377
Phenotypes for gene: WBP11 were set to malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems
Review for gene: WBP11 was set to GREEN
Added comment: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies.
Sources: Literature
Mendeliome v0.6207 TTF2 Zornitza Stark Gene: ttf2 has been classified as Red List (Low Evidence).
Mendeliome v0.6207 TTF2 Zornitza Stark gene: TTF2 was added
gene: TTF2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: TTF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TTF2 were set to 30022773
Phenotypes for gene: TTF2 were set to congenital hypothyroidism, thyroid dysgenesis, No OMIM #
Review for gene: TTF2 was set to RED
Added comment: 1 case only
Sources: Expert Review
Mendeliome v0.6206 DUOXA1 Zornitza Stark Gene: duoxa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6206 DUOXA1 Zornitza Stark Classified gene: DUOXA1 as Amber List (moderate evidence)
Mendeliome v0.6206 DUOXA1 Zornitza Stark Gene: duoxa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6204 DUOX1 Zornitza Stark Gene: duox1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6204 DUOX1 Zornitza Stark Classified gene: DUOX1 as Amber List (moderate evidence)
Mendeliome v0.6204 DUOX1 Zornitza Stark Gene: duox1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6202 TTF1 Zornitza Stark Gene: ttf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6202 TTF1 Zornitza Stark Phenotypes for gene: TTF1 were changed from to congenital hypothyroidism, thyroid dysgenesis, No OMIM #
Mendeliome v0.6199 TTF1 Zornitza Stark Classified gene: TTF1 as Amber List (moderate evidence)
Mendeliome v0.6199 TTF1 Zornitza Stark Gene: ttf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6198 TTF1 Zornitza Stark reviewed gene: TTF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30022773; Phenotypes: congenital hypothyroidism, thyroid dysgenesis, No OMIM #; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6198 CDCA8 Zornitza Stark Gene: cdca8 has been classified as Green List (High Evidence).
Mendeliome v0.6198 CDCA8 Zornitza Stark Classified gene: CDCA8 as Green List (high evidence)
Mendeliome v0.6198 CDCA8 Zornitza Stark Gene: cdca8 has been classified as Green List (High Evidence).
Mendeliome v0.6197 CDCA8 Zornitza Stark gene: CDCA8 was added
gene: CDCA8 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CDCA8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CDCA8 were set to 28025328; 29546359
Phenotypes for gene: CDCA8 were set to Congenital hypothyroidism, thyroid dysgenesis, no OMIM #
Mode of pathogenicity for gene: CDCA8 was set to Other
Review for gene: CDCA8 was set to GREEN
Added comment: 4 families (1 with bilallelic variants [parent affected as HTZ], 3 with monoallelic variants) with functional evidence of variants. GREEN for mono allelic, RED for biallelic.
Sources: Expert Review
Mendeliome v0.6196 DNAJC30 Zornitza Stark Gene: dnajc30 has been classified as Green List (High Evidence).
Mendeliome v0.6196 DNAJC30 Zornitza Stark Classified gene: DNAJC30 as Green List (high evidence)
Mendeliome v0.6196 DNAJC30 Zornitza Stark Gene: dnajc30 has been classified as Green List (High Evidence).
Mendeliome v0.6195 DNAJC30 Zornitza Stark gene: DNAJC30 was added
gene: DNAJC30 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAJC30 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC30 were set to 33465056
Phenotypes for gene: DNAJC30 were set to Leber Hereditary Optic Neuropathy
Review for gene: DNAJC30 was set to GREEN
Added comment: 33 individuals from 29 families had homozygous DNAJC30 missense variants. Three different variants identified (one responsible for most cases). All three variants absent from gnomAD. Incomplete penetrance and male predominance in affected individuals both typical of LHON due to mtDNA mutations. All 3 variants in the J domain of the protein. Functional evidence.
Sources: Literature
Mendeliome v0.6194 NFS1 Zornitza Stark Classified gene: NFS1 as Green List (high evidence)
Mendeliome v0.6194 NFS1 Zornitza Stark Gene: nfs1 has been classified as Green List (High Evidence).
Mendeliome v0.6192 SLC7A6OS Zornitza Stark Gene: slc7a6os has been classified as Red List (Low Evidence).
Mendeliome v0.6192 SLC7A6OS Zornitza Stark gene: SLC7A6OS was added
gene: SLC7A6OS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC7A6OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC7A6OS were set to 33085104
Phenotypes for gene: SLC7A6OS were set to Progressive myoclonus epilepsy
Review for gene: SLC7A6OS was set to RED
Added comment: Two unrelated families reported with same homozygous splice site variant, shared haplotype (founder effect). Limited functional data.
Sources: Literature
Mendeliome v0.6191 TLR8 Zornitza Stark Gene: tlr8 has been classified as Green List (High Evidence).
Mendeliome v0.6191 TLR8 Zornitza Stark Classified gene: TLR8 as Green List (high evidence)
Mendeliome v0.6191 TLR8 Zornitza Stark Gene: tlr8 has been classified as Green List (High Evidence).
Mendeliome v0.6190 TLR8 Zornitza Stark gene: TLR8 was added
gene: TLR8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TLR8 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TLR8 were set to 33512449
Phenotypes for gene: TLR8 were set to Immunodeficiency; bone marrow failure
Mode of pathogenicity for gene: TLR8 was set to Other
Review for gene: TLR8 was set to GREEN
Added comment: Six unrelated males reported with a phenotype comprising neutropaenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure. Three different variants reported, the variant was somatic in 5/6 individuals. GoF mechanism demonstrated.
Sources: Literature
Mendeliome v0.6189 PIGF Zornitza Stark Gene: pigf has been classified as Red List (Low Evidence).
Mendeliome v0.6189 PIGF Zornitza Stark Classified gene: PIGF as Red List (low evidence)
Mendeliome v0.6189 PIGF Zornitza Stark Gene: pigf has been classified as Red List (Low Evidence).
Mendeliome v0.6188 BRWD1 Zornitza Stark Gene: brwd1 has been classified as Green List (High Evidence).
Mendeliome v0.6188 BRWD1 Zornitza Stark Classified gene: BRWD1 as Green List (high evidence)
Mendeliome v0.6188 BRWD1 Zornitza Stark Gene: brwd1 has been classified as Green List (High Evidence).
Mendeliome v0.6187 PIGF Paul De Fazio changed review comment from: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature; to: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness - only one of the two had seizures (GTCS), the other was 14mo and noted to have tonic posturing.

Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated by flow cytometry and a rescue assay. Alkaline phosphatase in both individuals was normal.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature
Mendeliome v0.6187 PIGF Paul De Fazio edited their review of gene: PIGF: Changed phenotypes: Glycosylphosphatidylinositol deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures
Mendeliome v0.6187 PIGF Paul De Fazio changed review comment from: The same missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature; to: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature
Mendeliome v0.6187 PIGF Paul De Fazio changed review comment from: Identified in 2 individuals with a phenotype similar to DOORS (syndrome
Sources: Literature; to: The same missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated.

Rated Red as the two families are likely to be related (founder mutation?).
Sources: Literature
Mendeliome v0.6187 PIGF Paul De Fazio gene: PIGF was added
gene: PIGF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PIGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGF were set to 33386993
Phenotypes for gene: PIGF were set to Glycosylphosphatidylinositol\ deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures
Review for gene: PIGF was set to RED
gene: PIGF was marked as current diagnostic
Added comment: Identified in 2 individuals with a phenotype similar to DOORS (syndrome
Sources: Literature
Mendeliome v0.6187 BRWD1 Paul De Fazio gene: BRWD1 was added
gene: BRWD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BRWD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRWD1 were set to 33389130
Phenotypes for gene: BRWD1 were set to Asthenoteratozoospermia, likely primary ciliary dyskinesia
Review for gene: BRWD1 was set to GREEN
gene: BRWD1 was marked as current diagnostic
Added comment: Biallelic missense variants reported in 3 unrelated individuals. Apart from asthenoteratozoospermia, all 3 had PCD or "PCD-likely" symptoms of re-occurring airway infections, bronchiectasis, and rhinosinusitis. One individual had situs inversus. Studies on cells from one indivdidual showed abnormal respiratory cilia structure. BRWD1 staining was absent from respiratory cilia in this individual (present in controls).

Rated Green as there are three unrelated individuals reported.
Sources: Literature
Mendeliome v0.6187 HIRA Zornitza Stark Gene: hira has been classified as Green List (High Evidence).
Mendeliome v0.6187 HIRA Zornitza Stark Classified gene: HIRA as Green List (high evidence)
Mendeliome v0.6187 HIRA Zornitza Stark Gene: hira has been classified as Green List (High Evidence).
Mendeliome v0.6186 EYA3 Zornitza Stark Gene: eya3 has been classified as Red List (Low Evidence).
Mendeliome v0.6186 EYA3 Zornitza Stark Classified gene: EYA3 as Red List (low evidence)
Mendeliome v0.6186 EYA3 Zornitza Stark Gene: eya3 has been classified as Red List (Low Evidence).
Mendeliome v0.6185 CLRN2 Zornitza Stark Classified gene: CLRN2 as Amber List (moderate evidence)
Mendeliome v0.6185 CLRN2 Zornitza Stark Gene: clrn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6184 POLR3B Zornitza Stark Gene: polr3b has been classified as Green List (High Evidence).
Mendeliome v0.6181 CFAP47 Zornitza Stark Gene: cfap47 has been classified as Green List (High Evidence).
Mendeliome v0.6181 CFAP47 Zornitza Stark Classified gene: CFAP47 as Green List (high evidence)
Mendeliome v0.6181 CFAP47 Zornitza Stark Gene: cfap47 has been classified as Green List (High Evidence).
Mendeliome v0.6180 C14orf39 Zornitza Stark Gene: c14orf39 has been classified as Green List (High Evidence).
Mendeliome v0.6180 C14orf39 Zornitza Stark Classified gene: C14orf39 as Green List (high evidence)
Mendeliome v0.6180 C14orf39 Zornitza Stark Gene: c14orf39 has been classified as Green List (High Evidence).
Mendeliome v0.6179 ENO1 Zornitza Stark Gene: eno1 has been classified as Red List (Low Evidence).
Mendeliome v0.6179 ENO1 Zornitza Stark Classified gene: ENO1 as Red List (low evidence)
Mendeliome v0.6179 ENO1 Zornitza Stark Gene: eno1 has been classified as Red List (Low Evidence).
Mendeliome v0.6178 HEY2 Zornitza Stark gene: HEY2 was added
gene: HEY2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HEY2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: HEY2 were set to 32820247
Phenotypes for gene: HEY2 were set to congenital heart defects and thoracic aortic aneurysms
Review for gene: HEY2 was set to RED
Added comment: A very large family affected by CHD and familial thoracic aortic aneurysms. Trio genome sequencing was carried out in an index patient with critical CHD, and family members had either exome or Sanger sequencing. Identified homozygous loss-of-function variant (c.318_319delAG, p.G108*) in HEY2 in 3 individuals in family with critical CHD, whereas the 20 heterozygous carriers show a spectrum of CVDs (CHD and FTAA, but varying expressivity and incomplete penetrance). Other studies show that knockout of HEY2 in mice results in cardiovascular defects (CVDs), including septal defects, cardiomyopathy, a thin-walled aorta, and valve anomalies.
Sources: Literature
Mendeliome v0.6177 FGF9 Zornitza Stark edited their review of gene: FGF9: Changed phenotypes: Multiple synostoses syndrome 3, OMIM # 612961, Craniosynostosis
Mendeliome v0.6177 FGF9 Zornitza Stark Gene: fgf9 has been classified as Green List (High Evidence).
Mendeliome v0.6177 FGF9 Zornitza Stark Phenotypes for gene: FGF9 were changed from to Multiple synostoses syndrome 3, OMIM # 612961; Craniosynostosis
Mendeliome v0.6174 OTUD5 Zornitza Stark Gene: otud5 has been classified as Red List (Low Evidence).
Mendeliome v0.6174 OTUD5 Zornitza Stark gene: OTUD5 was added
gene: OTUD5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OTUD5 were set to 33131077
Phenotypes for gene: OTUD5 were set to X-linked severe neurodevelopmental delay, hydrocephalus, and early lethality
Review for gene: OTUD5 was set to RED
Added comment: 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with IUGR, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. WGS in four individuals identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals. No functional studies.
Sources: Literature
Mendeliome v0.6173 BCAT2 Bryony Thompson Gene: bcat2 has been classified as Green List (High Evidence).
Mendeliome v0.6173 BCAT2 Bryony Thompson Classified gene: BCAT2 as Green List (high evidence)
Mendeliome v0.6173 BCAT2 Bryony Thompson Gene: bcat2 has been classified as Green List (High Evidence).
Mendeliome v0.6172 BCAT2 Bryony Thompson changed review comment from: A single case reported with compound heterozygous variants with functional studies demonstrating that the two variants resulted in decreased BCAT2 enzyme activity. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS; to: 6 cases from 5 unrelated families with homozygous or compound heterozygous variant, and supporting functional studies demonstrating decreased BCAT2 enzyme activity for some of the variants. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS
Mendeliome v0.6172 BCAT2 Bryony Thompson gene: BCAT2 was added
gene: BCAT2 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: BCAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAT2 were set to 14755340; 25653144
Phenotypes for gene: BCAT2 were set to Hypervalinemia or hyperleucine-isoleucinemia MIM#618850; disorder of branched-chain amino acid metabolism
Review for gene: BCAT2 was set to AMBER
Added comment: A single case reported with compound heterozygous variants with functional studies demonstrating that the two variants resulted in decreased BCAT2 enzyme activity. Also, a null mouse model has a phenotype similar to human maple syrup urine disease.
Sources: NHS GMS
Mendeliome v0.6170 KCNN2 Sebastian Lunke Gene: kcnn2 has been classified as Green List (High Evidence).
Mendeliome v0.6169 SATB1 Zornitza Stark Classified gene: SATB1 as Green List (high evidence)
Mendeliome v0.6169 SATB1 Zornitza Stark Gene: satb1 has been classified as Green List (High Evidence).
Mendeliome v0.6168 KCNN2 Sebastian Lunke Classified gene: KCNN2 as Green List (high evidence)
Mendeliome v0.6168 KCNN2 Sebastian Lunke Gene: kcnn2 has been classified as Green List (High Evidence).
Mendeliome v0.6167 ENO1 Kristin Rigbye gene: ENO1 was added
gene: ENO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ENO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ENO1 were set to 32488097
Phenotypes for gene: ENO1 were set to Polymicrogyria
Review for gene: ENO1 was set to RED
Added comment: ENO1 identified as a polymicrogyria candidate gene from the smallest case of 1p36 duplication reported to date, in a 35yo F (onset at 8mo) presenting intellectual disability, microcephaly, epilepsy and perisylvian polymicrogyria. The duplication only encompassed 2 genes, ENO1 and RERE, and gene expression analysis performed using the patient cells revealed reduced expression, mimicking haploinsufficiency. Eno1 inactivation in rats was shown to cause a brain development defect. According to OMIM, ENO1 is deleted in glioblastoma, which is tolerated by the expression of ENO2.
Sources: Literature
Mendeliome v0.6167 METAP1 Zornitza Stark Gene: metap1 has been classified as Red List (Low Evidence).
Mendeliome v0.6167 METAP1 Zornitza Stark Classified gene: METAP1 as Red List (low evidence)
Mendeliome v0.6167 METAP1 Zornitza Stark Gene: metap1 has been classified as Red List (Low Evidence).
Mendeliome v0.6166 METAP1 Paul De Fazio gene: METAP1 was added
gene: METAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: METAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METAP1 were set to PMID: 32764695
Phenotypes for gene: METAP1 were set to Intellectual disability, aggression, neurodevelopmental delay
Review for gene: METAP1 was set to RED
gene: METAP1 was marked as current diagnostic
Added comment: Biallelic nonsense (NMD-predicted) variant identified in 4 sibs in a consanguineous family with dev delay. One sib had bilateral clinodactyly of her toes and her left 3rd finger, other sibs were not dysmorphic. Rated red due to single consanguineous family.
Sources: Literature
Mendeliome v0.6166 MYADML2 Zornitza Stark Gene: myadml2 has been classified as Red List (Low Evidence).
Mendeliome v0.6166 MYADML2 Zornitza Stark Classified gene: MYADML2 as Red List (low evidence)
Mendeliome v0.6166 MYADML2 Zornitza Stark Gene: myadml2 has been classified as Red List (Low Evidence).
Mendeliome v0.6165 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Red List (Low Evidence).
Mendeliome v0.6164 KCNN2 Ain Roesley gene: KCNN2 was added
gene: KCNN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNN2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNN2 were set to 33242881
Phenotypes for gene: KCNN2 were set to neurodevelopmental movement disorders
Penetrance for gene: KCNN2 were set to unknown
Review for gene: KCNN2 was set to GREEN
Added comment: - 11 probands all de novo except for 1 mother-daughter pair.
- a mix of null and missense variants
- 2/11 with microcephaly, 10/11 motor delay, 7/11 language delay (excluding 2 with regression), all with varying degrees of ID, 3/11 seizures, 7/11 movement disorder, 4/11 cerebellar ataxia, 6/11 MRI anomalies

additional variants were noted in 2 patients: 1x cHet for variants in MED12L and 1x de novo TNK2 variant

patch clamp functional studies were also done
Sources: Literature
Mendeliome v0.6164 MYADML2 Paul De Fazio gene: MYADML2 was added
gene: MYADML2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYADML2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYADML2 were set to 32778762
Phenotypes for gene: MYADML2 were set to Cranial asymmetry, reduced bone maturation, multiple dislocations, lumbar lordosis, and prominent clavicles
Review for gene: MYADML2 was set to RED
gene: MYADML2 was marked as current diagnostic
Added comment: 5 sibs from a consanguineous family identified to have biallelic deletion encompassing part of the PYCR1 gene and the coding region of the MYADML2 gene.

According to the authors: "All five affected sibs had the most common features of ARCL (autosomal recessive cutis laxa) but not many of the less common ones. We attributed the anomalies not typical for ARCL to MYADML2 deficit, because no other genetic defect possibly a candidate to underlie the skeletal phenotype was found."

Phenotype may still be explained by the PYCR1 deletion alone.
Sources: Literature
Mendeliome v0.6163 HYAL2 Zornitza Stark Gene: hyal2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6163 HYAL2 Zornitza Stark Classified gene: HYAL2 as Amber List (moderate evidence)
Mendeliome v0.6163 HYAL2 Zornitza Stark Gene: hyal2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6161 SLC6A20 Zornitza Stark Gene: slc6a20 has been classified as Green List (High Evidence).
Mendeliome v0.6158 SUOX Zornitza Stark Gene: suox has been classified as Green List (High Evidence).
Mendeliome v0.6155 PDE2A Zornitza Stark Phenotypes for gene: PDE2A were changed from Paroxysmal dyskinesia to Paroxysmal dyskinesia; Intellectual developmental disorder with paroxysmal dyskinesia or seizures, MIM# 619150Intellectual developmental disorder with paroxysmal dyskinesia or seizures, MIM# 619150
Mendeliome v0.6154 ADH5 Zornitza Stark Phenotypes for gene: ADH5 were changed from Aplastic anaemia; myelodysplasia; short stature to AMED syndrome, digenic, MIM# 619151; Aplastic anaemia; myelodysplasia; short stature
Mendeliome v0.6153 ADH5 Zornitza Stark edited their review of gene: ADH5: Changed phenotypes: AMED syndrome, digenic, MIM# 619151, Aplastic anaemia, myelodysplasia, short stature
Mendeliome v0.6153 PDE2A Zornitza Stark edited their review of gene: PDE2A: Changed phenotypes: Paroxysmal dyskinesia, Intellectual developmental disorder with paroxysmal dyskinesia or seizures, MIM# 619150Intellectual developmental disorder with paroxysmal dyskinesia or seizures, MIM# 619150
Mendeliome v0.6153 PRDM13 Zornitza Stark Phenotypes for gene: PRDM13 were changed from Retinal dystrophy to Retinal dystrophy; Chorioretinal atrophy, progressive bifocal, MIM# 600790
Mendeliome v0.6152 PRDM13 Zornitza Stark edited their review of gene: PRDM13: Changed phenotypes: Retinal dystrophy, Chorioretinal atrophy, progressive bifocal, MIM# 600790
Mendeliome v0.6150 NOS1AP Zornitza Stark Classified gene: NOS1AP as Green List (high evidence)
Mendeliome v0.6150 NOS1AP Zornitza Stark Gene: nos1ap has been classified as Green List (High Evidence).
Mendeliome v0.6149 NOS1AP Zornitza Stark edited their review of gene: NOS1AP: Added comment: Nephrotic syndrome type 22 (NPHS22) is an autosomal recessive renal disease characterized by onset of progressive kidney dysfunction in infancy. Affected individuals usually present with edema associated with hypoproteinemia, proteinuria, and microscopic hematuria. Renal biopsy shows effacement of the podocyte foot processes, glomerulosclerosis, and thickening of the glomerular basement membrane. The disease is steroid-resistant and progressive, resulting in end-stage renal disease usually necessitating kidney transplant.

Two unrelated families and animal model.

No PMID yet: https://advances.sciencemag.org/content/7/1/eabe1386; Changed rating: GREEN; Changed phenotypes: Nephrotic syndrome, type 22, MIM# 619155; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6148 DCT Zornitza Stark Gene: dct has been classified as Green List (High Evidence).
Mendeliome v0.6148 DCT Zornitza Stark Classified gene: DCT as Green List (high evidence)
Mendeliome v0.6148 DCT Zornitza Stark Gene: dct has been classified as Green List (High Evidence).
Mendeliome v0.6146 SDHAF1 Zornitza Stark Gene: sdhaf1 has been classified as Green List (High Evidence).
Mendeliome v0.6142 NDUFC2 Zornitza Stark Gene: ndufc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6142 NDUFC2 Zornitza Stark Classified gene: NDUFC2 as Amber List (moderate evidence)
Mendeliome v0.6142 NDUFC2 Zornitza Stark Gene: ndufc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6141 NDUFC2 Zornitza Stark gene: NDUFC2 was added
gene: NDUFC2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NDUFC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFC2 were set to 32969598
Phenotypes for gene: NDUFC2 were set to Mitochondrial complex I deficiency, nuclear type 36, MIM# 619170
Review for gene: NDUFC2 was set to AMBER
Added comment: Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome. Two unrelated families reported, some functional data.
Sources: Expert list
Mendeliome v0.6140 UPB1 Zornitza Stark Gene: upb1 has been classified as Green List (High Evidence).
Mendeliome v0.6137 UROC1 Zornitza Stark Gene: uroc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6134 UROC1 Zornitza Stark Classified gene: UROC1 as Amber List (moderate evidence)
Mendeliome v0.6134 UROC1 Zornitza Stark Gene: uroc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6133 DLX4 Zornitza Stark Gene: dlx4 has been classified as Red List (Low Evidence).
Mendeliome v0.6133 DLX4 Zornitza Stark gene: DLX4 was added
gene: DLX4 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DLX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DLX4 were set to 25954033; 29738288
Phenotypes for gene: DLX4 were set to Orofacial cleft 15, MIM# 616788
Review for gene: DLX4 was set to RED
Added comment: Single family reported and a SNP association study.
Sources: Expert list
Mendeliome v0.6132 DLG1 Zornitza Stark Gene: dlg1 has been classified as Red List (Low Evidence).
Mendeliome v0.6132 DLG1 Zornitza Stark gene: DLG1 was added
gene: DLG1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DLG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DLG1 were set to 28926086
Phenotypes for gene: DLG1 were set to Non-syndromic cleft lip and palate
Review for gene: DLG1 was set to RED
Added comment: GWAS study PMID: 28926086 found genome-wide significance for several SNPs within this gene, identifying it as a candidate gene for non-syndromic cleft lip with or without cleft palate.
Sources: Expert list
Mendeliome v0.6131 PLEKHA7 Zornitza Stark Gene: plekha7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6128 PLEKHA7 Zornitza Stark Classified gene: PLEKHA7 as Amber List (moderate evidence)
Mendeliome v0.6128 PLEKHA7 Zornitza Stark Gene: plekha7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6127 GYS2 Zornitza Stark Gene: gys2 has been classified as Green List (High Evidence).
Mendeliome v0.6123 OPA3 Zornitza Stark Gene: opa3 has been classified as Green List (High Evidence).
Mendeliome v0.6119 FOXF1 Zornitza Stark changed review comment from: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity. Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period. Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs.; to: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity. Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period. Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs.

Over 50 families reported.
Mendeliome v0.6119 FOXF1 Zornitza Stark Gene: foxf1 has been classified as Green List (High Evidence).
Mendeliome v0.6119 FOXF1 Zornitza Stark Phenotypes for gene: FOXF1 were changed from to Alveolar capillary dysplasia with misalignment of pulmonary veins, MIM# 265380
Mendeliome v0.6116 FOXF1 Zornitza Stark reviewed gene: FOXF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19500772, 23505205; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins, MIM# 265380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6116 FOXF1 Kristin Rigbye reviewed gene: FOXF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23505205, 27071622, 27855150; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins (MIM#265380), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6116 STEAP3 Zornitza Stark Gene: steap3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6113 STEAP3 Zornitza Stark Classified gene: STEAP3 as Amber List (moderate evidence)
Mendeliome v0.6113 STEAP3 Zornitza Stark Gene: steap3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6112 FTH1 Zornitza Stark Gene: fth1 has been classified as Red List (Low Evidence).
Mendeliome v0.6112 FTH1 Zornitza Stark gene: FTH1 was added
gene: FTH1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FTH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FTH1 were set to 11389486
Phenotypes for gene: FTH1 were set to Hemochromatosis, type 5, MIM# 615517
Review for gene: FTH1 was set to RED
Added comment: One multi-generational family with 5' UTR variant.
Sources: Expert list
Mendeliome v0.6111 CYBRD1 Zornitza Stark Gene: cybrd1 has been classified as Red List (Low Evidence).
Mendeliome v0.6110 BMP6 Zornitza Stark Gene: bmp6 has been classified as Green List (High Evidence).
Mendeliome v0.6110 BMP6 Zornitza Stark Classified gene: BMP6 as Green List (high evidence)
Mendeliome v0.6110 BMP6 Zornitza Stark Gene: bmp6 has been classified as Green List (High Evidence).
Mendeliome v0.6108 CREB3L3 Bryony Thompson Classified gene: CREB3L3 as Amber List (moderate evidence)
Mendeliome v0.6108 CREB3L3 Bryony Thompson Gene: creb3l3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6107 CREB3L3 Bryony Thompson gene: CREB3L3 was added
gene: CREB3L3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CREB3L3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CREB3L3 were set to 32580631; 29954705; 27982131; 27291420; 26427795; 21666694
Phenotypes for gene: CREB3L3 were set to Hyperlipidaemia; hypertriglyceridemia
Review for gene: CREB3L3 was set to AMBER
Added comment: PMID: 26427795 - a loss of function variant (c.359delG p.K120fsX20) was identified in 2 affected adult siblings and a 13 yo normotriglyceridemic daughter of one of the siblings.
PMID: 21666694 - Lipoprotein profiles of the families of 4 individuals with CREB3L3 nonsense mutations showed a significantly elevated mean plasma TG level in 11 mutation carriers compared with 5 non-carrier first-degree relatives (9.67 ± 4.70 vs. 1.66 ± 0.55 mM, P = 0.021, Wilcoxon test). 3 of those families have the same variant - Lys245GlufsTer130, which has 126 (281,946 alleles) hets in gnomAD v2.1.
PMID: 32580631 - case-control analysis of nonmonogenic severe hypertriglyceridemia cases (N=265) vs normolipidemic controls (N=477), identified 5 cases with LoF variants (3 of whom had the Lys245GlufsTer130 frameshift) and none in controls. OR 20.2 (95% CI 1.11–366.1) p = 0.002, adjusted p = 0.03.
The frequency of Lys245GlufsTer130 is higher than expected for a dominant disorder, but other loss of function variants have been identified. The gene may be associated with variable penetrance. There are multiple supporting null mouse models with hyperlipidaemia.
Sources: Expert list
Mendeliome v0.6106 GPIHBP1 Bryony Thompson Gene: gpihbp1 has been classified as Green List (High Evidence).
Mendeliome v0.6106 GPIHBP1 Bryony Thompson Classified gene: GPIHBP1 as Green List (high evidence)
Mendeliome v0.6106 GPIHBP1 Bryony Thompson Gene: gpihbp1 has been classified as Green List (High Evidence).
Mendeliome v0.6103 CBY1 Bryony Thompson Gene: cby1 has been classified as Green List (High Evidence).
Mendeliome v0.6103 CBY1 Bryony Thompson Classified gene: CBY1 as Green List (high evidence)
Mendeliome v0.6103 CBY1 Bryony Thompson Gene: cby1 has been classified as Green List (High Evidence).
Mendeliome v0.6102 CBY1 Bryony Thompson gene: CBY1 was added
gene: CBY1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CBY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CBY1 were set to 33131181; 25103236; 25220153
Phenotypes for gene: CBY1 were set to intellectual disability; cerebellar ataxia; molar tooth sign; polydactyly; Joubert syndrome
Review for gene: CBY1 was set to GREEN
Added comment: Three cases in two unrelated consanguineous families with homozygous loss of function variants. Multiple null model organisms recapitulate the human phenotype: Null mouse model had cystic kidneys, a phenotype common to ciliopathies. Reducing Cby levels in Xenopus laevis model reduced the density of multiciliated cells, the number of basal bodies per multiciliated cell, and the numbers of neural tube primary cilia; it also led to abnormal development of the neural crest, central nervous system, and pronephros. Depletion of cby1 in zebrafish results in ciliopathy‐related phenotypes.
Sources: Literature
Mendeliome v0.6101 ZMYND15 Bryony Thompson Gene: zmynd15 has been classified as Green List (High Evidence).
Mendeliome v0.6101 ZMYND15 Bryony Thompson Classified gene: ZMYND15 as Green List (high evidence)
Mendeliome v0.6101 ZMYND15 Bryony Thompson Gene: zmynd15 has been classified as Green List (High Evidence).
Mendeliome v0.6099 PNPLA1 Zornitza Stark Gene: pnpla1 has been classified as Green List (High Evidence).
Mendeliome v0.6099 PNPLA1 Zornitza Stark Phenotypes for gene: PNPLA1 were changed from to Ichthyosis, congenital, autosomal recessive 10, MIM# 615024
Mendeliome v0.6096 PNPLA1 Zornitza Stark reviewed gene: PNPLA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22246504, 24344921, 26691440; Phenotypes: Ichthyosis, congenital, autosomal recessive 10, MIM# 615024; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6096 TMEM251 Bryony Thompson Gene: tmem251 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6096 TMEM251 Bryony Thompson Classified gene: TMEM251 as Amber List (moderate evidence)
Mendeliome v0.6096 TMEM251 Bryony Thompson Gene: tmem251 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.6095 TMEM251 Bryony Thompson gene: TMEM251 was added
gene: TMEM251 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM251 were set to 33252156
Phenotypes for gene: TMEM251 were set to Dysostosis multiplex‐like skeletal dysplasia; severe short stature
Review for gene: TMEM251 was set to AMBER
Added comment: Two unrelated consanguineous families with homozygous variants (c.133C>T; p.Arg45Trp and c.215dupA; p.Tyr72Ter), with co-segregation data in one family. Preliminary in vitro functional assays conducted - Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes.
Sources: Literature
Mendeliome v0.6094 LOR Zornitza Stark Gene: lor has been classified as Green List (High Evidence).
Mendeliome v0.6094 LOR Zornitza Stark Phenotypes for gene: LOR were changed from to Vohwinkel syndrome with ichthyosis, MIM# 604117
Mendeliome v0.6091 LOR Zornitza Stark reviewed gene: LOR: Rating: GREEN; Mode of pathogenicity: None; Publications: 8673107, 9326398, 9326323, 25234742, 25142840; Phenotypes: Vohwinkel syndrome with ichthyosis, MIM# 604117; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6091 CYP4F22 Zornitza Stark Gene: cyp4f22 has been classified as Green List (High Evidence).
Mendeliome v0.6091 CYP4F22 Zornitza Stark Phenotypes for gene: CYP4F22 were changed from to Ichthyosis, congenital, autosomal recessive 5, MIM# 604777
Mendeliome v0.6088 CYP4F22 Zornitza Stark reviewed gene: CYP4F22: Rating: GREEN; Mode of pathogenicity: None; Publications: 16436457; Phenotypes: Ichthyosis, congenital, autosomal recessive 5, MIM# 604777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6088 CERS3 Zornitza Stark Gene: cers3 has been classified as Green List (High Evidence).
Mendeliome v0.6088 CERS3 Zornitza Stark Phenotypes for gene: CERS3 were changed from to Ichthyosis, congenital, autosomal recessive 9, MIM# 615023
Mendeliome v0.6085 CERS3 Zornitza Stark reviewed gene: CERS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23754960, 23549421, 31168818, 30578701; Phenotypes: Ichthyosis, congenital, autosomal recessive 9, MIM# 615023; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6085 ALOX12B Zornitza Stark Gene: alox12b has been classified as Green List (High Evidence).
Mendeliome v0.6085 ALOX12B Zornitza Stark Phenotypes for gene: ALOX12B were changed from to Ichthyosis, congenital, autosomal recessive 2, MIM# 242100
Mendeliome v0.6082 ALOX12B Zornitza Stark reviewed gene: ALOX12B: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116617, 11773004; Phenotypes: Ichthyosis, congenital, autosomal recessive 2, MIM# 242100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6082 ALX3 Zornitza Stark Gene: alx3 has been classified as Green List (High Evidence).
Mendeliome v0.6082 ALX3 Zornitza Stark Phenotypes for gene: ALX3 were changed from to Frontonasal dysplasia 1, MIM#136760
Mendeliome v0.6079 ALX1 Zornitza Stark Gene: alx1 has been classified as Green List (High Evidence).
Mendeliome v0.6079 ALX1 Zornitza Stark Phenotypes for gene: ALX1 were changed from to Frontonasal dysplasia 3, MIM#613456
Mendeliome v0.6076 ALX1 Zornitza Stark reviewed gene: ALX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27324866, 20451171, 23059813; Phenotypes: Frontonasal dysplasia 3, MIM#613456; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6076 HIST1H1E Zornitza Stark Gene: hist1h1e has been classified as Green List (High Evidence).
Mendeliome v0.6073 EED Zornitza Stark Gene: eed has been classified as Green List (High Evidence).
Mendeliome v0.6070 CLCN1 Zornitza Stark Gene: clcn1 has been classified as Green List (High Evidence).
Mendeliome v0.6070 CLCN1 Zornitza Stark Phenotypes for gene: CLCN1 were changed from to Myotonia congenita, dominant 160800; Myotonia congenita, recessive 255700
Mendeliome v0.6067 CLCN1 Zornitza Stark reviewed gene: CLCN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 1379744, 7981750, 8533761; Phenotypes: Myotonia congenita, dominant 160800, Myotonia congenita, recessive 255700; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.6067 TUBG1 Zornitza Stark Gene: tubg1 has been classified as Green List (High Evidence).
Mendeliome v0.6067 TUBG1 Zornitza Stark Phenotypes for gene: TUBG1 were changed from to Cortical dysplasia, complex, with other brain malformations 4, MIM# 615412
Mendeliome v0.6064 TUBG1 Zornitza Stark reviewed gene: TUBG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23603762, 31086189; Phenotypes: Cortical dysplasia, complex, with other brain malformations 4, MIM# 615412; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6064 TUBB3 Zornitza Stark Gene: tubb3 has been classified as Green List (High Evidence).
Mendeliome v0.6064 TUBB3 Zornitza Stark Phenotypes for gene: TUBB3 were changed from to Cortical dysplasia, complex, with other brain malformations 1, MIM# 614039; Fibrosis of extraocular muscles, congenital, 3A, MIM# 600638
Mendeliome v0.6061 TUBB3 Zornitza Stark reviewed gene: TUBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20829227, 25059107, 33318778, 20074521; Phenotypes: Cortical dysplasia, complex, with other brain malformations 1, MIM# 614039, Fibrosis of extraocular muscles, congenital, 3A, MIM# 600638; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6061 TUBB2B Zornitza Stark Gene: tubb2b has been classified as Green List (High Evidence).
Mendeliome v0.6061 TUBB2B Zornitza Stark Phenotypes for gene: TUBB2B were changed from to Cortical dysplasia, complex, with other brain malformations 7, MIM# 610031
Mendeliome v0.6058 TUBB2B Zornitza Stark reviewed gene: TUBB2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 19465910, 22333901, 26732629, 33082561; Phenotypes: Cortical dysplasia, complex, with other brain malformations 7, MIM# 610031; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6058 TUBB Zornitza Stark Gene: tubb has been classified as Green List (High Evidence).
Mendeliome v0.6058 TUBB Zornitza Stark Phenotypes for gene: TUBB were changed from to Cortical dysplasia, complex, with other brain malformations 6, MIM# 615771
Mendeliome v0.6055 TUBB Zornitza Stark reviewed gene: TUBB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23246003, 32085672; Phenotypes: Cortical dysplasia, complex, with other brain malformations 6, MIM# 615771; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6055 FZD4 Zornitza Stark Gene: fzd4 has been classified as Green List (High Evidence).
Mendeliome v0.6052 TSPAN12 Zornitza Stark Gene: tspan12 has been classified as Green List (High Evidence).
Mendeliome v0.6049 PPP2R5D Zornitza Stark Gene: ppp2r5d has been classified as Green List (High Evidence).
Mendeliome v0.6045 KAT6B Zornitza Stark Gene: kat6b has been classified as Green List (High Evidence).
Mendeliome v0.6041 DVL1 Zornitza Stark Gene: dvl1 has been classified as Green List (High Evidence).
Mendeliome v0.6037 ZFP36L1 Zornitza Stark Gene: zfp36l1 has been classified as Red List (Low Evidence).
Mendeliome v0.6037 ZFP36L1 Zornitza Stark Classified gene: ZFP36L1 as Red List (low evidence)
Mendeliome v0.6037 ZFP36L1 Zornitza Stark Gene: zfp36l1 has been classified as Red List (Low Evidence).
Mendeliome v0.6035 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Added comment: PMID 33390987: Four unrelated individuals reported with same de novo missense variant, p. Gly180Trp. The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk.; Changed publications: 31439720, 33390987
Mendeliome v0.6035 TSPYL1 Zornitza Stark Phenotypes for gene: TSPYL1 were changed from Sudden infant death with dysgenesis of the testes syndrome (MIM#608800) to Sudden infant death with dysgenesis of the testes syndrome (MIM#608800); sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Mendeliome v0.6033 TSPYL1 Zornitza Stark Classified gene: TSPYL1 as Green List (high evidence)
Mendeliome v0.6033 TSPYL1 Zornitza Stark Gene: tspyl1 has been classified as Green List (High Evidence).
Mendeliome v0.6029 ZNF526 Zornitza Stark Classified gene: ZNF526 as Green List (high evidence)
Mendeliome v0.6029 ZNF526 Zornitza Stark Gene: znf526 has been classified as Green List (High Evidence).
Mendeliome v0.6028 CYLD Zornitza Stark Phenotypes for gene: CYLD were changed from Brooke-Spiegler syndrome, 605041; Cylindromatosis, familial, 132700; Trichoepithelioma, multiple familial, 1, 601606; Frontotemporal dementia and amyotrophic lateral sclerosis to Brooke-Spiegler syndrome, 605041; Cylindromatosis, familial, 132700; Trichoepithelioma, multiple familial, 1, 601606; Frontotemporal dementia and/or amytrophic lateral sclerosis 8, MIM# 619132
Mendeliome v0.6027 CYLD Zornitza Stark reviewed gene: CYLD: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Frontotemporal dementia and/or amytrophic lateral sclerosis 8, MIM# 619132; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.6026 TSPYL1 Eleanor Williams reviewed gene: TSPYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32885560, 33075815; Phenotypes: Sudden infant death with dysgenesis of the testes syndrome OMIM:608800, sudden infant death-dysgenesis of the testes syndrome MONDO:0012124; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6026 INTS6 Zornitza Stark Gene: ints6 has been classified as Red List (Low Evidence).
Mendeliome v0.6026 INTS6 Zornitza Stark Classified gene: INTS6 as Red List (low evidence)
Mendeliome v0.6026 INTS6 Zornitza Stark Gene: ints6 has been classified as Red List (Low Evidence).
Mendeliome v0.6025 BCS1L Zornitza Stark Gene: bcs1l has been classified as Green List (High Evidence).
Mendeliome v0.6022 MRPS22 Zornitza Stark Gene: mrps22 has been classified as Green List (High Evidence).
Mendeliome v0.6022 MRPS22 Zornitza Stark Phenotypes for gene: MRPS22 were changed from to Combined oxidative phosphorylation deficiency 5 MIM#611719; Ovarian dysgenesis 7 MIM#618117
Mendeliome v0.6019 KRT10 Elena Savva reviewed gene: KRT10: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 26176760, 20798280, 31638346, 18219278, 16505000; Phenotypes: Epidermolytic hyperkeratosis, MIM#113800, Ichthyosis with confetti, MIM#609165, Ichthyosis, cyclic, with epidermolytic hyperkeratosis, MIM#607602; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.6019 BRPF1 Elena Savva reviewed gene: BRPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32652122, 27939640; Phenotypes: Intellectual developmental disorder with dysmorphic facies and ptosis MIM#617333; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.6019 MRPS22 Elena Savva reviewed gene: MRPS22: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29566152; Phenotypes: Combined oxidative phosphorylation deficiency 5 MIM#611719, Ovarian dysgenesis 7 MIM#618117; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.6019 CELF2 Zornitza Stark Gene: celf2 has been classified as Green List (High Evidence).
Mendeliome v0.6019 CELF2 Zornitza Stark Classified gene: CELF2 as Green List (high evidence)
Mendeliome v0.6019 CELF2 Zornitza Stark Gene: celf2 has been classified as Green List (High Evidence).
Mendeliome v0.6018 CELF2 Zornitza Stark gene: CELF2 was added
gene: CELF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 33131106
Phenotypes for gene: CELF2 were set to Developmental and epileptic encephalopathy
Review for gene: CELF2 was set to GREEN
Added comment: Five unrelated individuals reported. Four with de novo variants, and one inherited from a mosaic mother. Notably, all identified variants, except for c.272‐1G>C, were clustered within 20 amino acid residues of the C‐terminus, which might be a nuclear localization signal.
Sources: Literature
Mendeliome v0.6017 FGF13 Zornitza Stark Gene: fgf13 has been classified as Green List (High Evidence).
Mendeliome v0.6017 FGF13 Zornitza Stark Classified gene: FGF13 as Green List (high evidence)
Mendeliome v0.6017 FGF13 Zornitza Stark Gene: fgf13 has been classified as Green List (High Evidence).
Mendeliome v0.6016 FGF13 Zornitza Stark gene: FGF13 was added
gene: FGF13 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy
Mode of pathogenicity for gene: FGF13 was set to Other
Review for gene: FGF13 was set to GREEN
Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay.

The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Mendeliome v0.6015 SCUBE3 Zornitza Stark Gene: scube3 has been classified as Green List (High Evidence).
Mendeliome v0.6015 SCUBE3 Zornitza Stark Classified gene: SCUBE3 as Green List (high evidence)
Mendeliome v0.6015 SCUBE3 Zornitza Stark Gene: scube3 has been classified as Green List (High Evidence).
Mendeliome v0.6014 SCUBE3 Zornitza Stark changed review comment from: Eighteen affected individuals from nine unrelated families reported with a consistent phenotype characterised by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies.
Sources: Literature; to: Eighteen affected individuals from nine unrelated families reported with a consistent phenotype characterised by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. Mouse model recapitulated phenotype.
Sources: Literature
Mendeliome v0.6014 SCUBE3 Zornitza Stark gene: SCUBE3 was added
gene: SCUBE3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature; skeletal abnormalities; craniofacial abnormalities; dental anomalies
Review for gene: SCUBE3 was set to GREEN
Added comment: Eighteen affected individuals from nine unrelated families reported with a consistent phenotype characterised by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies.
Sources: Literature
Mendeliome v0.6013 UBR7 Zornitza Stark Gene: ubr7 has been classified as Green List (High Evidence).
Mendeliome v0.6013 UBR7 Zornitza Stark Classified gene: UBR7 as Green List (high evidence)
Mendeliome v0.6013 UBR7 Zornitza Stark Gene: ubr7 has been classified as Green List (High Evidence).
Mendeliome v0.6012 UBR7 Zornitza Stark gene: UBR7 was added
gene: UBR7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBR7 were set to 33340455
Phenotypes for gene: UBR7 were set to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Review for gene: UBR7 was set to GREEN
Added comment: Seven individuals from 6 unrelated families. All had developmental delay, and all males had urogenital anomalies, namely cryptorchidism in 5/6 and small penis in 1/6. Six individuals had seizures and hypotonia. Hypothyroidism was present in 4/7 individuals, and ptosis was noted in 6/7 individuals. Five individuals exhibited cardiac abnormalities: two had ventricular septal defect, one had atrial septal defect, one had a patent ductus arteriosus requiring surgery, and the other had a patent ductus arteriosus and a patent foramen ovale that both closed spontaneously. Five individuals had short stature (height < 3rd percentile). Physical examination revealed various dysmorphic features, including prominent forehead (3/7), hypertelorism (4/7), telecanthus (1/7), epicanthus(1/7), downslanting palpebral fissures (3/7), thick eyebrow (1/7), low-set ears (3/7), long philtrum (2/7), unilateral single transverse palmar crease (1/7), and hypertrichosis (1/7).
Sources: Literature
Mendeliome v0.6011 RNU7-1 Zornitza Stark Gene: rnu7-1 has been classified as Green List (High Evidence).
Mendeliome v0.6010 RNU7-1 Zornitza Stark Classified gene: RNU7-1 as Green List (high evidence)
Mendeliome v0.6010 RNU7-1 Zornitza Stark Gene: rnu7-1 has been classified as Green List (High Evidence).
Mendeliome v0.6009 RABL2A Zornitza Stark Gene: rabl2a has been classified as Red List (Low Evidence).
Mendeliome v0.6007 RABL2A Zornitza Stark Classified gene: RABL2A as Red List (low evidence)
Mendeliome v0.6007 RABL2A Zornitza Stark Gene: rabl2a has been classified as Red List (Low Evidence).
Mendeliome v0.6006 AKT1 Zornitza Stark Classified gene: AKT1 as Green List (high evidence)
Mendeliome v0.6006 AKT1 Zornitza Stark Gene: akt1 has been classified as Green List (High Evidence).
Mendeliome v0.6005 CEP250 Zornitza Stark Gene: cep250 has been classified as Green List (High Evidence).
Mendeliome v0.6002 RABL2A Eleanor Williams gene: RABL2A was added
gene: RABL2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RABL2A was set to Unknown
Publications for gene: RABL2A were set to 33075816
Phenotypes for gene: RABL2A were set to male infertility; ciliopathy
Review for gene: RABL2A was set to RED
Added comment: PMID: 33075816 - Ding et al 2020 - with the aim of identifying variants that affect male fertility, the authors report on mice expressing two RABL2A SNPs found to be rare (MAF between 2% and 0.02% in gnomAD, with a deleterious prediction from SIFT and PolyPhen-2, and to affect protein stability. Mice homozygous for these variants (p.L119F and p.V158F) were found to be show ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects and hydrocephalus.
Sources: Literature
Mendeliome v0.6002 VCAN Zornitza Stark Gene: vcan has been classified as Green List (High Evidence).
Mendeliome v0.5999 CAPN5 Zornitza Stark Gene: capn5 has been classified as Green List (High Evidence).
Mendeliome v0.5996 UBIAD1 Zornitza Stark Gene: ubiad1 has been classified as Green List (High Evidence).
Mendeliome v0.5993 TGFBI Zornitza Stark Gene: tgfbi has been classified as Green List (High Evidence).
Mendeliome v0.5990 TACSTD2 Zornitza Stark Gene: tacstd2 has been classified as Green List (High Evidence).
Mendeliome v0.5987 KIF27 Zornitza Stark Gene: kif27 has been classified as Red List (Low Evidence).
Mendeliome v0.5987 KIF27 Zornitza Stark Classified gene: KIF27 as Red List (low evidence)
Mendeliome v0.5987 KIF27 Zornitza Stark Gene: kif27 has been classified as Red List (Low Evidence).
Mendeliome v0.5986 ZEB1 Zornitza Stark Gene: zeb1 has been classified as Green List (High Evidence).
Mendeliome v0.5983 ZNF469 Zornitza Stark Gene: znf469 has been classified as Green List (High Evidence).
Mendeliome v0.5980 PIKFYVE Zornitza Stark Gene: pikfyve has been classified as Green List (High Evidence).
Mendeliome v0.5977 OVOL2 Zornitza Stark Gene: ovol2 has been classified as Green List (High Evidence).
Mendeliome v0.5974 KRT3 Zornitza Stark Gene: krt3 has been classified as Green List (High Evidence).
Mendeliome v0.5971 DCN Zornitza Stark Gene: dcn has been classified as Green List (High Evidence).
Mendeliome v0.5968 COL8A2 Zornitza Stark Gene: col8a2 has been classified as Green List (High Evidence).
Mendeliome v0.5965 STX3 Zornitza Stark Gene: stx3 has been classified as Green List (High Evidence).
Mendeliome v0.5965 STX3 Zornitza Stark Phenotypes for gene: STX3 were changed from to Microvillus inclusion disease
Mendeliome v0.5962 STX3 Zornitza Stark reviewed gene: STX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24726755, 29266534, 25358429, 29282386, 30909251, 29282386; Phenotypes: Microvillus inclusion disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5962 SPINT2 Zornitza Stark Gene: spint2 has been classified as Green List (High Evidence).
Mendeliome v0.5959 SLC9A3 Zornitza Stark Gene: slc9a3 has been classified as Green List (High Evidence).
Mendeliome v0.5956 SLC5A1 Zornitza Stark Gene: slc5a1 has been classified as Green List (High Evidence).
Mendeliome v0.5953 SLC39A4 Zornitza Stark Gene: slc39a4 has been classified as Green List (High Evidence).
Mendeliome v0.5950 SLC26A3 Zornitza Stark Gene: slc26a3 has been classified as Green List (High Evidence).
Mendeliome v0.5947 SLC51B Zornitza Stark Gene: slc51b has been classified as Red List (Low Evidence).
Mendeliome v0.5947 SLC51B Zornitza Stark gene: SLC51B was added
gene: SLC51B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: SLC51B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC51B were set to 28898457
Phenotypes for gene: SLC51B were set to Congenital diarrhoea; Cholestasis
Review for gene: SLC51B was set to RED
Added comment: Two siblings reported with homozygous LOF variant in this gene and congenital diarrhoea/cholestasis.
Sources: Expert Review
Mendeliome v0.5946 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Red List (Low Evidence).
Mendeliome v0.5943 SLC10A2 Zornitza Stark Classified gene: SLC10A2 as Red List (low evidence)
Mendeliome v0.5943 SLC10A2 Zornitza Stark Gene: slc10a2 has been classified as Red List (Low Evidence).
Mendeliome v0.5942 PLVAP Zornitza Stark Gene: plvap has been classified as Green List (High Evidence).
Mendeliome v0.5942 PLVAP Zornitza Stark Phenotypes for gene: PLVAP were changed from to Diarrhoea 10, protein-losing enteropathy type, MIM# 618183
Mendeliome v0.5939 PLVAP Zornitza Stark reviewed gene: PLVAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 29875123, 29661969, 26207260, 31215290; Phenotypes: Diarrhoea 10, protein-losing enteropathy type, MIM# 618183; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5939 NEUROG3 Zornitza Stark Gene: neurog3 has been classified as Green List (High Evidence).
Mendeliome v0.5936 TMPRSS15 Zornitza Stark Gene: tmprss15 has been classified as Green List (High Evidence).
Mendeliome v0.5933 TTC37 Zornitza Stark Gene: ttc37 has been classified as Green List (High Evidence).
Mendeliome v0.5930 WNT2B Zornitza Stark Gene: wnt2b has been classified as Green List (High Evidence).
Mendeliome v0.5927 MYO5B Zornitza Stark Gene: myo5b has been classified as Green List (High Evidence).
Mendeliome v0.5927 MYO5B Zornitza Stark Phenotypes for gene: MYO5B were changed from to Microvillus inclusion disease, MIM# 251850; Cholestasis
Mendeliome v0.5924 MYO5B Zornitza Stark reviewed gene: MYO5B: Rating: GREEN; Mode of pathogenicity: None; Publications: 30564347, 29266534, 28027573, 27532546; Phenotypes: Microvillus inclusion disease, MIM# 251850, Cholestasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5924 LCT Zornitza Stark Gene: lct has been classified as Green List (High Evidence).
Mendeliome v0.5922 FBRSL1 Zornitza Stark Gene: fbrsl1 has been classified as Green List (High Evidence).
Mendeliome v0.5922 CAMK2B Zornitza Stark Gene: camk2b has been classified as Green List (High Evidence).
Mendeliome v0.5919 FBRSL1 Sue White Classified gene: FBRSL1 as Green List (high evidence)
Mendeliome v0.5919 FBRSL1 Sue White Gene: fbrsl1 has been classified as Green List (High Evidence).
Mendeliome v0.5918 RALGAPB Seb Lunke Gene: ralgapb has been classified as Green List (High Evidence).
Mendeliome v0.5918 RALGAPB Seb Lunke Classified gene: RALGAPB as Green List (high evidence)
Mendeliome v0.5918 RALGAPB Seb Lunke Gene: ralgapb has been classified as Green List (High Evidence).
Mendeliome v0.5917 RALGAPB Elena Savva gene: RALGAPB was added
gene: RALGAPB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RALGAPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RALGAPB were set to PMID: 32853829
Phenotypes for gene: RALGAPB were set to Neurodevelopmental disorders, autism
Review for gene: RALGAPB was set to GREEN
Added comment: PMID: 32853829 - 2 patients with de novo missense variants, 1 patient with a de novo PTC with autism spectrum disorder from a large cohort.
Reviews previous publications and identifies 10 de novo variants (5 PTCs, 5 missense) in patients with ASD (7/10), epilepsy (2/10) and developmental delay (1/10).
Functional studies of patient cells show reduced mRNA expression (PTC).
Sources: Literature
Mendeliome v0.5917 RPL3L Seb Lunke Gene: rpl3l has been classified as Green List (High Evidence).
Mendeliome v0.5917 RPL3L Seb Lunke Classified gene: RPL3L as Green List (high evidence)
Mendeliome v0.5917 RPL3L Seb Lunke Gene: rpl3l has been classified as Green List (High Evidence).
Mendeliome v0.5916 LSM11 Seb Lunke changed review comment from: Comment on list classification: Very little evidence at this stage, just one consanguineous family with a some functional data.; to: Comment on list classification: Very little evidence at this stage, just one consanguineous family with some functional data.
Mendeliome v0.5916 LSM11 Seb Lunke Gene: lsm11 has been classified as Red List (Low Evidence).
Mendeliome v0.5916 LSM11 Seb Lunke Classified gene: LSM11 as Red List (low evidence)
Mendeliome v0.5916 LSM11 Seb Lunke Added comment: Comment on list classification: Very little evidence at this stage, just one consanguineous family with a some functional data.
Mendeliome v0.5916 LSM11 Seb Lunke Gene: lsm11 has been classified as Red List (Low Evidence).
Mendeliome v0.5915 DPH2 Seb Lunke Gene: dph2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5915 DPH2 Seb Lunke Classified gene: DPH2 as Amber List (moderate evidence)
Mendeliome v0.5915 DPH2 Seb Lunke Gene: dph2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5914 RPL3L Elena Savva gene: RPL3L was added
gene: RPL3L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPL3L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPL3L were set to PMID: 32514796; 32870709
Phenotypes for gene: RPL3L were set to Neonatal dilated cardiomyopathy
Review for gene: RPL3L was set to GREEN
Added comment: PMID: 32514796 - 5 hom/chet individuals from three independent families who presented with severe neonatal dilated cardiomyopathy. Unaffected sibs were either carriers of a single variant or homozygous wildtype.

PMID: 32870709 - 1 hom patient w/ neonatal DCM
Sources: Literature
Mendeliome v0.5914 LSM11 Ee Ming Wong gene: LSM11 was added
gene: LSM11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LSM11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM11 were set to PMID: 33230297
Phenotypes for gene: LSM11 were set to type I interferonopathy Aicardi–Goutières syndrome
Review for gene: LSM11 was set to AMBER
gene: LSM11 was marked as current diagnostic
Added comment: - Two affected siblings from a consanguineous family carrying a homozygous variant in LSM11
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
- Knockdown of LSM11 in THP-1 cells results in an increase in misprocessed RDH mRNA and
interferon signaling
Sources: Literature
Mendeliome v0.5914 DPH2 Paul De Fazio changed review comment from: One family reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency.

Another family was previously reported with biallelic nonsense variants (PMID:27421267) with a comparable phenotype, this family also has biallelic variants in KALRN and the authors thought those variants more likely causative.

In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952.
Sources: Literature; to: One 19 month old reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency (gross motor delay, not walking, fine motor and expressive language delays, macrocephaly)

Another family (sibs) was previously reported with biallelic nonsense variants (PMID:27421267) with a comparable phenotype, this family also has biallelic variants in KALRN and the authors thought those variants more likely causative. Patients had ID and microcephaly (in contrast to the 19 month old above).

In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952.
Sources: Literature
Mendeliome v0.5914 DPH2 Paul De Fazio gene: DPH2 was added
gene: DPH2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH2 were set to 32576952; 27421267
Phenotypes for gene: DPH2 were set to Diphthamide-deficiency syndrome
Review for gene: DPH2 was set to AMBER
gene: DPH2 was marked as current diagnostic
Added comment: One family reported (PMID:32576952) with biallelic (one missense, one nonsense) variants in DPH2, with phenotype similar to DPH1 deficiency.

Another family was previously reported with biallelic nonsense variants (PMID:27421267) with a comparable phenotype, this family also has biallelic variants in KALRN and the authors thought those variants more likely causative.

In vitro functional assays support reduced diphthamide synthesis activity for the variants identified in PMID:32576952.
Sources: Literature
Mendeliome v0.5914 EPCAM Zornitza Stark Gene: epcam has been classified as Green List (High Evidence).
Mendeliome v0.5911 DGAT1 Zornitza Stark Gene: dgat1 has been classified as Green List (High Evidence).
Mendeliome v0.5911 DGAT1 Zornitza Stark Phenotypes for gene: DGAT1 were changed from to Diarrhoea 7, protein-losing enteropathy type, MIM# 615863
Mendeliome v0.5908 DGAT1 Zornitza Stark reviewed gene: DGAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33261563, 32786057, 31778854, 28373485, 29604290; Phenotypes: Diarrhoea 7, protein-losing enteropathy type, MIM# 615863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5908 CPA6 Zornitza Stark Gene: cpa6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5905 CPA6 Zornitza Stark Classified gene: CPA6 as Amber List (moderate evidence)
Mendeliome v0.5905 CPA6 Zornitza Stark Gene: cpa6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5904 CPA6 Zornitza Stark edited their review of gene: CPA6: Added comment: Homozygous p.A270V variant reported in four siblings with Febrile seizures, familial, 11 (MIM 614418)(PMID:21922598), some functional data. Present in gnomad as hets but no homs. Also note one of the heterozygous individuals initially reported was subsequently found to have a second missense variant, PMID 23105115.

Disputed association between mono allelic variants and disease: variants reported have high frequency in gnomad, not in keeping with Mendelian disorder.; Changed rating: AMBER; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5904 HSD17B10 Zornitza Stark Gene: hsd17b10 has been classified as Green List (High Evidence).
Mendeliome v0.5902 HMGCS2 Zornitza Stark Gene: hmgcs2 has been classified as Green List (High Evidence).
Mendeliome v0.5899 HMGCL Zornitza Stark Gene: hmgcl has been classified as Green List (High Evidence).
Mendeliome v0.5896 GLUD1 Zornitza Stark Gene: glud1 has been classified as Green List (High Evidence).
Mendeliome v0.5891 AGPAT2 Zornitza Stark Gene: agpat2 has been classified as Green List (High Evidence).
Mendeliome v0.5888 LPIN1 Zornitza Stark Gene: lpin1 has been classified as Green List (High Evidence).
Mendeliome v0.5888 LPIN1 Zornitza Stark Phenotypes for gene: LPIN1 were changed from to Myoglobinuria, acute recurrent, autosomal recessive, MIM# 268200
Mendeliome v0.5885 LPIN1 Zornitza Stark reviewed gene: LPIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18817903, 32549891, 32522502, 32410653; Phenotypes: Myoglobinuria, acute recurrent, autosomal recessive, MIM# 268200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5885 MLYCD Zornitza Stark Gene: mlycd has been classified as Green List (High Evidence).
Mendeliome v0.5882 SLC25A20 Zornitza Stark Gene: slc25a20 has been classified as Green List (High Evidence).
Mendeliome v0.5879 GABRD Zornitza Stark Gene: gabrd has been classified as Red List (Low Evidence).
Mendeliome v0.5876 GABRD Zornitza Stark Classified gene: GABRD as Red List (low evidence)
Mendeliome v0.5876 GABRD Zornitza Stark Gene: gabrd has been classified as Red List (Low Evidence).
Mendeliome v0.5875 SPR Zornitza Stark Gene: spr has been classified as Green List (High Evidence).
Mendeliome v0.5875 SPR Zornitza Stark Phenotypes for gene: SPR were changed from to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, MIM# 612716
Mendeliome v0.5872 PRRT2 Zornitza Stark Gene: prrt2 has been classified as Green List (High Evidence).
Mendeliome v0.5872 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from to Convulsions, familial infantile, with paroxysmal choreoathetosis 602066; Episodic kinesigenic dyskinesia 1 128200; Seizures, benign familial infantile, 2 605751
Mendeliome v0.5869 PRRT2 Zornitza Stark reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33126500; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis 602066, Episodic kinesigenic dyskinesia 1 128200, Seizures, benign familial infantile, 2 605751; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5869 KCNQ3 Zornitza Stark Gene: kcnq3 has been classified as Green List (High Evidence).
Mendeliome v0.5866 PRKACB Zornitza Stark Gene: prkacb has been classified as Green List (High Evidence).
Mendeliome v0.5866 PRKACB Zornitza Stark Phenotypes for gene: PRKACB were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability to Cardioacrofacial dysplasia 2, MIM# 619143; Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Mendeliome v0.5865 PRKACB Zornitza Stark reviewed gene: PRKACB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardioacrofacial dysplasia 2, MIM# 619143; Mode of inheritance: None
Mendeliome v0.5865 PRKACA Zornitza Stark Phenotypes for gene: PRKACA were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth to Cardioacrofacial dysplasia 1, MIM# 619142; Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Mendeliome v0.5864 PRKACA Zornitza Stark reviewed gene: PRKACA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardioacrofacial dysplasia 1, MIM# 619142; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5864 SCARF2 Zornitza Stark Gene: scarf2 has been classified as Green List (High Evidence).
Mendeliome v0.5860 GSTO1 Zornitza Stark Gene: gsto1 has been classified as Red List (Low Evidence).
Mendeliome v0.5858 GSTO1 Zornitza Stark Classified gene: GSTO1 as Red List (low evidence)
Mendeliome v0.5858 GSTO1 Zornitza Stark Gene: gsto1 has been classified as Red List (Low Evidence).
Mendeliome v0.5857 PRR12 Zornitza Stark Gene: prr12 has been classified as Green List (High Evidence).
Mendeliome v0.5854 PRSS56 Zornitza Stark Gene: prss56 has been classified as Green List (High Evidence).
Mendeliome v0.5851 GJA8 Zornitza Stark Gene: gja8 has been classified as Green List (High Evidence).
Mendeliome v0.5848 ATIC Zornitza Stark Gene: atic has been classified as Green List (High Evidence).
Mendeliome v0.5848 ATIC Zornitza Stark Phenotypes for gene: ATIC were changed from to AICA-ribosiduria due to ATIC deficiency, MIM# 608688
Mendeliome v0.5845 ATIC Zornitza Stark reviewed gene: ATIC: Rating: GREEN; Mode of pathogenicity: None; Publications: 15114530, 32557644; Phenotypes: AICA-ribosiduria due to ATIC deficiency, MIM# 608688; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5845 FZD5 Zornitza Stark Gene: fzd5 has been classified as Green List (High Evidence).
Mendeliome v0.5845 FZD5 Zornitza Stark Classified gene: FZD5 as Green List (high evidence)
Mendeliome v0.5845 FZD5 Zornitza Stark Gene: fzd5 has been classified as Green List (High Evidence).
Mendeliome v0.5843 STRA6 Zornitza Stark Gene: stra6 has been classified as Green List (High Evidence).
Mendeliome v0.5840 SOX2 Zornitza Stark Gene: sox2 has been classified as Green List (High Evidence).
Mendeliome v0.5840 SOX2 Zornitza Stark Phenotypes for gene: SOX2 were changed from to Microphthalmia, syndromic 3, MIM# 206900; Optic nerve hypoplasia and abnormalities of the central nervous system, MIM# 206900
Mendeliome v0.5837 SOX2 Zornitza Stark reviewed gene: SOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30450772, 28121235, 25542770, 24498598, 24211324, 24033328, 21326281; Phenotypes: Microphthalmia, syndromic 3, MIM# 206900, Optic nerve hypoplasia and abnormalities of the central nervous system, MIM# 206900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5837 SIX6 Zornitza Stark Marked gene: SIX6 as ready
Mendeliome v0.5837 SIX6 Zornitza Stark Gene: six6 has been classified as Green List (High Evidence).
Mendeliome v0.5837 SIX6 Zornitza Stark Phenotypes for gene: SIX6 were changed from to Optic disc anomalies with retinal and/or macular dystrophy, MIM# 212550
Mendeliome v0.5836 SIX6 Zornitza Stark Publications for gene: SIX6 were set to
Mendeliome v0.5835 SIX6 Zornitza Stark Mode of inheritance for gene: SIX6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5834 SIX6 Zornitza Stark reviewed gene: SIX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23167593, 24702266, 33108933, 31207931, 24702266; Phenotypes: Optic disc anomalies with retinal and/or macular dystrophy, MIM# 212550; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5834 RERE Zornitza Stark Gene: rere has been classified as Green List (High Evidence).
Mendeliome v0.5830 RAX Zornitza Stark Gene: rax has been classified as Green List (High Evidence).
Mendeliome v0.5826 RARB Zornitza Stark Gene: rarb has been classified as Green List (High Evidence).
Mendeliome v0.5819 RARA Zornitza Stark edited their review of gene: RARA: Added comment: Single case report of de novo missense variant in association with syndromic coloboma.; Changed publications: 31343737; Changed phenotypes: Syndromic chorioretinal coloboma
Mendeliome v0.5819 PXDN Zornitza Stark Gene: pxdn has been classified as Green List (High Evidence).
Mendeliome v0.5819 PXDN Zornitza Stark Phenotypes for gene: PXDN were changed from to Anterior segment dysgenesis 7, with sclerocornea, MIM# 269400
Mendeliome v0.5816 PXDN Zornitza Stark reviewed gene: PXDN: Rating: GREEN; Mode of pathogenicity: None; Publications: 21907015, 24939590, 32499604, 32224865, 32015378, 31817535; Phenotypes: Anterior segment dysgenesis 7, with sclerocornea, MIM# 269400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5816 SMOC1 Zornitza Stark Gene: smoc1 has been classified as Green List (High Evidence).
Mendeliome v0.5813 MFRP Zornitza Stark Gene: mfrp has been classified as Green List (High Evidence).
Mendeliome v0.5810 MAB21L2 Zornitza Stark Gene: mab21l2 has been classified as Green List (High Evidence).
Mendeliome v0.5810 MAB21L2 Zornitza Stark Phenotypes for gene: MAB21L2 were changed from to Microphthalmia/coloboma and skeletal dysplasia syndrome, MIM# 615877
Mendeliome v0.5807 MAB21L2 Zornitza Stark reviewed gene: MAB21L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24906020, 25719200, 31037784, 30375740, 30073347, 26116559; Phenotypes: Microphthalmia/coloboma and skeletal dysplasia syndrome, MIM# 615877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5807 PDSS1 Zornitza Stark Gene: pdss1 has been classified as Green List (High Evidence).
Mendeliome v0.5804 POLR1A Zornitza Stark Gene: polr1a has been classified as Green List (High Evidence).
Mendeliome v0.5804 POLR1A Zornitza Stark Phenotypes for gene: POLR1A were changed from Acrofacial dysostosis, Cincinnati type, (MIM#616462) to Acrofacial dysostosis, Cincinnati type, (MIM#616462); Leukodystrophy
Mendeliome v0.5803 POLR1A Zornitza Stark Phenotypes for gene: POLR1A were changed from to Acrofacial dysostosis, Cincinnati type, (MIM#616462)
Mendeliome v0.5800 POLR1A Ain Roesley reviewed gene: POLR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25913037, 28051070; Phenotypes: Acrofacial dysostosis, Cincinnati type, (MIM#616462); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5800 LOXL3 Zornitza Stark Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5800 LOXL3 Zornitza Stark Classified gene: LOXL3 as Amber List (moderate evidence)
Mendeliome v0.5800 LOXL3 Zornitza Stark Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5798 RBP4 Zornitza Stark Gene: rbp4 has been classified as Green List (High Evidence).
Mendeliome v0.5795 VAX1 Zornitza Stark Gene: vax1 has been classified as Red List (Low Evidence).
Mendeliome v0.5792 VAX1 Zornitza Stark Classified gene: VAX1 as Red List (low evidence)
Mendeliome v0.5792 VAX1 Zornitza Stark Gene: vax1 has been classified as Red List (Low Evidence).
Mendeliome v0.5791 VSX2 Zornitza Stark Gene: vsx2 has been classified as Green List (High Evidence).
Mendeliome v0.5788 WDR37 Zornitza Stark Gene: wdr37 has been classified as Green List (High Evidence).
Mendeliome v0.5785 ALDH1A3 Zornitza Stark Gene: aldh1a3 has been classified as Green List (High Evidence).
Mendeliome v0.5781 VEGFC Zornitza Stark Gene: vegfc has been classified as Green List (High Evidence).
Mendeliome v0.5778 KDELR2 Zornitza Stark Phenotypes for gene: KDELR2 were changed from Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms to Osteogenesis imperfecta 21, MIM# 619131; Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms
Mendeliome v0.5777 KDELR2 Zornitza Stark edited their review of gene: KDELR2: Changed phenotypes: Osteogenesis imperfecta 21, MIM# 619131, Increased susceptibility to fractures, joint hypermobility, Scoliosis, Bowing of the legs, Bowing of the arms
Mendeliome v0.5775 RNASEH2B Zornitza Stark Gene: rnaseh2b has been classified as Green List (High Evidence).
Mendeliome v0.5772 PDGFB Zornitza Stark Gene: pdgfb has been classified as Green List (High Evidence).
Mendeliome v0.5769 XYLT1 Zornitza Stark reviewed gene: XYLT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30554721, 24581741, 23982343; Phenotypes: Desbuquois dysplasia 2, MIM# 615777, Baratela-Scott syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5769 TUSC3 Zornitza Stark Gene: tusc3 has been classified as Green List (High Evidence).
Mendeliome v0.5769 TUSC3 Zornitza Stark Phenotypes for gene: TUSC3 were changed from to Mental retardation, autosomal recessive 7, MIM# 611093, MONDO:0012615; TUSC3-CDG (Disorders of protein N-glycosylation)
Mendeliome v0.5766 TUSC3 Zornitza Stark reviewed gene: TUSC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18452889, 18455129, 21739581, 27148795, 31606977; Phenotypes: Mental retardation, autosomal recessive 7, MIM# 611093, MONDO:0012615, TUSC3-CDG (Disorders of protein N-glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5766 TMEM165 Zornitza Stark Gene: tmem165 has been classified as Green List (High Evidence).
Mendeliome v0.5763 SLC35D1 Zornitza Stark Phenotypes for gene: SLC35D1 were changed from Schneckenbecken dysplasia, MIM 269250 to Schneckenbecken dysplasia, MIM 269250, MONDO:0010013; O-xylosyl/N-acetylgalactosaminylglycan synthesis deficiencies (Disorders of protein O-glycosylation)
Mendeliome v0.5761 SLC35D1 Zornitza Stark reviewed gene: SLC35D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17952091, 19508970, 31423530; Phenotypes: Schneckenbecken dysplasia 269250, O-xylosyl/N-acetylgalactosaminylglycan synthesis deficiencies (Disorders of protein O-glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5761 SLC35C1 Zornitza Stark Gene: slc35c1 has been classified as Green List (High Evidence).
Mendeliome v0.5756 GNE Zornitza Stark Gene: gne has been classified as Green List (High Evidence).
Mendeliome v0.5756 GNE Zornitza Stark Phenotypes for gene: GNE were changed from to Nonaka myopathy 605820; Sialuria MIM#269921; ADUDP-GlcNAc epimerase/kinase deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Mendeliome v0.5753 GNE Zornitza Stark reviewed gene: GNE: Rating: GREEN; Mode of pathogenicity: None; Publications: 12177386, 12473753, 32053088, 29923088, 10356312, 11326336, 11486897, 27142465; Phenotypes: Nonaka myopathy 605820, Sialuria MIM#269921, ADUDP-GlcNAc epimerase/kinase deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5753 EXT2 Zornitza Stark Gene: ext2 has been classified as Green List (High Evidence).
Mendeliome v0.5752 TBL1X Zornitza Stark Gene: tbl1x has been classified as Green List (High Evidence).
Mendeliome v0.5752 TBL1X Zornitza Stark Classified gene: TBL1X as Green List (high evidence)
Mendeliome v0.5752 TBL1X Zornitza Stark Gene: tbl1x has been classified as Green List (High Evidence).
Mendeliome v0.5751 CHSY1 Zornitza Stark edited their review of gene: CHSY1: Changed phenotypes: Temtamy preaxial brachydactyly syndrome, MIM# 605282, MONDO:0011533, CHSY1-CDG (Disorders of protein O-glycosylation, O-mannosylglycan synthesis deficiencies)
Mendeliome v0.5751 CHSY1 Zornitza Stark Gene: chsy1 has been classified as Green List (High Evidence).
Mendeliome v0.5751 CHSY1 Zornitza Stark Phenotypes for gene: CHSY1 were changed from to Temtamy preaxial brachydactyly syndrome, MIM# 605282, MONDO:0011533; CHSY1-CDG (Disorders of protein O-glycosylation, O-mannosylglycan synthesis deficiencies)
Mendeliome v0.5748 CHSY1 Zornitza Stark reviewed gene: CHSY1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21129728, 21129727, 24269551; Phenotypes: VTemtamy preaxial brachydactyly syndrome, MIM# 605282, MONDO:0011533, CHSY1-CDG (Disorders of protein O-glycosylation, O-mannosylglycan synthesis deficiencies); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5748 DHDDS Zornitza Stark Gene: dhdds has been classified as Green List (High Evidence).
Mendeliome v0.5743 FBLN1 Zornitza Stark Gene: fbln1 has been classified as Red List (Low Evidence).
Mendeliome v0.5740 FBLN1 Zornitza Stark Classified gene: FBLN1 as Red List (low evidence)
Mendeliome v0.5740 FBLN1 Zornitza Stark Gene: fbln1 has been classified as Red List (Low Evidence).
Mendeliome v0.5739 ST3GAL5 Zornitza Stark Gene: st3gal5 has been classified as Green List (High Evidence).
Mendeliome v0.5739 ST3GAL5 Zornitza Stark Phenotypes for gene: ST3GAL5 were changed from to Salt and pepper developmental regression syndrome 609056; GM3 synthase deficiency, MONDO:0018274; Lactosylceramide alpha-2,3-sialyltransferase deficiency (Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation)
Mendeliome v0.5736 ST3GAL5 Zornitza Stark reviewed gene: ST3GAL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23436467, 22990144, 15502825, 27232954, 30691927, 30688114, 30576498; Phenotypes: Salt and pepper developmental regression syndrome 609056, GM3 synthase deficiency, MONDO:0018274, Lactosylceramide alpha-2,3-sialyltransferase deficiency (Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5736 SUCLA2 Zornitza Stark Gene: sucla2 has been classified as Green List (High Evidence).
Mendeliome v0.5733 RFT1 Zornitza Stark Gene: rft1 has been classified as Green List (High Evidence).
Mendeliome v0.5730 CHST6 Zornitza Stark Gene: chst6 has been classified as Green List (High Evidence).
Mendeliome v0.5727 MGAT2 Zornitza Stark Gene: mgat2 has been classified as Green List (High Evidence).
Mendeliome v0.5724 MPI Zornitza Stark Gene: mpi has been classified as Green List (High Evidence).
Mendeliome v0.5721 PGM3 Zornitza Stark Gene: pgm3 has been classified as Green List (High Evidence).
Mendeliome v0.5718 PGM3 Zornitza Stark changed review comment from: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported.; to: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation.

Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity.

More than 10 unrelated families reported.
Mendeliome v0.5718 PGAP3 Zornitza Stark Gene: pgap3 has been classified as Green List (High Evidence).
Mendeliome v0.5718 PGAP3 Zornitza Stark Phenotypes for gene: PGAP3 were changed from to Hyperphosphatasia with mental retardation syndrome 4, MIM# 615716, MONDO:0014318
Mendeliome v0.5715 PGAP3 Zornitza Stark reviewed gene: PGAP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24439110, 29620724, 30345601, 30217754; Phenotypes: Hyperphosphatasia with mental retardation syndrome 4, MIM# 615716, MONDO:0014318; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5715 PGAP2 Zornitza Stark Gene: pgap2 has been classified as Green List (High Evidence).
Mendeliome v0.5715 PGAP2 Zornitza Stark Phenotypes for gene: PGAP2 were changed from to Hyperphosphatasia with mental retardation syndrome 3, MIM# 614207, MONDO:0013628
Mendeliome v0.5712 PGAP2 Zornitza Stark reviewed gene: PGAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23561846, 23561847, 31805394, 29119105, 27871432; Phenotypes: Hyperphosphatasia with mental retardation syndrome 3, MIM# 614207, MONDO:0013628; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5712 PIGV Zornitza Stark Gene: pigv has been classified as Green List (High Evidence).
Mendeliome v0.5712 PIGV Zornitza Stark Phenotypes for gene: PIGV were changed from to Hyperphosphatasia with mental retardation syndrome 1, MIM# 239300, MONDO:0009398
Mendeliome v0.5709 PIGV Zornitza Stark reviewed gene: PIGV: Rating: GREEN; Mode of pathogenicity: None; Publications: 20802478, 22315194, 28817240, 24129430; Phenotypes: Hyperphosphatasia with mental retardation syndrome 1, MIM# 239300, MONDO:0009398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5708 PIGO Zornitza Stark Gene: pigo has been classified as Green List (High Evidence).
Mendeliome v0.5708 PIGO Zornitza Stark Phenotypes for gene: PIGO were changed from to Hyperphosphatasia with mental retardation syndrome 2, MIM# 614749, MONDO:0013882
Mendeliome v0.5705 PIGO Zornitza Stark reviewed gene: PIGO: Rating: GREEN; Mode of pathogenicity: None; Publications: 22683086, 31698102, 28900819, 28545593, 28337824; Phenotypes: Hyperphosphatasia with mental retardation syndrome 2, MIM# 614749, MONDO:0013882; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5705 PIGN Zornitza Stark Gene: pign has been classified as Green List (High Evidence).
Mendeliome v0.5702 PIGA Zornitza Stark Gene: piga has been classified as Green List (High Evidence).
Mendeliome v0.5699 PIGL Zornitza Stark Gene: pigl has been classified as Green List (High Evidence).
Mendeliome v0.5696 B3GALT6 Zornitza Stark Gene: b3galt6 has been classified as Green List (High Evidence).
Mendeliome v0.5696 B3GALT6 Zornitza Stark Phenotypes for gene: B3GALT6 were changed from to Al-Gazali syndrome, MIM# 609465; Ehlers-Danlos syndrome, spondylodysplastic type, 2, MIM# 615349, MONDO:0014139; Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures, MIM# 271640, MONDO:0010075
Mendeliome v0.5693 B3GALT6 Zornitza Stark reviewed gene: B3GALT6: Rating: GREEN; Mode of pathogenicity: None; Publications: 25149931, 29443383, 23664117, 29931299, 23664117, 23664118, 31614862; Phenotypes: Al-Gazali syndrome, MIM# 609465, Ehlers-Danlos syndrome, spondylodysplastic type, 2, MIM# 615349, MONDO:0014139, Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures, MIM# 271640, MONDO:0010075; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5693 B3GALNT2 Zornitza Stark Gene: b3galnt2 has been classified as Green List (High Evidence).
Mendeliome v0.5690 MPDU1 Zornitza Stark Gene: mpdu1 has been classified as Green List (High Evidence).
Mendeliome v0.5687 DPAGT1 Zornitza Stark Gene: dpagt1 has been classified as Green List (High Evidence).
Mendeliome v0.5684 DPAGT1 Zornitza Stark changed review comment from: Type I CDG. More than 20 unrelated families reported. Most affected individuals have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. Additional features that may be observed include apnoea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties.

Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM 614750 is a milder allelic disorder.; to: Type I CDG. More than 20 unrelated families reported. Most affected individuals have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. Additional features that may be observed include apnoea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties.

Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM 614750 is a milder allelic disorder. More than 5 unrelated families reported with this presentation.
Mendeliome v0.5684 DOLK Zornitza Stark Gene: dolk has been classified as Green List (High Evidence).
Mendeliome v0.5681 SLC2A1 Zornitza Stark Gene: slc2a1 has been classified as Green List (High Evidence).
Mendeliome v0.5681 SLC2A1 Zornitza Stark Phenotypes for gene: SLC2A1 were changed from to GLUT1 deficiency syndrome 1, infantile onset, severe, MIM#606777; Dystonia 9, MIM#601042; Stomatin-deficient cryohydrocytosis with neurologic defects, MIM#608885; GLUT1 deficiency syndrome 2, childhood onset, MIM#612126; {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM#614847
Mendeliome v0.5678 MTX2 Zornitza Stark Phenotypes for gene: MTX2 were changed from Mandibuloacral dysplasia; lipodystrophy; arterial calcification to Mandibuloacral dysplasia progeroid syndrome, MIM# 619127; Mandibuloacral dysplasia; lipodystrophy; arterial calcification
Mendeliome v0.5677 MTX2 Zornitza Stark edited their review of gene: MTX2: Changed phenotypes: Mandibuloacral dysplasia progeroid syndrome, MIM# 619127, Mandibuloacral dysplasia, lipodystrophy, arterial calcification
Mendeliome v0.5677 SLC2A1 Elena Savva reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:18451999, 20129935, 10980529, 20221955, 31196579; Phenotypes: GLUT1 deficiency syndrome 1, infantile onset, severe, MIM#606777, Dystonia 9, MIM#601042, Stomatin-deficient cryohydrocytosis with neurologic defects, MIM#608885, GLUT1 deficiency syndrome 2, childhood onset, MIM#612126, {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM#614847; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5677 ERCC1 Zornitza Stark Gene: ercc1 has been classified as Green List (High Evidence).
Mendeliome v0.5674 POR Zornitza Stark Gene: por has been classified as Green List (High Evidence).
Mendeliome v0.5674 POR Zornitza Stark Phenotypes for gene: POR were changed from to Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, MIM#201750; Disordered steroidogenesis due to cytochrome P450 oxidoreductase, MIM#613571
Mendeliome v0.5671 MYH6 Zornitza Stark Gene: myh6 has been classified as Green List (High Evidence).
Mendeliome v0.5671 MYH6 Zornitza Stark Phenotypes for gene: MYH6 were changed from to Atrial septal defect 3 MIM#614089; Congenital heart disease; Cardiomyopathy, dilated, 1EE MIM#613252; Cardiomyopathy, hypertrophic, 14 MIM#613251; {Sick sinus syndrome 3} MIM#614090
Mendeliome v0.5668 MYH6 Zornitza Stark reviewed gene: MYH6: Rating: GREEN; Mode of pathogenicity: None; Publications: 32656206, 31638415, 29969989, 29536580, 29332214, 30681346; Phenotypes: Atrial septal defect 3 MIM#614089, Congenital heart disease, Cardiomyopathy, dilated, 1EE MIM#613252, Cardiomyopathy, hypertrophic, 14 MIM#613251, {Sick sinus syndrome 3} MIM#614090; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5668 EZH2 Zornitza Stark Gene: ezh2 has been classified as Green List (High Evidence).
Mendeliome v0.5665 POR Elena Savva reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27068427; Phenotypes: Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, MIM#201750, Disordered steroidogenesis due to cytochrome P450 oxidoreductase, MIM#613571; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5665 MYH6 Elena Savva reviewed gene: MYH6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 3 MIM#614089, Cardiomyopathy, dilated, 1EE MIM#613252, Cardiomyopathy, hypertrophic, 14 MIM#613251, {Sick sinus syndrome 3} MIM#614090; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5665 COG6 Zornitza Stark Gene: cog6 has been classified as Green List (High Evidence).
Mendeliome v0.5662 COG5 Zornitza Stark Gene: cog5 has been classified as Green List (High Evidence).
Mendeliome v0.5659 FIGLA Zornitza Stark Gene: figla has been classified as Green List (High Evidence).
Mendeliome v0.5656 ESR1 Zornitza Stark Gene: esr1 has been classified as Green List (High Evidence).
Mendeliome v0.5656 ESR1 Zornitza Stark Phenotypes for gene: ESR1 were changed from to Estrogen resistance, MIM# 615363
Mendeliome v0.5653 ESR1 Zornitza Stark reviewed gene: ESR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27754803, 23841731, 24152274; Phenotypes: Estrogen resistance, MIM# 615363; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5653 SHMT2 Zornitza Stark Phenotypes for gene: SHMT2 were changed from Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB), MIM#619121; Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Mendeliome v0.5652 SHMT2 Zornitza Stark edited their review of gene: SHMT2: Changed phenotypes: Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB), MIM#619121, Congenital microcephaly, Infantile axial hypotonia, Spastic paraparesis, Global developmental delay, Intellectual disability, Abnormality of the corpus callosum, Abnormal cortical gyration, Hypertrophic cardiomyopathy, Abnormality of the face, Proximal placement of thumb, 2-3 toe syndactyly
Mendeliome v0.5652 BMP15 Zornitza Stark Gene: bmp15 has been classified as Green List (High Evidence).
Mendeliome v0.5652 BMP15 Zornitza Stark Phenotypes for gene: BMP15 were changed from to Ovarian dysgenesis 2, MIM# 300510; Premature ovarian failure 4, MIM# 300510
Mendeliome v0.5649 BMP15 Zornitza Stark reviewed gene: BMP15: Rating: GREEN; Mode of pathogenicity: None; Publications: 15136966, 16508750, 16464940; Phenotypes: Ovarian dysgenesis 2, MIM# 300510, Premature ovarian failure 4, MIM# 300510; Mode of inheritance: Other
Mendeliome v0.5649 PANX1 Zornitza Stark Gene: panx1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5649 PANX1 Zornitza Stark Classified gene: PANX1 as Amber List (moderate evidence)
Mendeliome v0.5649 PANX1 Zornitza Stark Gene: panx1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5647 NANOS3 Bryony Thompson Gene: nanos3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5647 NANOS3 Bryony Thompson Classified gene: NANOS3 as Amber List (moderate evidence)
Mendeliome v0.5647 NANOS3 Bryony Thompson Gene: nanos3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5646 NANOS3 Bryony Thompson gene: NANOS3 was added
gene: NANOS3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NANOS3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NANOS3 were set to 25054146; 24091668
Phenotypes for gene: NANOS3 were set to Primary ovarian insufficiency
Review for gene: NANOS3 was set to AMBER
Added comment: A homozygous missense (p.Glu120Lys) was identified in two Brazillian sisters with primary amenorrhea, and supporting in vitro functional assays. A heterozygous missense (p.Arg153Trp) was identified in a Chinese woman with POI, with supporting in vitro functional assays. Also, supporting null mouse model.
Sources: Literature
Mendeliome v0.5645 MSH5 Bryony Thompson Gene: msh5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5645 MSH5 Bryony Thompson Classified gene: MSH5 as Amber List (moderate evidence)
Mendeliome v0.5645 MSH5 Bryony Thompson Gene: msh5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5644 MSH5 Bryony Thompson gene: MSH5 was added
gene: MSH5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MSH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MSH5 were set to 28175301; 9916805; 24970489
Phenotypes for gene: MSH5 were set to Premature ovarian failure 13 MIM#617442
Review for gene: MSH5 was set to AMBER
Added comment: A homozygous missense mutation (p.D487Y) in two sisters with POI. Also, homologous mutation in mice results in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. Null mouse model is viable, but sterile. A case with congenital adrenal hyperplasia, ovarian failure and Ehlers-Danlos syndrome had a de novo t(6;14)(p21;q32) translocation, including CYP21A2,TNXB and MSH5.
Sources: Literature
Mendeliome v0.5643 PATL2 Zornitza Stark Gene: patl2 has been classified as Green List (High Evidence).
Mendeliome v0.5643 PATL2 Zornitza Stark Classified gene: PATL2 as Green List (high evidence)
Mendeliome v0.5643 PATL2 Zornitza Stark Gene: patl2 has been classified as Green List (High Evidence).
Mendeliome v0.5639 FANCM Bryony Thompson Classified gene: FANCM as Green List (high evidence)
Mendeliome v0.5639 FANCM Bryony Thompson Added comment: Comment on list classification: Green for POI
Mendeliome v0.5639 FANCM Bryony Thompson Gene: fancm has been classified as Green List (High Evidence).
Mendeliome v0.5638 EIF4ENIF1 Bryony Thompson Gene: eif4enif1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5638 PGRMC1 Zornitza Stark Gene: pgrmc1 has been classified as Red List (Low Evidence).
Mendeliome v0.5637 EIF4ENIF1 Bryony Thompson Classified gene: EIF4ENIF1 as Amber List (moderate evidence)
Mendeliome v0.5637 EIF4ENIF1 Bryony Thompson Gene: eif4enif1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5635 POF1B Zornitza Stark Gene: pof1b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5632 POF1B Zornitza Stark Classified gene: POF1B as Amber List (moderate evidence)
Mendeliome v0.5632 POF1B Zornitza Stark Gene: pof1b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5631 DIAPH2 Bryony Thompson Gene: diaph2 has been classified as Red List (Low Evidence).
Mendeliome v0.5631 DIAPH2 Bryony Thompson Classified gene: DIAPH2 as Red List (low evidence)
Mendeliome v0.5631 DIAPH2 Bryony Thompson Gene: diaph2 has been classified as Red List (Low Evidence).
Mendeliome v0.5630 CCDC141 Bryony Thompson Gene: ccdc141 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5630 POU5F1 Zornitza Stark gene: POU5F1 was added
gene: POU5F1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: POU5F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU5F1 were set to 21273125
Phenotypes for gene: POU5F1 were set to Premature ovarian failure
Review for gene: POU5F1 was set to RED
Added comment: Single individual reported in 2011 and a missense variant.
Sources: Expert list
Mendeliome v0.5629 CCDC141 Bryony Thompson Classified gene: CCDC141 as Amber List (moderate evidence)
Mendeliome v0.5629 CCDC141 Bryony Thompson Gene: ccdc141 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5627 SGO2 Zornitza Stark Gene: sgo2 has been classified as Red List (Low Evidence).
Mendeliome v0.5627 SGO2 Zornitza Stark gene: SGO2 was added
gene: SGO2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGO2 were set to 27629923
Phenotypes for gene: SGO2 were set to Perrault syndrome
Review for gene: SGO2 was set to RED
Added comment: Single affected individual reported, though deafness was thought to be explained by a CLDN14 variant. Protein is known to be involved in meiosis.
Sources: Expert list
Mendeliome v0.5626 SOHLH2 Zornitza Stark Gene: sohlh2 has been classified as Red List (Low Evidence).
Mendeliome v0.5625 SYCE1 Zornitza Stark Gene: syce1 has been classified as Green List (High Evidence).
Mendeliome v0.5625 SYCE1 Zornitza Stark Classified gene: SYCE1 as Green List (high evidence)
Mendeliome v0.5625 SYCE1 Zornitza Stark Gene: syce1 has been classified as Green List (High Evidence).
Mendeliome v0.5624 SYCE1 Zornitza Stark gene: SYCE1 was added
gene: SYCE1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SYCE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYCE1 were set to 25062452; 32917591; 32741963; 32402064; 31925770; 31916078
Phenotypes for gene: SYCE1 were set to Premature ovarian failure 12, MIM# 616947; Spermatogenic failure 15 ,MIM#616950
Review for gene: SYCE1 was set to GREEN
Added comment: More than 5 families reported with POF/SF and bi-allelic variants in this gene. Mechanism is thought to be disruption of meiosis, mouse model data also supports gene-disease association.
Sources: Expert list
Mendeliome v0.5623 DACH2 Zornitza Stark Gene: dach2 has been classified as Red List (Low Evidence).
Mendeliome v0.5622 TUBB8 Zornitza Stark Gene: tubb8 has been classified as Green List (High Evidence).
Mendeliome v0.5619 WEE2 Zornitza Stark Gene: wee2 has been classified as Green List (High Evidence).
Mendeliome v0.5616 ZP1 Zornitza Stark Gene: zp1 has been classified as Green List (High Evidence).
Mendeliome v0.5616 ZP1 Zornitza Stark Classified gene: ZP1 as Green List (high evidence)
Mendeliome v0.5616 ZP1 Zornitza Stark Gene: zp1 has been classified as Green List (High Evidence).
Mendeliome v0.5613 ZP3 Zornitza Stark Gene: zp3 has been classified as Green List (High Evidence).
Mendeliome v0.5613 ZP3 Zornitza Stark Classified gene: ZP3 as Green List (high evidence)
Mendeliome v0.5613 ZP3 Zornitza Stark Gene: zp3 has been classified as Green List (High Evidence).
Mendeliome v0.5611 ECEL1P2 Zornitza Stark Gene: ecel1p2 has been classified as Red List (Low Evidence).
Mendeliome v0.5611 ECEL1P2 Zornitza Stark Classified gene: ECEL1P2 as Red List (low evidence)
Mendeliome v0.5611 ECEL1P2 Zornitza Stark Gene: ecel1p2 has been classified as Red List (Low Evidence).
Mendeliome v0.5609 CDC40 Zornitza Stark Gene: cdc40 has been classified as Red List (Low Evidence).
Mendeliome v0.5609 CDC40 Zornitza Stark gene: CDC40 was added
gene: CDC40 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC40 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC40 were set to 33220177
Phenotypes for gene: CDC40 were set to Pontocerebellar hypoplasia; microcephaly; seizures
Review for gene: CDC40 was set to RED
Added comment: Single individual reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID, thrombocytopaenia, anaemia. Interaction with PPIL1 and mouse model support gene-disease association. Gene referred to as PRP17 in paper.
Sources: Literature
Mendeliome v0.5608 PPIL1 Zornitza Stark Gene: ppil1 has been classified as Green List (High Evidence).
Mendeliome v0.5608 PPIL1 Zornitza Stark Classified gene: PPIL1 as Green List (high evidence)
Mendeliome v0.5608 PPIL1 Zornitza Stark Gene: ppil1 has been classified as Green List (High Evidence).
Mendeliome v0.5607 PPIL1 Zornitza Stark gene: PPIL1 was added
gene: PPIL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia; microcephaly; seizures
Review for gene: PPIL1 was set to GREEN
Added comment: 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Mendeliome v0.5606 FRA12A Bryony Thompson Classified STR: FRA12A as Amber List (moderate evidence)
Mendeliome v0.5606 FRA12A Bryony Thompson Str: fra12a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5605 FRA12A Bryony Thompson STR: FRA12A was added
STR: FRA12A was added to Mendeliome. Sources: Other
5'UTR tags were added to STR: FRA12A.
Mode of inheritance for STR: FRA12A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: FRA12A were set to 17236128
Phenotypes for STR: FRA12A were set to Mental retardation, FRA12A type MIM#136630
Review for STR: FRA12A was set to AMBER
Added comment: NM_173602.2:c.-137CGG[X]
All individuals expressing FRA12A had CGG-repeat expansion. The length of the expanded allele in 3 unaffected FRA12A carriers was 650–850 bp. In the two affected patients from 2 families with FRA12A, the length of the expanded allele was ∼1,050-1,150 bp.
70 controls used to determine the "normal" repeat range.
Sources: Other
Mendeliome v0.5604 DIP2B Bryony Thompson Classified gene: DIP2B as No list
Mendeliome v0.5604 DIP2B Bryony Thompson Added comment: Comment on list classification: Only repeat expansion reported. Added as an STR
Mendeliome v0.5603 DIP2B Bryony Thompson Classified gene: DIP2B as No list
Mendeliome v0.5603 DIP2B Bryony Thompson Added comment: Comment on list classification: Only repeat expansion reported. Added as an STR
Mendeliome v0.5601 CANVAS_ACAGG Bryony Thompson changed review comment from: A novel RFC1 repeat expansion motif, (ACAGG)exp, identified in three affected individuals from 2 families in an Asian-Pacific cohort for CANVAS. Southern blot was used to identify the repeat was ~1000kb in one of the cases, equivalent to ~1000 repeats.
Sources: Literature; to: A novel RFC1 repeat expansion motif, (ACAGG)exp, identified homozygous in three affected individuals from 2 families in an Asian-Pacific cohort for CANVAS. Southern blot was used to identify the repeat was ~1000kb in one of the cases, equivalent to ~1000 repeats.
Sources: Literature
Mendeliome v0.5601 CANVAS_ACAGG Bryony Thompson Str: canvas_acagg has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5601 CANVAS_ACAGG Bryony Thompson Classified STR: CANVAS_ACAGG as Amber List (moderate evidence)
Mendeliome v0.5601 CANVAS_ACAGG Bryony Thompson Added comment: Comment on list classification: Used the pathogenic cut-off of 400 repeats from original CANVAS repeat
Mendeliome v0.5601 CANVAS_ACAGG Bryony Thompson Str: canvas_acagg has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5600 CANVAS_ACAGG Bryony Thompson STR: CANVAS_ACAGG was added
STR: CANVAS_ACAGG was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: CANVAS_ACAGG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: CANVAS_ACAGG were set to 33103729
Phenotypes for STR: CANVAS_ACAGG were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome; fasciculations; elevated serum creatine kinase levels; denervation
Review for STR: CANVAS_ACAGG was set to AMBER
Added comment: A novel RFC1 repeat expansion motif, (ACAGG)exp, identified in three affected individuals from 2 families in an Asian-Pacific cohort for CANVAS. Southern blot was used to identify the repeat was ~1000kb in one of the cases, equivalent to ~1000 repeats.
Sources: Literature
Mendeliome v0.5599 CANVAS Bryony Thompson Str: canvas has been classified as Green List (High Evidence).
Mendeliome v0.5599 CANVAS Bryony Thompson Classified STR: CANVAS as Green List (high evidence)
Mendeliome v0.5599 CANVAS Bryony Thompson Str: canvas has been classified as Green List (High Evidence).
Mendeliome v0.5598 CANVAS Bryony Thompson STR: CANVAS was added
STR: CANVAS was added to Mendeliome. Sources: Expert list
Mode of inheritance for STR: CANVAS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: CANVAS were set to 30926972; 32851396
Phenotypes for STR: CANVAS were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome MIM#614575
Review for STR: CANVAS was set to GREEN
STR: CANVAS was marked as clinically relevant
Added comment: Simple tandem repeat (AAAAG)11 replaced with (AAGGG)n in intron 2 of RFC1. Loss of function is not the mechanism of disease. Maori population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp. (AAAGG)n repeat alone is not pathogenic.
Sources: Expert list
Mendeliome v0.5597 RFC1 Bryony Thompson Classified gene: RFC1 as No list
Mendeliome v0.5595 RNASEH2C Zornitza Stark Gene: rnaseh2c has been classified as Green List (High Evidence).
Mendeliome v0.5592 CFAP52 Zornitza Stark Gene: cfap52 has been classified as Green List (High Evidence).
Mendeliome v0.5592 CFAP52 Zornitza Stark Classified gene: CFAP52 as Green List (high evidence)
Mendeliome v0.5592 CFAP52 Zornitza Stark Gene: cfap52 has been classified as Green List (High Evidence).
Mendeliome v0.5591 CFAP45 Zornitza Stark Gene: cfap45 has been classified as Green List (High Evidence).
Mendeliome v0.5591 CFAP45 Zornitza Stark Classified gene: CFAP45 as Green List (high evidence)
Mendeliome v0.5591 CFAP45 Zornitza Stark Gene: cfap45 has been classified as Green List (High Evidence).
Mendeliome v0.5590 LMX1B Zornitza Stark Phenotypes for gene: LMX1B were changed from Nail-patella syndrome (MIM#161200), MONDO:0008061; LMX1B-related nephropathy to Nail-patella syndrome (MIM#161200), MONDO:0008061; LMX1B-related nephropathy; Focal segmental glomerulosclerosis-10 (FSGS10), MIM#256020
Mendeliome v0.5589 LMX1B Zornitza Stark edited their review of gene: LMX1B: Changed phenotypes: Nail-patella syndrome (MIM#161200), MONDO:0008061, LMX1B-related nephropathy, Focal segmental glomerulosclerosis-10 (FSGS10), MIM#256020
Mendeliome v0.5589 RAP1A Zornitza Stark Gene: rap1a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5586 RAP1A Zornitza Stark Classified gene: RAP1A as Amber List (moderate evidence)
Mendeliome v0.5586 RAP1A Zornitza Stark Gene: rap1a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5584 RAP1B Zornitza Stark Classified gene: RAP1B as Green List (high evidence)
Mendeliome v0.5584 RAP1B Zornitza Stark Gene: rap1b has been classified as Green List (High Evidence).
Mendeliome v0.5583 RAP1B Zornitza Stark Gene: rap1b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5580 RAP1B Zornitza Stark Classified gene: RAP1B as Amber List (moderate evidence)
Mendeliome v0.5580 RAP1B Zornitza Stark Gene: rap1b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5579 EMC10 Zornitza Stark Gene: emc10 has been classified as Red List (Low Evidence).
Mendeliome v0.5579 EMC10 Zornitza Stark gene: EMC10 was added
gene: EMC10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EMC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EMC10 were set to 32869858
Phenotypes for gene: EMC10 were set to Intellectual disability
Review for gene: EMC10 was set to RED
Added comment: Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders.

One Saudi family with 2 affected individuals with mild ID, speech delay, and GDD.
WES and Sanger sequencing revealed a homozygous splice acceptor site variant (c.679‐1G>A) in EMC10 . Variant segregated within the family. RT‐qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients.
Sources: Literature
Mendeliome v0.5578 FBXO28 Zornitza Stark Gene: fbxo28 has been classified as Green List (High Evidence).
Mendeliome v0.5578 FBXO28 Zornitza Stark Classified gene: FBXO28 as Green List (high evidence)
Mendeliome v0.5578 FBXO28 Zornitza Stark Gene: fbxo28 has been classified as Green List (High Evidence).
Mendeliome v0.5577 FBXO28 Zornitza Stark gene: FBXO28 was added
gene: FBXO28 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXO28 were set to 33280099
Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy
Review for gene: FBXO28 was set to GREEN
Added comment: Nine new individuals with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and all 10 known cases reviewed to delineate the phenotypic spectrum. All had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features.
Sources: Literature
Mendeliome v0.5575 CFAP45 Zornitza Stark gene: CFAP45 was added
gene: CFAP45 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP45 were set to 33139725
Phenotypes for gene: CFAP45 were set to Situs inversus; asthenospermia
Review for gene: CFAP45 was set to GREEN
Added comment: Three unrelated individuals reported with bi-alleic LOF variants, mouse model recapitulated phenotype.
Sources: Literature
Mendeliome v0.5573 CLCN6 Zornitza Stark Classified gene: CLCN6 as Green List (high evidence)
Mendeliome v0.5573 CLCN6 Zornitza Stark Gene: clcn6 has been classified as Green List (High Evidence).
Mendeliome v0.5572 CLCN6 Zornitza Stark edited their review of gene: CLCN6: Added comment: Three unrelated families reported with recurrent GOF de novo c.1658A>G (p.Tyr553Cys) and severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans.; Changed rating: GREEN; Changed publications: 25794116, 21107136, 33217309; Changed phenotypes: Neurodegeneration, Benign partial epilepsy, febrile seizures, NCL; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5572 GDF6 Zornitza Stark Phenotypes for gene: GDF6 were changed from Klippel-Feil syndrome 1, autosomal dominant 118100; Leber congenital amaurosis 17 615360; Microphthalmia with coloboma 6, digenic 613703; Microphthalmia, isolated 4 613094; Multiple synostoses syndrome 4 617898 to Klippel-Feil syndrome 1, autosomal dominant 118100; Leber congenital amaurosis 17 615360; Microphthalmia with coloboma 6, digenic 613703; Microphthalmia, isolated 4 613094; Multiple synostoses syndrome 4 617898; CAKUT
Mendeliome v0.5571 GDF6 Zornitza Stark Gene: gdf6 has been classified as Green List (High Evidence).
Mendeliome v0.5571 GDF6 Zornitza Stark Phenotypes for gene: GDF6 were changed from to Klippel-Feil syndrome 1, autosomal dominant 118100; Leber congenital amaurosis 17 615360; Microphthalmia with coloboma 6, digenic 613703; Microphthalmia, isolated 4 613094; Multiple synostoses syndrome 4 617898
Mendeliome v0.5567 GDF6 Belinda Chong reviewed gene: GDF6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32737436; Phenotypes: Klippel-Feil syndrome 1, autosomal dominant 118100, Leber congenital amaurosis 17 615360, Microphthalmia with coloboma 6, digenic 613703, Microphthalmia, isolated 4 613094, Multiple synostoses syndrome 4 617898; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.5567 VPS4A Kristin Rigbye changed review comment from: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain.
1x homozygous missense in the MIT domain (milder phenotype and unaffected parents).
Demonstrated defective CD71 trafficking in all 3 patients.

PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly).
Demonstrated that the variants had a dominant-negative effect on VPS4A function.
"The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Sources: Literature; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain.
1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance).
Demonstrated defective CD71 trafficking in all 3 patients.

PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly).
Demonstrated that the variants had a dominant-negative effect on VPS4A function.

"The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Mendeliome v0.5567 VPS4A Elena Savva changed review comment from: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."; to: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain.
1x homozygous missense in the MIT domain (milder phenotype and unaffected parents).
Demonstrated defective CD71 trafficking in all 3 patients.

Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Mendeliome v0.5567 VPS4A Elena Savva Added comment: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents). Demonstrated defective CD71 trafficking in all 3 patients. PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Mendeliome v0.5567 VPS4A Elena Savva Gene: vps4a has been classified as Green List (High Evidence).
Mendeliome v0.5566 VPS4A Elena Savva Classified gene: VPS4A as Green List (high evidence)
Mendeliome v0.5566 VPS4A Elena Savva Gene: vps4a has been classified as Green List (High Evidence).
Mendeliome v0.5565 DAAM2 Zornitza Stark reviewed gene: DAAM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33232676; Phenotypes: Steroid-resistant nephrotic syndrome (SRNS); Mode of inheritance: None
Mendeliome v0.5565 DAAM2 Zornitza Stark Gene: daam2 has been classified as Green List (High Evidence).
Mendeliome v0.5564 DAAM2 Zornitza Stark Classified gene: DAAM2 as Green List (high evidence)
Mendeliome v0.5564 DAAM2 Zornitza Stark Gene: daam2 has been classified as Green List (High Evidence).
Mendeliome v0.5563 HS2ST1 Zornitza Stark Gene: hs2st1 has been classified as Green List (High Evidence).
Mendeliome v0.5563 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Mendeliome v0.5563 BICRA Elena Savva Classified gene: BICRA as Green List (high evidence)
Mendeliome v0.5563 BICRA Elena Savva Gene: bicra has been classified as Green List (High Evidence).
Mendeliome v0.5562 HS2ST1 Zornitza Stark Classified gene: HS2ST1 as Green List (high evidence)
Mendeliome v0.5562 HS2ST1 Zornitza Stark Gene: hs2st1 has been classified as Green List (High Evidence).
Mendeliome v0.5561 KDM4B Zornitza Stark Gene: kdm4b has been classified as Green List (High Evidence).
Mendeliome v0.5561 KDM4B Zornitza Stark Classified gene: KDM4B as Green List (high evidence)
Mendeliome v0.5561 KDM4B Zornitza Stark Gene: kdm4b has been classified as Green List (High Evidence).
Mendeliome v0.5560 SMG8 Zornitza Stark Classified gene: SMG8 as Green List (high evidence)
Mendeliome v0.5560 SMG8 Zornitza Stark Gene: smg8 has been classified as Green List (High Evidence).
Mendeliome v0.5559 UNC45B Zornitza Stark Gene: unc45b has been classified as Green List (High Evidence).
Mendeliome v0.5559 UNC45B Zornitza Stark Classified gene: UNC45B as Green List (high evidence)
Mendeliome v0.5559 UNC45B Zornitza Stark Gene: unc45b has been classified as Green List (High Evidence).
Mendeliome v0.5558 VPS4A Kristin Rigbye gene: VPS4A was added
gene: VPS4A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS4A were set to PMID: 33186543; 33186545
Phenotypes for gene: VPS4A were set to Neurodevelopmental disorder
Review for gene: VPS4A was set to GREEN
Added comment: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain.
1x homozygous missense in the MIT domain (milder phenotype and unaffected parents).
Demonstrated defective CD71 trafficking in all 3 patients.

PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly).
Demonstrated that the variants had a dominant-negative effect on VPS4A function.
"The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Sources: Literature
Mendeliome v0.5558 AGO2 Zornitza Stark Gene: ago2 has been classified as Green List (High Evidence).
Mendeliome v0.5558 AGO2 Zornitza Stark Classified gene: AGO2 as Green List (high evidence)
Mendeliome v0.5558 AGO2 Zornitza Stark Gene: ago2 has been classified as Green List (High Evidence).
Mendeliome v0.5556 DAAM2 Ain Roesley gene: DAAM2 was added
gene: DAAM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAAM2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DAAM2 were set to steroid-resistant nephrotic syndrome (SRNS)
Penetrance for gene: DAAM2 were set to unknown
Review for gene: DAAM2 was set to GREEN
Added comment: - steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis on histologic analysis of kidney biopsies and foot process effacement shown by electron microscopy (authors have suggested the term nephrotic syndrome type 22 (NPHS22))
- 4 unrelated families, 3 of which were consanguineous
- 4 unique missense and 1 stop
- in vitro studies done for the missense variants
Sources: Literature
Mendeliome v0.5556 RRP7A Zornitza Stark Gene: rrp7a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5556 RRP7A Zornitza Stark Classified gene: RRP7A as Amber List (moderate evidence)
Mendeliome v0.5556 RRP7A Zornitza Stark Gene: rrp7a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5555 RRP7A Zornitza Stark gene: RRP7A was added
gene: RRP7A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RRP7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RRP7A were set to 33199730
Phenotypes for gene: RRP7A were set to Microcephaly
Review for gene: RRP7A was set to AMBER
Added comment: 10 affected individuals from a single large consanguineous family where bi-allelic variant segregated with severe microcephaly (-6-8SD), variable ID. Supportive functional data from mouse and zebrafish.
Sources: Literature
Mendeliome v0.5554 HS2ST1 Ain Roesley gene: HS2ST1 was added
gene: HS2ST1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Penetrance for gene: HS2ST1 were set to unknown
Review for gene: HS2ST1 was set to GREEN
Added comment: - 4 affected from 3 unrelated families
- 3 unique missense and 2 PTCs
- Developmental Delay, Corpus Callosum Hypoplasia or Aplasia, and Skeletal and Renal Abnormalities
Sources: Literature
Mendeliome v0.5554 MINPP1 Zornitza Stark Gene: minpp1 has been classified as Green List (High Evidence).
Mendeliome v0.5554 MINPP1 Zornitza Stark Classified gene: MINPP1 as Green List (high evidence)
Mendeliome v0.5554 MINPP1 Zornitza Stark Gene: minpp1 has been classified as Green List (High Evidence).
Mendeliome v0.5553 KDM4B Kristin Rigbye gene: KDM4B was added
gene: KDM4B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM4B were set to PMID: 33232677
Phenotypes for gene: KDM4B were set to Global developmental delay, intellectual disability and neuroanatomical defects
Review for gene: KDM4B was set to GREEN
Added comment: Nine individuals with mono-allelic de novo or inherited variants in KDM4B.

All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria.

In a knockout mouse the total brain volume was significantly reduced with decreased
size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly.
Sources: Literature
Mendeliome v0.5553 MINPP1 Zornitza Stark gene: MINPP1 was added
gene: MINPP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Review for gene: MINPP1 was set to GREEN
Added comment: 8 individuals from 6 unrelated families reported with bi-allelic LOF variants. All presented with almost complete absence of motor and cognitive development, progressive or congenital microcephaly, spastic tetraplegia or dystonia, and vision impairments. For most, the first symptoms included neonatal severe axial hypotonia and epilepsy that started during the first months or years of life. Prenatal symptoms of microcephaly associated with increased thalami echogenicity were detected in one, while the seven other individuals presented with progressive microcephaly. Some exhibited rapidly progressive phenotype and the affected children died in their infancy or middle-childhood. Strikingly, all the affected children had a unique brain MRI showing a mild to severe PCH, fluid-filled posterior fossa, with dilated lateral ventricles. In addition, severe atrophy at the level of the basal ganglia or thalami often associated with typical T2 hypersignal were identified in all the patients MRI.

Supportive functional data showing accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions.
Sources: Literature
Mendeliome v0.5552 UNC45B Paul De Fazio gene: UNC45B was added
gene: UNC45B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UNC45B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC45B were set to 33217308
Phenotypes for gene: UNC45B were set to Progressive Myopathy with Eccentric Cores
Review for gene: UNC45B was set to GREEN
gene: UNC45B was marked as current diagnostic
Added comment: 10 individuals from 8 families reported with biallelic variants clinically manifesting with childhood-onset, progressive proximal and axial muscle weakness and various degrees of respiratory insufficiency. 4 missense variants and a +5 splice variant reported, p.Arg754Gln is recurrent. Functional studies support pathogenicity.
Sources: Literature
Mendeliome v0.5549 DNAJB11 Zornitza Stark edited their review of gene: DNAJB11: Added comment: Single family reported with bi-allelic variant and severe, fetal onset renal cystic disease, dilation and proliferation of pancreatic duct cells, and liver ductal plate malformation, an association known as Ivemark II syndrome.; Changed publications: 29706351, 29777155, 33129895; Changed phenotypes: Polycystic kidney disease 6 with or without polycystic liver disease, MIM#618061, Ivermark II syndrome.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.5549 MYLPF Zornitza Stark Phenotypes for gene: MYLPF were changed from Distal arthrogryoposis to Distal arthrogryposis type 1C (DA1C), MIM#619110
Mendeliome v0.5548 MYLPF Zornitza Stark edited their review of gene: MYLPF: Changed rating: AMBER; Changed phenotypes: Distal arthrogryposis type 1C (DA1C), MIM#619110; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5548 HHAT Zornitza Stark Gene: hhat has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5548 HHAT Zornitza Stark Classified gene: HHAT as Amber List (moderate evidence)
Mendeliome v0.5548 HHAT Zornitza Stark Gene: hhat has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5547 HHAT Zornitza Stark gene: HHAT was added
gene: HHAT was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HHAT were set to 24784881; 30912300
Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome 600092
Review for gene: HHAT was set to AMBER
Added comment: Two unrelated families reported. Clinical features include progressive microcephaly, cerebellar vermis hypoplasia, and skeletal dysplasia. Variable features include infantile-onset seizures, dwarfism, generalized chondrodysplasia, and micromelia.
Sources: Expert list
Mendeliome v0.5545 H3F3B Zornitza Stark Phenotypes for gene: H3F3B were changed from to Intellectual disability; regression; seizures
Mendeliome v0.5542 H3F3B Zornitza Stark Classified gene: H3F3B as Green List (high evidence)
Mendeliome v0.5542 H3F3B Zornitza Stark Gene: h3f3b has been classified as Green List (High Evidence).
Mendeliome v0.5541 H3F3B Zornitza Stark edited their review of gene: H3F3B: Added comment: 13 unrelated individuals reported with missense variants in H3F3B. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; Changed rating: GREEN; Changed publications: 33268356; Changed phenotypes: Intellectual disability, regression, seizures; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5541 H3F3A Zornitza Stark Phenotypes for gene: H3F3A were changed from to Intellectual disability; regression; seizures
Mendeliome v0.5538 H3F3A Zornitza Stark Classified gene: H3F3A as Green List (high evidence)
Mendeliome v0.5538 H3F3A Zornitza Stark Gene: h3f3a has been classified as Green List (High Evidence).
Mendeliome v0.5537 H3F3A Zornitza Stark edited their review of gene: H3F3A: Changed phenotypes: Intellectual disability, regression, seizures
Mendeliome v0.5537 H3F3A Zornitza Stark edited their review of gene: H3F3A: Added comment: 33 unrelated individuals reported with missense variants in H3F3A. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; Changed rating: GREEN; Changed publications: 33268356; Changed phenotypes: Intellectual disability, regression; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5537 ALDH7A1 Zornitza Stark Gene: aldh7a1 has been classified as Green List (High Evidence).
Mendeliome v0.5534 PRPS1 Zornitza Stark Gene: prps1 has been classified as Green List (High Evidence).
Mendeliome v0.5534 PRPS1 Zornitza Stark Phenotypes for gene: PRPS1 were changed from to Arts syndrome MIM#301835; Charcot-Marie-Tooth disease, X-linked recessive, 5 MIM#311070; Deafness, X-linked 1 MIM#304500; Gout, PRPS-related MIM#300661; Phosphoribosylpyrophosphate synthetase superactivity MIM#300661
Mendeliome v0.5530 HIVEP2 Zornitza Stark Gene: hivep2 has been classified as Green List (High Evidence).
Mendeliome v0.5527 PRPS1 Elena Savva reviewed gene: PRPS1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32781272, 17701896, 7593598; Phenotypes: Arts syndrome MIM#301835, Charcot-Marie-Tooth disease, X-linked recessive, 5 MIM#311070, Deafness, X-linked 1 MIM#304500, Gout, PRPS-related MIM#300661, Phosphoribosylpyrophosphate synthetase superactivity MIM#300661; 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 v0.5527 YIPF5 Zornitza Stark Gene: yipf5 has been classified as Green List (High Evidence).
Mendeliome v0.5527 YIPF5 Zornitza Stark Classified gene: YIPF5 as Green List (high evidence)
Mendeliome v0.5527 YIPF5 Zornitza Stark Gene: yipf5 has been classified as Green List (High Evidence).
Mendeliome v0.5526 YIPF5 Zornitza Stark gene: YIPF5 was added
gene: YIPF5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Neonatal diabetes; microcephaly; seizures
Review for gene: YIPF5 was set to GREEN
Added comment: Six individuals from 5 unrelated consanguineous families reported with bi-allelic variants in this gene and neonatal/early-onset diabetes, severe microcephaly, and epilepsy. Functional data supports gene-disease association.
Sources: Literature
Mendeliome v0.5523 SLC38A8 Zornitza Stark Gene: slc38a8 has been classified as Green List (High Evidence).
Mendeliome v0.5523 SLC38A8 Zornitza Stark Phenotypes for gene: SLC38A8 were changed from to Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218; foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216
Mendeliome v0.5520 CAPN15 Zornitza Stark Gene: capn15 has been classified as Green List (High Evidence).
Mendeliome v0.5520 CAPN15 Zornitza Stark Classified gene: CAPN15 as Green List (high evidence)
Mendeliome v0.5520 CAPN15 Zornitza Stark Gene: capn15 has been classified as Green List (High Evidence).
Mendeliome v0.5519 TONSL Zornitza Stark Gene: tonsl has been classified as Green List (High Evidence).
Mendeliome v0.5519 TONSL Zornitza Stark Phenotypes for gene: TONSL were changed from to Spondyloepimetaphyseal dysplasia, sponastrime type OMIM:271510; spondyloepimetaphyseal dysplasia, sponastrime type MONDO:0010068
Mendeliome v0.5516 FKBP8 Zornitza Stark Gene: fkbp8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5516 FKBP8 Zornitza Stark Classified gene: FKBP8 as Amber List (moderate evidence)
Mendeliome v0.5516 FKBP8 Zornitza Stark Gene: fkbp8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5515 NPPA Zornitza Stark Classified gene: NPPA as Amber List (moderate evidence)
Mendeliome v0.5515 NPPA Zornitza Stark Gene: nppa has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5514 NPPA Zornitza Stark Gene: nppa has been classified as Green List (High Evidence).
Mendeliome v0.5511 FOXA2 Zornitza Stark Gene: foxa2 has been classified as Green List (High Evidence).
Mendeliome v0.5511 FOXA2 Zornitza Stark Classified gene: FOXA2 as Green List (high evidence)
Mendeliome v0.5511 FOXA2 Zornitza Stark Gene: foxa2 has been classified as Green List (High Evidence).
Mendeliome v0.5507 USP7 Zornitza Stark edited their review of gene: USP7: Added comment: Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development with significant speech delay, behavioral abnormalities, such as autism, and mild dysmorphic facies. Additional features are variable, but may include hypotonia, feeding problems, delayed walking with unsteady gait, hypogonadism in males, and ocular anomalies, such as strabismus. Some patients develop seizures and some have mild white matter abnormalities on brain imaging.; Changed publications: 26365382, 30679821; Changed phenotypes: Hao-Fountain syndrome, MIM# 616863, Intellectual disability, Autism
Mendeliome v0.5507 FKBP8 Eleanor Williams gene: FKBP8 was added
gene: FKBP8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FKBP8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FKBP8 were set to 32969478
Phenotypes for gene: FKBP8 were set to spina bifida HP:0002414
Review for gene: FKBP8 was set to AMBER
Added comment: Not associated with a phenotype in OMIM.

PMID: 32969478 - Tian et al 2020 - performed Sanger sequencing of FKBP8 on DNA samples from 472 spina bifida (SB) affected fetuses and 565 unaffected controls. 5 different rare heterozygous variants (MAF ≤ 0.001) were identified among the SB patients, while no deleterious rare variants were identified in the controls. 4 of the variants are missense, the other is a stop-gain. 2 cases were in white-Hispanic patients while the other 3 were non-white Hispanic. Functional studies showed that p.Glu140* affected FKBP8 localization to the mitochondria and impaired its interaction with BCL2 ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein level. Gene expression was studied in mouse Fkbp8-/- embryos and found to be abnormal. Previous mouse models have shown neural tube defects.

Sufficient cases to rate green, but only the FKBP8 gene looked at so perhaps some caution required while further evidence is gathered.
Sources: Literature
Mendeliome v0.5507 TONSL Eleanor Williams reviewed gene: TONSL: Rating: GREEN; Mode of pathogenicity: None; Publications: 30773277, 30773278, 32959051; Phenotypes: Spondyloepimetaphyseal dysplasia, sponastrime type OMIM:271510, spondyloepimetaphyseal dysplasia, sponastrime type MONDO:0010068; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5507 CAPN15 Eleanor Williams changed review comment from: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families).
Sources: Literature; to: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Capn15 knockout mice showed similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth.

Sources: Literature
Mendeliome v0.5507 SLC38A8 Eleanor Williams reviewed gene: SLC38A8: Rating: GREEN; Mode of pathogenicity: None; Publications: 32744312; Phenotypes: Foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis OMIM:609218, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome MONDO:0012216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5507 MYF5 Zornitza Stark Gene: myf5 has been classified as Green List (High Evidence).
Mendeliome v0.5503 TARS2 Zornitza Stark edited their review of gene: TARS2: Added comment: Second family reported, single affected individual, compound heterozygous missense variants, computational data only in support of pathogenicity.; Changed publications: 24827421, 26811336, 33153448
Mendeliome v0.5503 COX16 Bryony Thompson Gene: cox16 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5503 COX16 Bryony Thompson Classified gene: COX16 as Amber List (moderate evidence)
Mendeliome v0.5503 COX16 Bryony Thompson Gene: cox16 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5502 COX16 Bryony Thompson gene: COX16 was added
gene: COX16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: COX16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX16 were set to 33169484
Phenotypes for gene: COX16 were set to Hypertrophic cardiomyopathy; encephalopathy; severe fatal lactic acidosis
Review for gene: COX16 was set to AMBER
Added comment: 2 unrelated patients with the same homozygous (non-consanguineous) nonsense variant c.244C>T (p.Arg82*), and isolated complex IV deficiency present in both patient fibroblasts/skeletal muscle biopsy. COX16 is involved in the biogenesis of complex IV, the terminal complex of the mitochondrial respiratory chain (RC)
Sources: Literature
Mendeliome v0.5501 THBD Bryony Thompson Classified gene: THBD as Green List (high evidence)
Mendeliome v0.5501 THBD Bryony Thompson Gene: thbd has been classified as Green List (High Evidence).
Mendeliome v0.5500 KCNJ18 Zornitza Stark Gene: kcnj18 has been classified as Red List (Low Evidence).
Mendeliome v0.5500 KCNJ18 Zornitza Stark gene: KCNJ18 was added
gene: KCNJ18 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KCNJ18 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ18 were set to 20074522; 27008341
Phenotypes for gene: KCNJ18 were set to {Thyrotoxic periodic paralysis, susceptibility to, 2}, MIM# 613239
Review for gene: KCNJ18 was set to RED
Added comment: Six variants reported in original publication, however note lack of segregation data and limited functional data. Subsequently, concerns raised about high nucleotide sequence homology between multiple potassium channel genes, with variant misattribution.
Sources: Expert Review
Mendeliome v0.5499 DPM3 Zornitza Stark Gene: dpm3 has been classified as Green List (High Evidence).
Mendeliome v0.5496 B3GAT3 Zornitza Stark Gene: b3gat3 has been classified as Green List (High Evidence).
Mendeliome v0.5493 SLC10A7 Zornitza Stark Gene: slc10a7 has been classified as Green List (High Evidence).
Mendeliome v0.5493 SLC10A7 Zornitza Stark Phenotypes for gene: SLC10A7 were changed from to Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis, MIM# 618363
Mendeliome v0.5490 SLC10A7 Zornitza Stark reviewed gene: SLC10A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 30082715, 29878199, 31191616; Phenotypes: Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis, MIM# 618363; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5486 GPAA1 Zornitza Stark Gene: gpaa1 has been classified as Green List (High Evidence).
Mendeliome v0.5486 GPAA1 Zornitza Stark Phenotypes for gene: GPAA1 were changed from to Glycosylphosphatidylinositol biosynthesis defect 15, MIM#617810
Mendeliome v0.5483 GPAA1 Zornitza Stark edited their review of gene: GPAA1: Added comment: At least 5 unrelated families reported with bi-allelic variants in this gene and delayed psychomotor development, variable intellectual disability, hypotonia, early-onset seizures in most, and cerebellar atrophy, resulting in cerebellar signs including gait ataxia and dysarthria. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.; Changed publications: 29100095
Mendeliome v0.5483 ATP7A Zornitza Stark Gene: atp7a has been classified as Green List (High Evidence).
Mendeliome v0.5483 ATP7A Zornitza Stark Phenotypes for gene: ATP7A were changed from to Occipital horn syndrome, 304150; X-linked recessive Menkes disease, 309400 Spinal muscular atrophy, distal, X-linked 3, 300489
Mendeliome v0.5480 PEX1 Zornitza Stark Gene: pex1 has been classified as Green List (High Evidence).
Mendeliome v0.5480 PEX1 Zornitza Stark Phenotypes for gene: PEX1 were changed from to Heimler syndrome 1 234580; Peroxisome biogenesis disorder 1A (Zellweger) 214100; . Peroxisome biogenesis disorder 1B (NALD/IRD) 601539
Mendeliome v0.5476 HDAC4 Bryony Thompson Classified gene: HDAC4 as Green List (high evidence)
Mendeliome v0.5476 HDAC4 Bryony Thompson Gene: hdac4 has been classified as Green List (High Evidence).
Mendeliome v0.5474 ATP7A Elena Savva reviewed gene: ATP7A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 21221114; Phenotypes: Occipital horn syndrome, 304150, X-linked recessive Menkes disease, 309400 Spinal muscular atrophy, distal, X-linked 3, 300489; 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 v0.5474 PEX1 Elena Savva reviewed gene: PEX1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26387595; Phenotypes: Heimler syndrome 1 234580, Peroxisome biogenesis disorder 1A (Zellweger) 214100, . Peroxisome biogenesis disorder 1B (NALD/IRD) 601539; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5474 TMEM218 Bryony Thompson Gene: tmem218 has been classified as Green List (High Evidence).
Mendeliome v0.5474 TMEM218 Bryony Thompson Classified gene: TMEM218 as Green List (high evidence)
Mendeliome v0.5474 TMEM218 Bryony Thompson Gene: tmem218 has been classified as Green List (High Evidence).
Mendeliome v0.5473 TMEM218 Bryony Thompson gene: TMEM218 was added
gene: TMEM218 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM218 were set to https://doi.org/10.1016/j.xhgg.2020.100016; 25161209
Phenotypes for gene: TMEM218 were set to Joubert syndrome; retinal dystrophy; polycystic kidneys; occipital encephalocele
Review for gene: TMEM218 was set to GREEN
Added comment: 11 cases in 6 families with homozygous or compound heterozygous missense and nonsense (1) variants, with a Joubert/Meckel syndrome phenotype. Clinical features included the molar tooth sign (N=2), occipital encephalocele (N=5, all fetuses), retinal dystrophy (N=4, all living individuals), polycystic kidneys (N=2), and polydactyly (N=2), without liver involvement. A null mouse model had nephronophthisis and retinal degeneration. No OMIM entry.
Sources: Literature
Mendeliome v0.5472 AGBL1 Zornitza Stark Gene: agbl1 has been classified as Red List (Low Evidence).
Mendeliome v0.5471 TLE6 Zornitza Stark Gene: tle6 has been classified as Green List (High Evidence).
Mendeliome v0.5471 TLE6 Zornitza Stark Classified gene: TLE6 as Green List (high evidence)
Mendeliome v0.5471 TLE6 Zornitza Stark Gene: tle6 has been classified as Green List (High Evidence).
Mendeliome v0.5469 OGT Zornitza Stark Gene: ogt has been classified as Green List (High Evidence).
Mendeliome v0.5466 EXTL3 Zornitza Stark Gene: extl3 has been classified as Green List (High Evidence).
Mendeliome v0.5466 EXTL3 Zornitza Stark Phenotypes for gene: EXTL3 were changed from to Immunoskeletal dysplasia with neurodevelopmental abnormalities, MIM# 617425
Mendeliome v0.5463 EXTL3 Zornitza Stark reviewed gene: EXTL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28132690, 28148688, 28331220; Phenotypes: Immunoskeletal dysplasia with neurodevelopmental abnormalities, MIM# 617425; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5463 SSR3 Zornitza Stark Gene: ssr3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5463 SSR3 Zornitza Stark Classified gene: SSR3 as Amber List (moderate evidence)
Mendeliome v0.5463 SSR3 Zornitza Stark Gene: ssr3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5462 SSR3 Zornitza Stark gene: SSR3 was added
gene: SSR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SSR3 were set to 30945312
Phenotypes for gene: SSR3 were set to Congenital disorder of glycosylation
Review for gene: SSR3 was set to AMBER
Added comment: Single individual reported with an unsolved type I CDG, intellectual disability, homozygous LOF variant in SSR3, supportive functional evidence.
Sources: Literature
Mendeliome v0.5461 LCP2 Zornitza Stark Gene: lcp2 has been classified as Red List (Low Evidence).
Mendeliome v0.5459 DPM2 Zornitza Stark Classified gene: DPM2 as Green List (high evidence)
Mendeliome v0.5459 DPM2 Zornitza Stark Gene: dpm2 has been classified as Green List (High Evidence).
Mendeliome v0.5458 ATP6V0A2 Zornitza Stark Gene: atp6v0a2 has been classified as Green List (High Evidence).
Mendeliome v0.5458 ATP6V0A2 Zornitza Stark Phenotypes for gene: ATP6V0A2 were changed from to Cutis laxa, autosomal recessive, type IIA, MIM# 219200; Wrinkly skin syndrome, MIM#278250
Mendeliome v0.5455 ATP6V0A2 Zornitza Stark reviewed gene: ATP6V0A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29952037, 22773132; Phenotypes: Cutis laxa, autosomal recessive, type IIA, MIM# 219200, Wrinkly skin syndrome, MIM#278250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5455 ALG9 Zornitza Stark Gene: alg9 has been classified as Green List (High Evidence).
Mendeliome v0.5449 ALG8 Zornitza Stark changed review comment from: Review of 15 reported individuals in PMID: 26066342: multiple prenatal abnormalities were present in 6/12 patients. In 13/15, there were symptoms at birth, 9/15 died within 12 months. Birth weight was appropriate in 11/12, only one was small for gestational age. Prematurity was reported in 7/12. Hydrops fetalis was noticed in 3, edemas in 11/13; gastrointestinal symptoms in 9/14; structural brain pathology, psychomental retardation, seizures, ataxia in 12/13, muscle hypotonia in 13/14. Common dysmorphic signs were: low set ears, macroglossia, hypertelorism, pes equinovarus, campto- and brachydactyly (13/15). In 10/11, there was coagulopathy, in 8/11 elevated transaminases; thrombocytopenia was present in 9/9. Eye involvement was reported in 9/14. CDG typical skin involvement was reported in 8/13.; to: Bi-allelic variants and CDG: Review of 15 reported individuals in PMID: 26066342. Multiple prenatal abnormalities were present in 6/12 patients. In 13/15, there were symptoms at birth, 9/15 died within 12 months. Birth weight was appropriate in 11/12, only one was small for gestational age. Prematurity was reported in 7/12. Hydrops fetalis was noticed in 3, edemas in 11/13; gastrointestinal symptoms in 9/14; structural brain pathology, psychomental retardation, seizures, ataxia in 12/13, muscle hypotonia in 13/14. Common dysmorphic signs were: low set ears, macroglossia, hypertelorism, pes equinovarus, campto- and brachydactyly (13/15). In 10/11, there was coagulopathy, in 8/11 elevated transaminases; thrombocytopenia was present in 9/9. Eye involvement was reported in 9/14. CDG typical skin involvement was reported in 8/13.
Mendeliome v0.5449 ALG8 Zornitza Stark Gene: alg8 has been classified as Green List (High Evidence).
Mendeliome v0.5446 ALG3 Zornitza Stark Gene: alg3 has been classified as Green List (High Evidence).
Mendeliome v0.5441 SLC3A2 Zornitza Stark Gene: slc3a2 has been classified as Red List (Low Evidence).
Mendeliome v0.5441 SLC3A2 Zornitza Stark Classified gene: SLC3A2 as Red List (low evidence)
Mendeliome v0.5441 SLC3A2 Zornitza Stark Gene: slc3a2 has been classified as Red List (Low Evidence).
Mendeliome v0.5440 HOXA4 Zornitza Stark Gene: hoxa4 has been classified as Red List (Low Evidence).
Mendeliome v0.5439 HOXA4 Zornitza Stark Phenotypes for gene: HOXA4 were changed from to Microtia-Atresia; CAKUT
Mendeliome v0.5436 HOXA4 Zornitza Stark Classified gene: HOXA4 as Red List (low evidence)
Mendeliome v0.5436 HOXA4 Zornitza Stark Gene: hoxa4 has been classified as Red List (Low Evidence).
Mendeliome v0.5435 ASTE1 Zornitza Stark Gene: aste1 has been classified as Red List (Low Evidence).
Mendeliome v0.5435 ASTE1 Zornitza Stark Phenotypes for gene: ASTE1 were changed from to palmar and plantar fibromatosis
Mendeliome v0.5432 ASTE1 Zornitza Stark Classified gene: ASTE1 as Red List (low evidence)
Mendeliome v0.5432 ASTE1 Zornitza Stark Gene: aste1 has been classified as Red List (Low Evidence).
Mendeliome v0.5431 HOXA4 Naomi Baker reviewed gene: HOXA4: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 33193662; Phenotypes: Microtia-Atresia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5431 ASTE1 Naomi Baker reviewed gene: ASTE1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 29104234; Phenotypes: palmar and plantar fibromatosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5431 SMARCA1 Zornitza Stark Gene: smarca1 has been classified as Red List (Low Evidence).
Mendeliome v0.5428 SMARCA1 Zornitza Stark Classified gene: SMARCA1 as Red List (low evidence)
Mendeliome v0.5428 SMARCA1 Zornitza Stark Gene: smarca1 has been classified as Red List (Low Evidence).
Mendeliome v0.5427 CDKAL1 Zornitza Stark Gene: cdkal1 has been classified as Red List (Low Evidence).
Mendeliome v0.5427 CDKAL1 Zornitza Stark Classified gene: CDKAL1 as Red List (low evidence)
Mendeliome v0.5427 CDKAL1 Zornitza Stark Gene: cdkal1 has been classified as Red List (Low Evidence).
Mendeliome v0.5426 TCHH Zornitza Stark Gene: tchh has been classified as Red List (Low Evidence).
Mendeliome v0.5423 TCHH Zornitza Stark Classified gene: TCHH as Red List (low evidence)
Mendeliome v0.5423 TCHH Zornitza Stark Gene: tchh has been classified as Red List (Low Evidence).
Mendeliome v0.5422 CRTAP Zornitza Stark Gene: crtap has been classified as Green List (High Evidence).
Mendeliome v0.5422 CRTAP Zornitza Stark Phenotypes for gene: CRTAP were changed from to Osteogenesis imperfecta, type VII MIM#610682
Mendeliome v0.5419 USP9X Zornitza Stark Gene: usp9x has been classified as Green List (High Evidence).
Mendeliome v0.5416 ALG6 Zornitza Stark Gene: alg6 has been classified as Green List (High Evidence).
Mendeliome v0.5412 RORB Zornitza Stark Gene: rorb has been classified as Green List (High Evidence).
Mendeliome v0.5412 RORB Zornitza Stark Phenotypes for gene: RORB were changed from to {Epilepsy, idiopathic generalized, susceptibility to, 15} (MIM#618357), AD; Genetic generalized epilepsy (GGE); Photosensitive generalized and occipital epilepsy
Mendeliome v0.5409 RORB Zornitza Stark reviewed gene: RORB: Rating: GREEN; Mode of pathogenicity: None; Publications: 27352968, 32162308; Phenotypes: {Epilepsy, idiopathic generalized, susceptibility to, 15} (MIM#618357), AD, Genetic generalized epilepsy (GGE), Photosensitive generalized and occipital epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5409 MYL9 Zornitza Stark Gene: myl9 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5409 MYL9 Zornitza Stark Classified gene: MYL9 as Amber List (moderate evidence)
Mendeliome v0.5409 MYL9 Zornitza Stark Gene: myl9 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5408 MYL9 Zornitza Stark gene: MYL9 was added
gene: MYL9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYL9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYL9 were set to 29453416; 33031641
Phenotypes for gene: MYL9 were set to Megacystis-microcolon-intestinal hypoperistalsis syndrome
Review for gene: MYL9 was set to AMBER
Added comment: Two unrelated families reported.
Sources: Literature
Mendeliome v0.5407 CRTAP Paul De Fazio reviewed gene: CRTAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 21955071, 19846465, 17192541; Phenotypes: Osteogenesis imperfecta, type VII MIM#610682; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5405 PHYKPL Zornitza Stark Gene: phykpl has been classified as Red List (Low Evidence).
Mendeliome v0.5405 PHYKPL Zornitza Stark Phenotypes for gene: PHYKPL were changed from to [?Phosphohydroxylysinuria] 615011
Mendeliome v0.5402 PHYKPL Zornitza Stark Classified gene: PHYKPL as Red List (low evidence)
Mendeliome v0.5402 PHYKPL Zornitza Stark Gene: phykpl has been classified as Red List (Low Evidence).
Mendeliome v0.5401 MTCL1 Bryony Thompson Classified gene: MTCL1 as Green List (high evidence)
Mendeliome v0.5401 MTCL1 Bryony Thompson Gene: mtcl1 has been classified as Green List (High Evidence).
Mendeliome v0.5400 MTCL1 Bryony Thompson edited their review of gene: MTCL1: Added comment: A new report of another case with a homozygous loss of function variant and a similar phenotype to the previously reported early onset homozygous Polish case (2 independent cases), and the supporting null mouse model.; Changed rating: GREEN; Changed publications: 30548255, 28283581, 32961396; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5400 PHYKPL Elena Savva reviewed gene: PHYKPL: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 23242558; Phenotypes: [?Phosphohydroxylysinuria] 615011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5400 POLE Zornitza Stark Gene: pole has been classified as Green List (High Evidence).
Mendeliome v0.5396 OFD1 Zornitza Stark Gene: ofd1 has been classified as Green List (High Evidence).
Mendeliome v0.5396 OFD1 Zornitza Stark Phenotypes for gene: OFD1 were changed from to Joubert syndrome 10, 300804; Simpson-Golabi-Behmel syndrome, type 2, 300209; Orofaciodigital syndrome I, 311200; Retinitis pigmentosa 23, 300424
Mendeliome v0.5393 OFD1 Elena Savva reviewed gene: OFD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31373179, 23033313, 16783569; Phenotypes: ?Retinitis pigmentosa 23, 300424, Joubert syndrome 10, 300804, Simpson-Golabi-Behmel syndrome, type 2, 300209, Orofaciodigital syndrome I, 311200; Mode of inheritance: Other
Mendeliome v0.5389 DZIP1 Zornitza Stark Gene: dzip1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5388 DZIP1 Zornitza Stark Classified gene: DZIP1 as Amber List (moderate evidence)
Mendeliome v0.5388 DZIP1 Zornitza Stark Gene: dzip1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5386 ADH5 Zornitza Stark Gene: adh5 has been classified as Green List (High Evidence).
Mendeliome v0.5386 ADH5 Zornitza Stark Classified gene: ADH5 as Green List (high evidence)
Mendeliome v0.5386 ADH5 Zornitza Stark Gene: adh5 has been classified as Green List (High Evidence).
Mendeliome v0.5385 ADH5 Zornitza Stark gene: ADH5 was added
gene: ADH5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ADH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADH5 were set to 33147438
Phenotypes for gene: ADH5 were set to Aplastic anaemia; myelodysplasia; short stature
Review for gene: ADH5 was set to GREEN
Added comment: 7 individuals reported with bi-allelic variants in this gene and a Fanconi syndrome-like phenotype. All had aplastic anaemia, 4 developed a myelodysplastic syndrome, and one developed AML. Short stature and abnormal skin pigmentation were additional features.

Note, all also had the ALDH2*2 allele, which is common in East Asian populations, and may be contributory.

Extensive experimental data.
Sources: Literature
Mendeliome v0.5384 NPHS2 Zornitza Stark Gene: nphs2 has been classified as Green List (High Evidence).
Mendeliome v0.5381 LRIF1 Bryony Thompson changed review comment from: A single consanguineous case with a homozygous truncating variant. DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus.
Sources: Literature; to: A single consanguineous case with a homozygous truncating variant, and D4Z4 repeat of 13 units on a 4qA haplotype (permissive haplotype). DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus.
Sources: Literature
Mendeliome v0.5381 LRIF1 Bryony Thompson Classified gene: LRIF1 as Amber List (moderate evidence)
Mendeliome v0.5381 LRIF1 Bryony Thompson Gene: lrif1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5380 LRIF1 Bryony Thompson gene: LRIF1 was added
gene: LRIF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRIF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRIF1 were set to 32467133
Phenotypes for gene: LRIF1 were set to Facioscapulohumeral muscular dystrophy
Review for gene: LRIF1 was set to AMBER
Added comment: A single consanguineous case with a homozygous truncating variant. DZ4Z hypomethylation and increased DUX expression was present in patient cells. siRNA-mediated depletion of LRIF1L in immortalized myoblasts derepressed the DUX4 locus.
Sources: Literature
Mendeliome v0.5379 DNAH8 Zornitza Stark Phenotypes for gene: DNAH8 were changed from Asthenozoospermia; primary ciliary dyskinesia to Spermatogenic failure 46, MIM#619095; Asthenozoospermia; primary ciliary dyskinesia
Mendeliome v0.5378 DNAH8 Zornitza Stark edited their review of gene: DNAH8: Changed phenotypes: Spermatogenic failure 46, MIM#619095, Asthenozoospermia, primary ciliary dyskinesia
Mendeliome v0.5378 MYRF Zornitza Stark Phenotypes for gene: MYRF were changed from Nanophthalmos; High hyperopia to Nanophthalmos and high hyperopia; Cardiac-urogenital syndrome, MIM# 618280; Encephalitis/encephalopathy, mild, with reversible myelin vacuolization, MIM# 618113
Mendeliome v0.5376 MYRF Zornitza Stark edited their review of gene: MYRF: Added comment: Association with Encephalitis/encephalopathy, mild, with reversible myelin vacuolization 618113: limited evidence, two multiplex families with same missense variant (likely founder effect) reported (p.Gln403Arg); Changed publications: 31048900, 31172260, 31266062, 31700225, 29446546, 29446546, 30532227, 31069960, 29265453; Changed phenotypes: Nanophthalmos and high hyperopia, Cardiac-urogenital syndrome, MIM# 618280, Encephalitis/encephalopathy, mild, with reversible myelin vacuolization, MIM# 618113
Mendeliome v0.5376 MYRF Zornitza Stark changed review comment from: Cardiac-urogenital syndrome is characterized by partial anomalous pulmonary venous return in association with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia, thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism. More than 10 unrelated individuals reported.; to: Cardiac-urogenital syndrome MIM# 618280 is characterized by partial anomalous pulmonary venous return in association with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia, thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism. More than 10 unrelated individuals reported.
Mendeliome v0.5376 MYRF Zornitza Stark edited their review of gene: MYRF: Added comment: Cardiac-urogenital syndrome is characterized by partial anomalous pulmonary venous return in association with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia, thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism. More than 10 unrelated individuals reported.; Changed publications: 31048900, 31172260, 31266062, 31700225, 29446546, 29446546, 30532227, 31069960; Changed phenotypes: Nanophthalmos and high hyperopia, Cardiac-urogenital syndrome, MIM# 618280
Mendeliome v0.5376 RLIM Zornitza Stark Gene: rlim has been classified as Green List (High Evidence).
Mendeliome v0.5373 DNAH2 Zornitza Stark Gene: dnah2 has been classified as Green List (High Evidence).
Mendeliome v0.5373 DNAH2 Zornitza Stark Classified gene: DNAH2 as Green List (high evidence)
Mendeliome v0.5373 DNAH2 Zornitza Stark Gene: dnah2 has been classified as Green List (High Evidence).
Mendeliome v0.5371 CLDN9 Zornitza Stark Phenotypes for gene: CLDN9 were changed from Deafness, autosomal recessive to Deafness, autosomal recessive 116, MIM#619093
Mendeliome v0.5370 CLDN9 Zornitza Stark edited their review of gene: CLDN9: Changed phenotypes: Deafness, autosomal recessive 116, MIM#619093
Mendeliome v0.5369 FGFR1 Zornitza Stark Gene: fgfr1 has been classified as Green List (High Evidence).
Mendeliome v0.5369 FGFR1 Zornitza Stark Phenotypes for gene: FGFR1 were changed from to Encephalocraniocutaneous lipomatosis, somatic mosaic 613001; Hartsfield syndrome 615465; Hypogonadotropic hypogonadism 2 with or without anosmia 147950; Jackson-Weiss syndrome 123150; Osteoglophonic dysplasia 166250; Pfeiffer syndrome 101600; Trigonocephaly 1 190440
Mendeliome v0.5365 B4GALT7 Zornitza Stark Gene: b4galt7 has been classified as Green List (High Evidence).
Mendeliome v0.5362 TBX6 Zornitza Stark Phenotypes for gene: TBX6 were changed from Skeletal dysplasia; spondylocostal dysostosis; congenital scoliosis to Spondylocostal dysostosis 5, 122600
Mendeliome v0.5361 KCNQ2 Zornitza Stark Gene: kcnq2 has been classified as Green List (High Evidence).
Mendeliome v0.5357 FGFR1 Elena Savva reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 18034870, 23812909, 26942290; Phenotypes: Encephalocraniocutaneous lipomatosis, somatic mosaic 613001, Hartsfield syndrome 615465, Hypogonadotropic hypogonadism 2 with or without anosmia 147950, Jackson-Weiss syndrome 123150, Osteoglophonic dysplasia 166250, Pfeiffer syndrome 101600, Trigonocephaly 1 190440; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5357 ADAR Zornitza Stark Gene: adar has been classified as Green List (High Evidence).
Mendeliome v0.5357 ADAR Zornitza Stark Phenotypes for gene: ADAR were changed from to Aicardi-Goutieres syndrome 6, MIM# 615010; Dyschromatosis symmetrica hereditaria, MIM# 127400
Mendeliome v0.5355 ADAR Zornitza Stark reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 6, MIM# 615010, Dyschromatosis symmetrica hereditaria, MIM# 127400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5355 NDUFB10 Zornitza Stark Classified gene: NDUFB10 as Green List (high evidence)
Mendeliome v0.5355 NDUFB10 Zornitza Stark Gene: ndufb10 has been classified as Green List (High Evidence).
Mendeliome v0.5353 FOXJ1 Zornitza Stark Phenotypes for gene: FOXJ1 were changed from hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry to Ciliary dyskinesia, primary, 43, MIM#618699; hydrocephalus; chronic destructive airway disease; randomization of left/right body asymmetry
Mendeliome v0.5352 FOXJ1 Zornitza Stark edited their review of gene: FOXJ1: Changed phenotypes: Ciliary dyskinesia, primary, 43, MIM#618699, hydrocephalus, chronic destructive airway disease, randomization of left/right body asymmetry
Mendeliome v0.5351 SCD5 Zornitza Stark Gene: scd5 has been classified as Red List (Low Evidence).
Mendeliome v0.5351 SCD5 Zornitza Stark gene: SCD5 was added
gene: SCD5 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SCD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCD5 were set to 31972369
Phenotypes for gene: SCD5 were set to Deafness, autosomal dominant 79, MIM#619086
Review for gene: SCD5 was set to RED
Added comment: Single 5-generation family reported with a missense variant segregating in 19 affected individuals. Variant is found at a low frequency in ExAC.
Sources: Expert list
Mendeliome v0.5349 SLC12A2 Zornitza Stark edited their review of gene: SLC12A2: Changed phenotypes: Delpire-McNeill syndrome, MIM#619083, Kilquist syndrome, MIM#619080, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies, Deafness, autosomal dominant 78, MIM# 619081
Mendeliome v0.5348 SLC12A2 Zornitza Stark edited their review of gene: SLC12A2: Changed phenotypes: Kilquist syndrome, MIM#619080, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies, Deafness, autosomal dominant 78, MIM# 619081
Mendeliome v0.5347 SLC12A2 Zornitza Stark edited their review of gene: SLC12A2: Changed phenotypes: Kilquist syndrome, MIM#619080, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies
Mendeliome v0.5347 OCLN Zornitza Stark Gene: ocln has been classified as Green List (High Evidence).
Mendeliome v0.5344 JAM3 Zornitza Stark Gene: jam3 has been classified as Green List (High Evidence).
Mendeliome v0.5341 NCKAP1 Zornitza Stark Gene: nckap1 has been classified as Green List (High Evidence).
Mendeliome v0.5338 ACAD9 Zornitza Stark Gene: acad9 has been classified as Green List (High Evidence).
Mendeliome v0.5334 ALDOB Zornitza Stark Gene: aldob has been classified as Green List (High Evidence).
Mendeliome v0.5330 MYO1A Zornitza Stark Gene: myo1a has been classified as Red List (Low Evidence).
Mendeliome v0.5330 MYO1A Zornitza Stark Classified gene: MYO1A as Red List (low evidence)
Mendeliome v0.5330 MYO1A Zornitza Stark Gene: myo1a has been classified as Red List (Low Evidence).
Mendeliome v0.5329 ARL2 Zornitza Stark Gene: arl2 has been classified as Red List (Low Evidence).
Mendeliome v0.5329 ARL2 Zornitza Stark gene: ARL2 was added
gene: ARL2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ARL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARL2 were set to 30945270
Phenotypes for gene: ARL2 were set to Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma-1 (MRCS1), MIM#619082
Review for gene: ARL2 was set to RED
Added comment: Single family reported, missense variant segregating with structural eye abnormalities in 4 individuals (father and three daughters).
Sources: Expert list
Mendeliome v0.5327 LMX1B Zornitza Stark commented on gene: LMX1B: Nail-patella syndrome (NPS) is an autosomal-dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Varying degrees of proteinuria or hematuria are present, and can occasionally progress to chronic renal failure. Some variants in the homeodomain of LMX1B cause isolated nephropathy without nail, patellar or skeletal abnormality (LMX1B-associated nephropathy).

>300 families reported.
Mendeliome v0.5326 UNC80 Zornitza Stark Gene: unc80 has been classified as Green List (High Evidence).
Mendeliome v0.5323 ZFHX4 Zornitza Stark Classified gene: ZFHX4 as Green List (high evidence)
Mendeliome v0.5323 ZFHX4 Zornitza Stark Gene: zfhx4 has been classified as Green List (High Evidence).
Mendeliome v0.5321 AP2S1 Zornitza Stark Gene: ap2s1 has been classified as Green List (High Evidence).
Mendeliome v0.5320 CARD8 Zornitza Stark Gene: card8 has been classified as Red List (Low Evidence).
Mendeliome v0.5317 ZFHX4 Bryony Thompson Gene: zfhx4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5316 ZFHX4 Bryony Thompson Classified gene: ZFHX4 as Amber List (moderate evidence)
Mendeliome v0.5316 ZFHX4 Bryony Thompson Gene: zfhx4 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5315 ZFHX4 Bryony Thompson changed review comment from: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature; to: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
PMID: 24038936 - a single case with developmental delay, macrocephaly, ventriculomegaly, hypermetropia, recurrent
infections, dysmorphism and a de novo deletion of the last 7 exons of the gene.
Sources: Literature
Mendeliome v0.5315 ZFHX4 Bryony Thompson gene: ZFHX4 was added
gene: ZFHX4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZFHX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZFHX4 were set to 33057194
Phenotypes for gene: ZFHX4 were set to Developmental disorders
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (5 frameshift, 5 missense, 4 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5314 UPF1 Bryony Thompson Gene: upf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5314 UPF1 Bryony Thompson Classified gene: UPF1 as Amber List (moderate evidence)
Mendeliome v0.5314 UPF1 Bryony Thompson Gene: upf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5313 UPF1 Bryony Thompson gene: UPF1 was added
gene: UPF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UPF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UPF1 were set to 33057194
Phenotypes for gene: UPF1 were set to Developmental disorders
Review for gene: UPF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 16 de novo variants (1 frameshift, 11 missense, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5312 U2AF2 Bryony Thompson Classified gene: U2AF2 as Amber List (moderate evidence)
Mendeliome v0.5312 U2AF2 Bryony Thompson Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5311 U2AF2 Bryony Thompson gene: U2AF2 was added
gene: U2AF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 33057194
Phenotypes for gene: U2AF2 were set to Developmental disorders
Review for gene: U2AF2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 8 missense, 1 synoymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5309 TCF7L2 Bryony Thompson Gene: tcf7l2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5306 TCF7L2 Bryony Thompson Classified gene: TCF7L2 as Amber List (moderate evidence)
Mendeliome v0.5306 TCF7L2 Bryony Thompson Gene: tcf7l2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5305 SRRM2 Bryony Thompson Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5305 SRRM2 Bryony Thompson Classified gene: SRRM2 as Amber List (moderate evidence)
Mendeliome v0.5305 SRRM2 Bryony Thompson Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5304 SRRM2 Bryony Thompson gene: SRRM2 was added
gene: SRRM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRRM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRRM2 were set to 33057194
Phenotypes for gene: SRRM2 were set to Developmental disorders
Review for gene: SRRM2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 28 de novo variants (11 frameshift, 7 missense, 1 splice acceptor, 5 stopgain, 4 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5303 SPEN Bryony Thompson Gene: spen has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5303 SPEN Bryony Thompson Classified gene: SPEN as Amber List (moderate evidence)
Mendeliome v0.5303 SPEN Bryony Thompson Gene: spen has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5302 SPEN Bryony Thompson gene: SPEN was added
gene: SPEN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPEN were set to 33057194
Phenotypes for gene: SPEN were set to Developmental disorders
Review for gene: SPEN was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 25 de novo variants (6 frameshift, 1 in-frame, 7 missense, 8 stopgain, 3 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5301 SATB1 Bryony Thompson Gene: satb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5301 SATB1 Bryony Thompson Classified gene: SATB1 as Amber List (moderate evidence)
Mendeliome v0.5301 SATB1 Bryony Thompson Gene: satb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5300 SATB1 Bryony Thompson gene: SATB1 was added
gene: SATB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SATB1 were set to 33057194
Phenotypes for gene: SATB1 were set to Developmental disorders
Review for gene: SATB1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 12 de novo (2 frameshift, 7 missense, 1 stopgain, 2 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5299 RAB14 Bryony Thompson Gene: rab14 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5299 RAB14 Bryony Thompson Classified gene: RAB14 as Amber List (moderate evidence)
Mendeliome v0.5299 RAB14 Bryony Thompson Gene: rab14 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5298 RAB14 Bryony Thompson gene: RAB14 was added
gene: RAB14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB14 were set to 33057194
Phenotypes for gene: RAB14 were set to Developmental disorders
Review for gene: RAB14 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (1 in-frame, 7 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5297 PSMC5 Bryony Thompson Gene: psmc5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5297 PSMC5 Bryony Thompson Classified gene: PSMC5 as Amber List (moderate evidence)
Mendeliome v0.5297 PSMC5 Bryony Thompson Gene: psmc5 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5296 PSMC5 Bryony Thompson gene: PSMC5 was added
gene: PSMC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMC5 were set to 33057194
Phenotypes for gene: PSMC5 were set to Developmental disorders
Review for gene: PSMC5 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 9 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5295 PRPF8 Bryony Thompson Gene: prpf8 has been classified as Green List (High Evidence).
Mendeliome v0.5295 PRPF8 Bryony Thompson Added comment: Comment on phenotypes: Established Retinitis pigmentosa gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 29 de novo variants (2 frameshift, 19 missense, 1 stopgain, 7 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5292 MSL2 Bryony Thompson Gene: msl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5292 MSL2 Bryony Thompson Classified gene: MSL2 as Amber List (moderate evidence)
Mendeliome v0.5292 MSL2 Bryony Thompson Gene: msl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5290 MSL2 Bryony Thompson gene: MSL2 was added
gene: MSL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MSL2 were set to 31332282; 33057194
Phenotypes for gene: MSL2 were set to Developmental disorders; autism
Review for gene: MSL2 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 13 de novo variants (9 frameshift, 4 missense) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
PMID: 31332282 - candidate gene in a single autism study, with recurrent de novo variants in a potential oligogenic model
Sources: Literature
Mendeliome v0.5289 MMGT1 Bryony Thompson Classified gene: MMGT1 as Amber List (moderate evidence)
Mendeliome v0.5289 MMGT1 Bryony Thompson Gene: mmgt1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5288 MMGT1 Bryony Thompson gene: MMGT1 was added
gene: MMGT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MMGT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MMGT1 were set to 33057194
Phenotypes for gene: MMGT1 were set to Developmental disorders
Review for gene: MMGT1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 3 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5286 MIB1 Bryony Thompson Added comment: Comment on phenotypes: Established congenital cardiac disease gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5284 MFN2 Bryony Thompson Added comment: Comment on phenotypes: Established cause of hereditary neuropathy.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 9 de novo variants (8 missense, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5282 KCNK3 Bryony Thompson Added comment: Comment on phenotypes: Established pulmonary hypertension gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (7 missense, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Mendeliome v0.5282 KCNK3 Bryony Thompson Phenotypes for gene: KCNK3 were changed from to Pulmonary hypertension, primary, 4 MIM#615344
Mendeliome v0.5280 HNRNPD Bryony Thompson Gene: hnrnpd has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5280 HNRNPD Bryony Thompson Classified gene: HNRNPD as Amber List (moderate evidence)
Mendeliome v0.5280 HNRNPD Bryony Thompson Gene: hnrnpd has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5279 HNRNPD Bryony Thompson gene: HNRNPD was added
gene: HNRNPD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPD were set to 33057194
Phenotypes for gene: HNRNPD were set to Developmental disorders
Review for gene: HNRNPD was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 8 de novo variants (5 frameshift, 1 missense, 1 splice acceptor, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5278 PRKG2 Zornitza Stark Gene: prkg2 has been classified as Green List (High Evidence).
Mendeliome v0.5278 PRKG2 Zornitza Stark Classified gene: PRKG2 as Green List (high evidence)
Mendeliome v0.5278 PRKG2 Zornitza Stark Gene: prkg2 has been classified as Green List (High Evidence).
Mendeliome v0.5277 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Mendeliome v0.5277 PLXND1 Zornitza Stark Classified gene: PLXND1 as Green List (high evidence)
Mendeliome v0.5277 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Mendeliome v0.5275 ECEL1 Zornitza Stark Gene: ecel1 has been classified as Green List (High Evidence).
Mendeliome v0.5275 ECEL1 Zornitza Stark Phenotypes for gene: ECEL1 were changed from to Arthrogryposis, distal, type 5D, MIM# 615065
Mendeliome v0.5274 MYMK Zornitza Stark changed review comment from: Sources: Expert list; to: Carey-Fineman-Ziter syndrome (CFZS) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. Intellect has been normal in molecularly confirmed cases. Defect in myoblast fusion. 6 unrelated families reported with CFZ phenotype and bi-allelic MYMK variants. p.Pro91Thr is a common founder variant, which is hypomorphic.
Mendeliome v0.5272 ECEL1 Zornitza Stark reviewed gene: ECEL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23261301, 23236030, 25099528, 24782201; Phenotypes: Arthrogryposis, distal, type 5D, MIM# 615065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5272 PRKG2 Arina Puzriakova gene: PRKG2 was added
gene: PRKG2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRKG2 were set to 33106379
Phenotypes for gene: PRKG2 were set to Acromesomelic dysplasia
Review for gene: PRKG2 was set to GREEN
Added comment: - PMID: 33106379 (2020) - Distinct homozygous variants in PRKG2 identified in two unrelated individuals, both with a skeletal dysplasia associated with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones.

Functional studies showed both variants result in NMD and disrupt the downstream MAPK signalling pathway in response to FGF2. The role of cGKII, encoded by PRKG2, in skeletal growth has been established in several animal models (references provided in paper).
Sources: Literature
Mendeliome v0.5271 FOXP4 Zornitza Stark Gene: foxp4 has been classified as Green List (High Evidence).
Mendeliome v0.5271 FOXP4 Zornitza Stark Classified gene: FOXP4 as Green List (high evidence)
Mendeliome v0.5271 FOXP4 Zornitza Stark Gene: foxp4 has been classified as Green List (High Evidence).
Mendeliome v0.5270 FOXP4 Zornitza Stark gene: FOXP4 was added
gene: FOXP4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to GREEN
Added comment: Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays.
Sources: Literature
Mendeliome v0.5269 ASAH1 Zornitza Stark Gene: asah1 has been classified as Green List (High Evidence).
Mendeliome v0.5269 ASAH1 Zornitza Stark Phenotypes for gene: ASAH1 were changed from to Spinal muscular atrophy with progressive myoclonic epilepsy, MIM# 159950; Farber lipogranulomatosis, MIM# 228000
Mendeliome v0.5267 ASAH1 Zornitza Stark reviewed gene: ASAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinal muscular atrophy with progressive myoclonic epilepsy, MIM# 159950, Farber lipogranulomatosis, MIM# 228000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5267 DHX32 Zornitza Stark Gene: dhx32 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5267 DHX32 Zornitza Stark Classified gene: DHX32 as Amber List (moderate evidence)
Mendeliome v0.5267 DHX32 Zornitza Stark Gene: dhx32 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5266 TNF Zornitza Stark Gene: tnf has been classified as Red List (Low Evidence).
Mendeliome v0.5265 TNF Zornitza Stark Classified gene: TNF as Red List (low evidence)
Mendeliome v0.5265 TNF Zornitza Stark Gene: tnf has been classified as Red List (Low Evidence).
Mendeliome v0.5264 ALK Zornitza Stark Gene: alk has been classified as Green List (High Evidence).
Mendeliome v0.5261 RHOB Zornitza Stark Gene: rhob has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5260 RHOB Zornitza Stark Classified gene: RHOB as Amber List (moderate evidence)
Mendeliome v0.5260 RHOB Zornitza Stark Gene: rhob has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5259 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979 to Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, intellectual disability, autosomal dominant
Mendeliome v0.5255 FBXO31 Zornitza Stark Classified gene: FBXO31 as Amber List (moderate evidence)
Mendeliome v0.5255 FBXO31 Zornitza Stark Gene: fbxo31 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5254 FBXO31 Kristin Rigbye changed review comment from: 2 unrelated probands with CP harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression.; to: 2 unrelated probands with CP harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression.

Extended patient phenotypes: Spastic diplegia, with esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus (patient 1); Spastic paraplegia with ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation (patient 2).
Mendeliome v0.5254 NHLRC2 Zornitza Stark Gene: nhlrc2 has been classified as Green List (High Evidence).
Mendeliome v0.5254 NHLRC2 Zornitza Stark Phenotypes for gene: NHLRC2 were changed from to Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) syndrome MIM#618278
Mendeliome v0.5251 RHOB Crystle Lee gene: RHOB was added
gene: RHOB was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RHOB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RHOB were set to 32989326
Phenotypes for gene: RHOB were set to Cerebral Palsy (PMID:32989326)
Mode of pathogenicity for gene: RHOB was set to Other
Review for gene: RHOB was set to AMBER
Added comment: Candidate disease-causing gene for CP. Recurrent de novo missense variant reported in 2 unrelated families with supporting functional studies.
Sources: Expert list
Mendeliome v0.5251 CTLA4 Zornitza Stark Gene: ctla4 has been classified as Green List (High Evidence).
Mendeliome v0.5249 VIM Zornitza Stark Gene: vim has been classified as Green List (High Evidence).
Mendeliome v0.5249 VIM Zornitza Stark Phenotypes for gene: VIM were changed from to Cataract 30, pulverulent 116300; frontonasal dysostosis and premature aging
Mendeliome v0.5248 NHLRC2 Paul De Fazio changed review comment from: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty)

PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Expression studies in patient-derived fibroblasts supported the frameshift variant leading to NMD. Zebrafish knockdown affected the integrity of cells in the midbrain region.

PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.; to: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty)

PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Expression studies in patient-derived fibroblasts supported the frameshift variant leading to NMD. Zebrafish knockdown affected the integrity of cells in the midbrain region.

PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.
Mendeliome v0.5248 NHLRC2 Paul De Fazio changed review comment from: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty)

PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Zebrafish knockdown affected the integrity of cells in the midbrain region.

PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.; to: 3 families with compound het variants in total, all share one missense variant (p.Asp148Ty)

PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Expression studies in patient-derived fibroblasts supported the frameshift variant leading to NMD. Zebrafish knockdown affected the integrity of cells in the midbrain region.

PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.
Mendeliome v0.5246 NHLRC2 Paul De Fazio reviewed gene: NHLRC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29423877, 32435055; Phenotypes: Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) syndrome MIM#618278; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5245 STN1 Zornitza Stark Classified gene: STN1 as Green List (high evidence)
Mendeliome v0.5245 STN1 Zornitza Stark Gene: stn1 has been classified as Green List (High Evidence).
Mendeliome v0.5244 ITPR3 Zornitza Stark Gene: itpr3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5244 VIM Ee Ming Wong reviewed gene: VIM: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 32066935; Phenotypes: frontonasal dysostosis, premature aging; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5244 ITPR3 Zornitza Stark Classified gene: ITPR3 as Amber List (moderate evidence)
Mendeliome v0.5244 ITPR3 Zornitza Stark Gene: itpr3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5243 ITPR3 Zornitza Stark gene: ITPR3 was added
gene: ITPR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITPR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ITPR3 were set to 32949214
Phenotypes for gene: ITPR3 were set to Charcot-Marie-Tooth disease
Review for gene: ITPR3 was set to AMBER
Added comment: Two unrelated families reported: variant segregated in four affected individuals in one family and was de novo in the second family where there was a single affected person. Some evidence for dominant-negative effect.
Sources: Literature
Mendeliome v0.5240 AMOTL1 Zornitza Stark Gene: amotl1 has been classified as Red List (Low Evidence).
Mendeliome v0.5239 KIRREL1 Zornitza Stark Gene: kirrel1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5239 KIRREL1 Zornitza Stark Classified gene: KIRREL1 as Amber List (moderate evidence)
Mendeliome v0.5239 KIRREL1 Zornitza Stark Gene: kirrel1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5238 KIRREL1 Zornitza Stark gene: KIRREL1 was added
gene: KIRREL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIRREL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIRREL1 were set to 31472902
Phenotypes for gene: KIRREL1 were set to Steroid-resistant nephrotic syndrome
Review for gene: KIRREL1 was set to AMBER
Added comment: Two unrelated families reported with bi-allelic variants and limited functional data.
Sources: Literature
Mendeliome v0.5237 GFRA1 Zornitza Stark Gene: gfra1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5237 GFRA1 Zornitza Stark Classified gene: GFRA1 as Amber List (moderate evidence)
Mendeliome v0.5237 GFRA1 Zornitza Stark Gene: gfra1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5236 GFRA1 Zornitza Stark gene: GFRA1 was added
gene: GFRA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GFRA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GFRA1 were set to 33020172
Phenotypes for gene: GFRA1 were set to Renal agenesis
Review for gene: GFRA1 was set to AMBER
Added comment: Two unrelated families reported with bi-allelic LOF variants identified in individuals with bilateral renal agenesis. GFRA1 gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system.
Sources: Literature
Mendeliome v0.5235 GNB2 Bryony Thompson reviewed gene: GNB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194; Phenotypes: Developmental disorder, sinus node dysfunction and atrioventricular block; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5235 GIGYF1 Bryony Thompson Gene: gigyf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5235 GIGYF1 Bryony Thompson Classified gene: GIGYF1 as Amber List (moderate evidence)
Mendeliome v0.5235 GIGYF1 Bryony Thompson Gene: gigyf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5234 GIGYF1 Bryony Thompson gene: GIGYF1 was added
gene: GIGYF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GIGYF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GIGYF1 were set to 33057194
Phenotypes for gene: GIGYF1 were set to Developmental disorder
Review for gene: GIGYF1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5233 FBXW7 Bryony Thompson Gene: fbxw7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5233 FBXW7 Bryony Thompson Classified gene: FBXW7 as Amber List (moderate evidence)
Mendeliome v0.5233 FBXW7 Bryony Thompson Gene: fbxw7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5232 FBXW7 Bryony Thompson gene: FBXW7 was added
gene: FBXW7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXW7 were set to 33057194
Phenotypes for gene: FBXW7 were set to Developmental disorder
Review for gene: FBXW7 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 12 de novo missense and 1 de novo synonymous variant identified in ~10,000 cases with developmental disorders (no other phenotype info provided)
Sources: Literature
Mendeliome v0.5230 PRKAR1B Zornitza Stark Gene: prkar1b has been classified as Green List (High Evidence).
Mendeliome v0.5230 PRKAR1B Zornitza Stark Classified gene: PRKAR1B as Green List (high evidence)
Mendeliome v0.5230 PRKAR1B Zornitza Stark Gene: prkar1b has been classified as Green List (High Evidence).
Mendeliome v0.5229 PRKAR1B Konstantinos Varvagiannis gene: PRKAR1B was added
gene: PRKAR1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Penetrance for gene: PRKAR1B were set to unknown
Review for gene: PRKAR1B was set to AMBER
Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Mendeliome v0.5229 NR1H4 Zornitza Stark Gene: nr1h4 has been classified as Green List (High Evidence).
Mendeliome v0.5229 NR1H4 Zornitza Stark Phenotypes for gene: NR1H4 were changed from to Cholestasis, progressive familial intrahepatic, 5, MIM# 617049
Mendeliome v0.5226 NR1H4 Zornitza Stark reviewed gene: NR1H4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26888176, 32443034; Phenotypes: Cholestasis, progressive familial intrahepatic, 5, MIM# 617049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5226 PTF1A Zornitza Stark Gene: ptf1a has been classified as Green List (High Evidence).
Mendeliome v0.5226 PTF1A Zornitza Stark Phenotypes for gene: PTF1A were changed from to Pancreatic agenesis 2, MIM# 615935; Pancreatic and cerebellar agenesis, MIM# 609069
Mendeliome v0.5223 PTF1A Zornitza Stark reviewed gene: PTF1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24212882, 21749365, 10507728, 15543146, 19650412; Phenotypes: Pancreatic agenesis 2, MIM# 615935, Pancreatic and cerebellar agenesis, MIM# 609069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5223 MPP5 Zornitza Stark Gene: mpp5 has been classified as Green List (High Evidence).
Mendeliome v0.5223 MPP5 Zornitza Stark Classified gene: MPP5 as Green List (high evidence)
Mendeliome v0.5223 MPP5 Zornitza Stark Gene: mpp5 has been classified as Green List (High Evidence).
Mendeliome v0.5222 MPP5 Konstantinos Varvagiannis gene: MPP5 was added
gene: MPP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MPP5 were set to 33073849
Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality
Penetrance for gene: MPP5 were set to unknown
Review for gene: MPP5 was set to GREEN
Added comment: Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants.

Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features.

All were investigated by exome sequencing (previous investigations not mentioned).

One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro). All variants had in silico predictions in favor of a deleterious effect (CADD score >24).

The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK p55 subfamily), determining cell polarity at tight junctions.

Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided]

The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness.

Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision.

Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice.
Sources: Literature
Mendeliome v0.5222 AKR1D1 Zornitza Stark Gene: akr1d1 has been classified as Green List (High Evidence).
Mendeliome v0.5222 AKR1D1 Zornitza Stark Phenotypes for gene: AKR1D1 were changed from to Bile acid synthesis defect, congenital, 2, MIM# 235555
Mendeliome v0.5219 AKR1D1 Zornitza Stark reviewed gene: AKR1D1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12970144, 20522910; Phenotypes: Bile acid synthesis defect, congenital, 2, MIM# 235555; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5219 SCYL1 Zornitza Stark Gene: scyl1 has been classified as Green List (High Evidence).
Mendeliome v0.5219 SCYL1 Zornitza Stark Phenotypes for gene: SCYL1 were changed from to Spinocerebellar ataxia, autosomal recessive 21, MIM# 616719
Mendeliome v0.5216 SCYL1 Zornitza Stark commented on gene: SCYL1: Autosomal recessive spinocerebellar ataxia-21 is a neurologic disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in early childhood. Affected individuals also have recurrent episodes of liver failure in the first decade, resulting in chronic liver fibrosis, as well as later onset of a peripheral neuropathy. Mild learning disabilities may also occur. More than 5 unrelated families reported.
Mendeliome v0.5216 SLC30A10 Zornitza Stark Gene: slc30a10 has been classified as Green List (High Evidence).
Mendeliome v0.5213 DDX23 Bryony Thompson Classified gene: DDX23 as Amber List (moderate evidence)
Mendeliome v0.5213 DDX23 Bryony Thompson Gene: ddx23 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5212 DDX23 Bryony Thompson gene: DDX23 was added
gene: DDX23 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX23 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX23 were set to 33057194
Phenotypes for gene: DDX23 were set to Developmental disorder
Review for gene: DDX23 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 6 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided)
Sources: Literature
Mendeliome v0.5211 ATP6V0A1 Bryony Thompson Classified gene: ATP6V0A1 as Amber List (moderate evidence)
Mendeliome v0.5211 ATP6V0A1 Bryony Thompson Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5210 ATP6V0A1 Bryony Thompson gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Phenotypes for gene: ATP6V0A1 were set to Developmental disorder; Rett syndrome-like
Review for gene: ATP6V0A1 was set to AMBER
Added comment: PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 11 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
PMID: 30842224 - identified a de novo missense variant in a single individual with atypical Rett syndrome phenotype
Sources: Literature
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Classified gene: ARHGAP35 as Amber List (moderate evidence)
Mendeliome v0.5209 ARHGAP35 Bryony Thompson Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5208 ARHGAP35 Bryony Thompson gene: ARHGAP35 was added
gene: ARHGAP35 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to 33057194
Phenotypes for gene: ARHGAP35 were set to Developmental disorder
Review for gene: ARHGAP35 was set to AMBER
Added comment: Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 16 de novo variants (3 frameshift, 2 in-frame, 10 missense, 1 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Literature
Mendeliome v0.5207 AP2S1 Bryony Thompson Added comment: Comment on phenotypes: Established hypercalcaemia gene.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 5 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided)
Mendeliome v0.5204 ASCL1 Zornitza Stark Gene: ascl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5201 ASCL1 Zornitza Stark Classified gene: ASCL1 as Amber List (moderate evidence)
Mendeliome v0.5201 ASCL1 Zornitza Stark Gene: ascl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5198 KDELR2 Zornitza Stark Gene: kdelr2 has been classified as Green List (High Evidence).
Mendeliome v0.5198 KDELR2 Zornitza Stark Classified gene: KDELR2 as Green List (high evidence)
Mendeliome v0.5198 KDELR2 Zornitza Stark Gene: kdelr2 has been classified as Green List (High Evidence).
Mendeliome v0.5197 KDELR2 Zornitza Stark gene: KDELR2 was added
gene: KDELR2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KDELR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KDELR2 were set to 33053334
Phenotypes for gene: KDELR2 were set to Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms
Review for gene: KDELR2 was set to GREEN
Added comment: 4 families with osteogenesis imperfecta reported with functional studies.
Sources: Expert list
Mendeliome v0.5196 SCN8A Zornitza Stark Gene: scn8a has been classified as Green List (High Evidence).
Mendeliome v0.5196 SCN8A Zornitza Stark Phenotypes for gene: SCN8A were changed from to Developmental and epileptic encephalopathy 13, MIM#614558, dominant and recessive; Myoclonus, familial, 2, MIM# 618364; paroxysmal kinesigenic dyskinesias; Cognitive impairment with or without cerebellar ataxia, MIM# 614306
Mendeliome v0.5192 SCN8A Zornitza Stark reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31625145, 29726066, 27098556, 28702509, 16236810, 31904124, 31887642, 31675620; Phenotypes: Developmental and epileptic encephalopathy 13, MIM#614558, dominant and recessive, Myoclonus, familial, 2, MIM# 618364, paroxysmal kinesigenic dyskinesias, Cognitive impairment with or without cerebellar ataxia, MIM# 614306; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.5191 ALPK1 Zornitza Stark edited their review of gene: ALPK1: Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache (ROSAH) syndrome, MIM#614979
Mendeliome v0.5190 ALPK1 Zornitza Stark Phenotypes for gene: ALPK1 were changed from Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome ROSAH syndrome, MIM#614979 to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache (ROSAH) syndrome, MIM#614979
Mendeliome v0.5189 ALPK1 Zornitza Stark Phenotypes for gene: ALPK1 were changed from Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; ROSAH syndrome; retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache to Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome; Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome ROSAH syndrome, MIM#614979
Mendeliome v0.5188 ALPK1 Zornitza Stark edited their review of gene: ALPK1: Changed phenotypes: Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndromeROSAH syndrome, MIM#614979
Mendeliome v0.5185 COG8 Zornitza Stark Gene: cog8 has been classified as Green List (High Evidence).
Mendeliome v0.5182 HBB Zornitza Stark Gene: hbb has been classified as Green List (High Evidence).
Mendeliome v0.5182 HBB Zornitza Stark Phenotypes for gene: HBB were changed from to Delta-beta thalassemia 141749; Erythrocytosis 6 617980; Heinz body anemia 140700; Hereditary persistence of fetal hemoglobin 141749; Methemoglobinemia, beta type 617971; Sickle cell anemia 603903; Thalassemia-beta, dominant inclusion-body 603902; Thalassemia, beta 613985
Mendeliome v0.5178 RAD51D Zornitza Stark Gene: rad51d has been classified as Red List (Low Evidence).
Mendeliome v0.5175 RAD51D Zornitza Stark Classified gene: RAD51D as Red List (low evidence)
Mendeliome v0.5175 RAD51D Zornitza Stark Gene: rad51d has been classified as Red List (Low Evidence).
Mendeliome v0.5174 HBB Elena Savva reviewed gene: HBB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31788855, 20301599, 29700171; Phenotypes: {Malaria, resistance to} 611162, Delta-beta thalassemia 141749, Erythrocytosis 6 617980, Heinz body anemia 140700, Hereditary persistence of fetal hemoglobin 141749, Methemoglobinemia, beta type 617971, Sickle cell anemia 603903, Thalassemia-beta, dominant inclusion-body 603902, Thalassemia, beta 613985; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.5174 TPO Zornitza Stark Gene: tpo has been classified as Green List (High Evidence).
Mendeliome v0.5174 TPO Zornitza Stark Phenotypes for gene: TPO were changed from to Thyroid dyshormonogenesis 2A, MIM# 274500
Mendeliome v0.5171 TPO Zornitza Stark reviewed gene: TPO: Rating: GREEN; Mode of pathogenicity: None; Publications: 8027236, 10084596; Phenotypes: Thyroid dyshormonogenesis 2A, MIM# 274500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5171 SLC35A3 Zornitza Stark Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures; OMIM #615553 to Arthrogryposis, mental retardation, and seizures OMIM #615553; Skeletal dysplasia; Congenital disorder of glycosylation
Mendeliome v0.5169 SLC35A3 Zornitza Stark Classified gene: SLC35A3 as Green List (high evidence)
Mendeliome v0.5169 SLC35A3 Zornitza Stark Gene: slc35a3 has been classified as Green List (High Evidence).
Mendeliome v0.5168 SLC35A3 Zornitza Stark edited their review of gene: SLC35A3: Added comment: Third unrelated family reported in PMID 28777481 with prenatally diagnosed anomalous vertebrae, including butterfly, and hemivertebrae throughout the spine, as well as cleft palate, micrognathia, patent foramen ovale, patent ductus arteriosus, posterior embryotoxon, short limbs, camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism including proptosis, nevus flammeus, and a cupped left ear. Unclear if this is a distinct phenotype (note Holstein cows with variants in this gene have a skeletal phenotype) or part of a spectrum for a CDG. However, abnormal protein glycosylation, consistent with a defective Golgi UDP-GlcNAc transporter demonstrated, so overall, promoted to Green for CDG.; Changed rating: GREEN; Changed publications: 28777481, 28328131, 24031089; Changed phenotypes: Arthrogryposis, mental retardation, and seizures OMIM #615553, Skeletal dysplasia, Congenital disorder of glycosylation; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5168 VAC14 Zornitza Stark Gene: vac14 has been classified as Green List (High Evidence).
Mendeliome v0.5164 PHOX2A Zornitza Stark reviewed gene: PHOX2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 16815872; Phenotypes: Fibrosis of extraocular muscles, congenital, 2 602078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5164 PHOX2A Zornitza Stark Classified gene: PHOX2A as Green List (high evidence)
Mendeliome v0.5164 PHOX2A Zornitza Stark Gene: phox2a has been classified as Green List (High Evidence).
Mendeliome v0.5163 COL25A1 Zornitza Stark Gene: col25a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5163 COL25A1 Zornitza Stark Phenotypes for gene: COL25A1 were changed from to Fibrosis of extraocular muscles, congenital, 5, MIM# 616219
Mendeliome v0.5160 COL25A1 Zornitza Stark Classified gene: COL25A1 as Amber List (moderate evidence)
Mendeliome v0.5160 COL25A1 Zornitza Stark Gene: col25a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5159 COL25A1 Zornitza Stark reviewed gene: COL25A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25500261, 26486031; Phenotypes: Fibrosis of extraocular muscles, congenital, 5, MIM# 616219; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5159 KIF21A Zornitza Stark Gene: kif21a has been classified as Green List (High Evidence).
Mendeliome v0.5159 KIF21A Zornitza Stark Phenotypes for gene: KIF21A were changed from to Fibrosis of extraocular muscles, congenital, 1/3B, MIM# 135700
Mendeliome v0.5156 KIF21A Zornitza Stark reviewed gene: KIF21A: Rating: GREEN; Mode of pathogenicity: None; Publications: 15621876, 15223798, 15621877, 18332320, 28930843, 27513105, 26190014, 24656932; Phenotypes: Fibrosis of extraocular muscles, congenital, 1/3B, MIM# 135700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5156 NDUFAF6 Zornitza Stark Gene: ndufaf6 has been classified as Green List (High Evidence).
Mendeliome v0.5153 WNT5A Zornitza Stark Gene: wnt5a has been classified as Green List (High Evidence).
Mendeliome v0.5150 CYP3A4 Zornitza Stark Gene: cyp3a4 has been classified as Green List (High Evidence).
Mendeliome v0.5146 KCTD17 Zornitza Stark Gene: kctd17 has been classified as Green List (High Evidence).
Mendeliome v0.5143 TAF1 Zornitza Stark Gene: taf1 has been classified as Green List (High Evidence).
Mendeliome v0.5140 CTNNA3 Bryony Thompson Gene: ctnna3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5140 CTNNA3 Bryony Thompson Classified gene: CTNNA3 as Amber List (moderate evidence)
Mendeliome v0.5140 CTNNA3 Bryony Thompson Gene: ctnna3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5139 CTNNA3 Bryony Thompson gene: CTNNA3 was added
gene: CTNNA3 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: CTNNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTNNA3 were set to 23136403; 21254927; 22421363; 30415094; 31539150
Phenotypes for gene: CTNNA3 were set to Arrhythmogenic right ventricular cardiomyopathy; Arrhythmogenic right ventricular dysplasia, familial, 13 MIM#615616
Review for gene: CTNNA3 was set to AMBER
Added comment: Gene is classified as Limited by the ClinGen ARVC GCEP (Classification - 08/06/2019). PMID: 23136403 - an assumed de novo missense (V94D) was identified in an Italian proband with arrhythmogenic right ventricular dysplasia. An inframe deletion (Leu765del) was identified in a proband with arrhythmogenic right ventricular dysplasia, and was also present in the proband's asymptomatic father and paternal aunt, who had mild right ventricular dilation on echocardiography and increased trabeculations in the right ventricular apex on MRI, respectively, as well as in the aunt's asymptomatic son. There was supporting in vitro functional assay evidence for both variants. PMID: 21254927 - a missense variant was found in one of 55 Danish ARVD patients, but was found 37 times in 276,338 (1 homozygous) reference alleles in gnomAD making it less likely as a causal variant. PMID: 22421363 - null mice exhibit progressive dilated cardiomyopathy, gap junction remodelling, and increased sensitivity to ventricular arrhythmia following acute ischaemia, but not spontaneous ARVC. Additional publications identified - PMID: 30415094 - a VUS identified in a sudden unexpected death case with slight LV hypertrophy. PMID: 31539150 - 2 VUS and a nonsense variant identified in 3 probands with atrial fibrillation, with the nonsense variant segregating in an affected first-degree relative.
Sources: ClinGen
Mendeliome v0.5135 CHRNE Zornitza Stark Gene: chrne has been classified as Green List (High Evidence).
Mendeliome v0.5132 COLQ Zornitza Stark Gene: colq has been classified as Green List (High Evidence).
Mendeliome v0.5128 COX5A Zornitza Stark Phenotypes for gene: COX5A were changed from pulmonary arterial hypertension; lactic acidemia; failure to thrive; isolated complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 20, MIM#619064; pulmonary arterial hypertension; lactic acidemia; failure to thrive; isolated complex IV deficiency
Mendeliome v0.5127 COX5A Zornitza Stark edited their review of gene: COX5A: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 20, MIM#619064, pulmonary arterial hypertension, lactic acidemia, failure to thrive, isolated complex IV deficiency
Mendeliome v0.5127 PET117 Zornitza Stark Phenotypes for gene: PET117 were changed from Developmental delay; Regression; Complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 19, MIM#619063; Developmental delay; Regression; Complex IV deficiency
Mendeliome v0.5126 PET117 Zornitza Stark edited their review of gene: PET117: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 19, MIM#619063, Developmental delay, Regression, Complex IV deficiency
Mendeliome v0.5125 APOPT1 Zornitza Stark Gene: apopt1 has been classified as Green List (High Evidence).
Mendeliome v0.5122 COX4I1 Zornitza Stark Gene: cox4i1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5122 COX4I1 Zornitza Stark Classified gene: COX4I1 as Amber List (moderate evidence)
Mendeliome v0.5122 COX4I1 Zornitza Stark Gene: cox4i1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5118 PET100 Zornitza Stark Gene: pet100 has been classified as Green List (High Evidence).
Mendeliome v0.5115 COX20 Zornitza Stark Gene: cox20 has been classified as Green List (High Evidence).
Mendeliome v0.5111 TACO1 Zornitza Stark Gene: taco1 has been classified as Green List (High Evidence).
Mendeliome v0.5108 PRKACA Zornitza Stark Gene: prkaca has been classified as Green List (High Evidence).
Mendeliome v0.5108 PRKACA Zornitza Stark Classified gene: PRKACA as Green List (high evidence)
Mendeliome v0.5108 PRKACA Zornitza Stark Gene: prkaca has been classified as Green List (High Evidence).
Mendeliome v0.5107 PRKACB Zornitza Stark Classified gene: PRKACB as Green List (high evidence)
Mendeliome v0.5107 PRKACB Zornitza Stark Gene: prkacb has been classified as Green List (High Evidence).
Mendeliome v0.5106 CNGA2 Zornitza Stark Gene: cnga2 has been classified as Red List (Low Evidence).
Mendeliome v0.5106 CNGA2 Zornitza Stark gene: CNGA2 was added
gene: CNGA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNGA2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CNGA2 were set to 28572688
Phenotypes for gene: CNGA2 were set to Congenital anosmia
Review for gene: CNGA2 was set to RED
Added comment: Single multiplex family with high-impact variant segregating with anosmia.
Sources: Literature
Mendeliome v0.5105 COX6B1 Zornitza Stark Gene: cox6b1 has been classified as Green List (High Evidence).
Mendeliome v0.5102 PRKACB Konstantinos Varvagiannis gene: PRKACB was added
gene: PRKACB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACB were set to unknown
Mode of pathogenicity for gene: PRKACB 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: PRKACB was set to GREEN
Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Mendeliome v0.5102 PRKACA Konstantinos Varvagiannis gene: PRKACA was added
gene: PRKACA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKACA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACA were set to 33058759; 31130284
Phenotypes for gene: PRKACA were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACA were set to unknown
Mode of pathogenicity for gene: PRKACA 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: PRKACA was set to GREEN
Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Mendeliome v0.5102 SCO1 Zornitza Stark Gene: sco1 has been classified as Green List (High Evidence).
Mendeliome v0.5099 COX10 Zornitza Stark Gene: cox10 has been classified as Green List (High Evidence).
Mendeliome v0.5096 GFPT1 Zornitza Stark Gene: gfpt1 has been classified as Green List (High Evidence).
Mendeliome v0.5093 BMP7 Zornitza Stark Gene: bmp7 has been classified as Red List (Low Evidence).
Mendeliome v0.5093 BMP7 Zornitza Stark gene: BMP7 was added
gene: BMP7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BMP7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP7 were set to 32266521; 24429398
Phenotypes for gene: BMP7 were set to Non-syndromic metopic craniosynostosis
Mode of pathogenicity for gene: BMP7 was set to Other
Review for gene: BMP7 was set to RED
Added comment: Non-syndromic metopic craniosynostosis: PMID 32266521 reports rs6127972 as a susceptibility SNP for non-syndromic metopic craniosynostosis

CAKUT: PMID 24429398 1 family with mouse model in large cohort of CAKUT.
Sources: Literature
Mendeliome v0.5091 SMARCC1 Zornitza Stark Gene: smarcc1 has been classified as Green List (High Evidence).
Mendeliome v0.5091 SMARCC1 Zornitza Stark Classified gene: SMARCC1 as Green List (high evidence)
Mendeliome v0.5091 SMARCC1 Zornitza Stark Gene: smarcc1 has been classified as Green List (High Evidence).
Mendeliome v0.5089 SLC18A3 Zornitza Stark Gene: slc18a3 has been classified as Green List (High Evidence).
Mendeliome v0.5085 SYT2 Zornitza Stark changed review comment from: Mono-allelic disease, PMID 25192047: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in two families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated.

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.; to: Mono-allelic disease, PMID 25192047 and 30533528: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated.

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.
Mendeliome v0.5085 SYT2 Zornitza Stark Gene: syt2 has been classified as Green List (High Evidence).
Mendeliome v0.5082 CHAT Zornitza Stark Gene: chat has been classified as Green List (High Evidence).
Mendeliome v0.5079 ALG2 Zornitza Stark Gene: alg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5076 ALG2 Zornitza Stark Classified gene: ALG2 as Amber List (moderate evidence)
Mendeliome v0.5076 ALG2 Zornitza Stark Gene: alg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.5075 AGRN Zornitza Stark Gene: agrn has been classified as Green List (High Evidence).
Mendeliome v0.5072 DPH1 Zornitza Stark Gene: dph1 has been classified as Green List (High Evidence).
Mendeliome v0.5068 LRP8 Bryony Thompson Gene: lrp8 has been classified as Red List (Low Evidence).
Mendeliome v0.5068 LRP8 Bryony Thompson Classified gene: LRP8 as Red List (low evidence)
Mendeliome v0.5068 LRP8 Bryony Thompson Gene: lrp8 has been classified as Red List (Low Evidence).
Mendeliome v0.5067 TCF21 Bryony Thompson Gene: tcf21 has been classified as Red List (Low Evidence).
Mendeliome v0.5067 TCF21 Bryony Thompson Classified gene: TCF21 as Red List (low evidence)
Mendeliome v0.5067 TCF21 Bryony Thompson Gene: tcf21 has been classified as Red List (Low Evidence).
Mendeliome v0.5066 SETD1A Zornitza Stark changed review comment from: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 3 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; to: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 4 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.
Mendeliome v0.5065 SETD1A Zornitza Stark edited their review of gene: SETD1A: Added comment: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 3 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; Changed phenotypes: Epilepsy, early-onset, with or without developmental delay, MIM# 618832, Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Mendeliome v0.5064 JARID2 Zornitza Stark Classified gene: JARID2 as Green List (high evidence)
Mendeliome v0.5064 JARID2 Zornitza Stark Gene: jarid2 has been classified as Green List (High Evidence).
Mendeliome v0.5061 NUDT2 Zornitza Stark Classified gene: NUDT2 as Green List (high evidence)
Mendeliome v0.5061 NUDT2 Zornitza Stark Gene: nudt2 has been classified as Green List (High Evidence).
Mendeliome v0.5060 AFF2 Zornitza Stark changed review comment from: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar.; to: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar. Missense variants found to be over-represented in an autism cohort.
Mendeliome v0.5060 AFF2 Zornitza Stark Gene: aff2 has been classified as Green List (High Evidence).
Mendeliome v0.5057 AFF2 Zornitza Stark commented on gene: AFF2: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar.
Mendeliome v0.5057 AUTS2 Zornitza Stark Gene: auts2 has been classified as Green List (High Evidence).
Mendeliome v0.5051 ITSN2 Zornitza Stark Gene: itsn2 has been classified as Green List (High Evidence).
Mendeliome v0.5051 ITSN2 Zornitza Stark Classified gene: ITSN2 as Green List (high evidence)
Mendeliome v0.5051 ITSN2 Zornitza Stark Gene: itsn2 has been classified as Green List (High Evidence).
Mendeliome v0.5050 ITSN2 Elena Savva gene: ITSN2 was added
gene: ITSN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITSN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITSN2 were set to PMID: 29773874
Phenotypes for gene: ITSN2 were set to Nephrotic syndrome
Review for gene: ITSN2 was set to GREEN
Added comment: PMID: 29773874: 2 families (3 patients) with homozygous missense or chet missense/PTC + null mice recapitulating the human phenotype.
Functional analysis of all variants shows an inability for Cdc42 activation as shown by wildtype overexpression
Sources: Literature
Mendeliome v0.5050 PI4K2A Zornitza Stark Gene: pi4k2a has been classified as Red List (Low Evidence).
Mendeliome v0.5050 PI4K2A Zornitza Stark gene: PI4K2A was added
gene: PI4K2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PI4K2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4K2A were set to 32418222
Phenotypes for gene: PI4K2A were set to Cutis laxa, intellectual disability, movement disorder
Review for gene: PI4K2A was set to RED
Added comment: Single individual reported with homozygous missense variant and functional data including mouse model.
Sources: Literature
Mendeliome v0.5049 NR5A1 Zornitza Stark Gene: nr5a1 has been classified as Green List (High Evidence).
Mendeliome v0.5046 HECW2 Zornitza Stark Gene: hecw2 has been classified as Green List (High Evidence).
Mendeliome v0.5045 HECW2 Zornitza Stark Phenotypes for gene: HECW2 were changed from to Neurodevelopmental disorder with hypotonia, seizures, and absent language, MIM# 617268; intellectual disability; epilepsy; regression; microcephaly
Mendeliome v0.5042 HECW2 Natasha Brown reviewed gene: HECW2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 29807643, 29395664, 27334371, 27389779; Phenotypes: intellectual disability, epilepsy, regression, microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.5041 ZMYND10 Zornitza Stark Gene: zmynd10 has been classified as Green List (High Evidence).
Mendeliome v0.5041 ZMYND10 Zornitza Stark Phenotypes for gene: ZMYND10 were changed from to Ciliary dyskinesia, primary, 22, MIM#615444
Mendeliome v0.5038 ZMYND10 Zornitza Stark reviewed gene: ZMYND10: Rating: GREEN; Mode of pathogenicity: None; Publications: 23891471, 23891469; Phenotypes: Ciliary dyskinesia, primary, 22, MIM#615444; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5038 SPAG1 Zornitza Stark Gene: spag1 has been classified as Green List (High Evidence).
Mendeliome v0.5038 SPAG1 Zornitza Stark Phenotypes for gene: SPAG1 were changed from to Ciliary dyskinesia, primary, 28 (MIM#615505)
Mendeliome v0.5035 SPAG1 Zornitza Stark reviewed gene: SPAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32622824, 32502479, 24055112; Phenotypes: Ciliary dyskinesia, primary, 28 (MIM#615505); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5035 MMP21 Zornitza Stark Gene: mmp21 has been classified as Green List (High Evidence).
Mendeliome v0.5032 DNAAF1 Zornitza Stark Gene: dnaaf1 has been classified as Green List (High Evidence).
Mendeliome v0.5032 DNAAF1 Zornitza Stark Phenotypes for gene: DNAAF1 were changed from to Ciliary dyskinesia, primary, 13, MIM# 613193
Mendeliome v0.5029 DNAAF1 Zornitza Stark reviewed gene: DNAAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19944400, 19944405, 32502479, 29228333, 27261005; Phenotypes: Ciliary dyskinesia, primary, 13, MIM# 613193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5029 LRRC6 Zornitza Stark Gene: lrrc6 has been classified as Green List (High Evidence).
Mendeliome v0.5029 LRRC6 Zornitza Stark Phenotypes for gene: LRRC6 were changed from to Ciliary dyskinesia, primary, 19, MIM# 614935
Mendeliome v0.5026 LRRC6 Zornitza Stark reviewed gene: LRRC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23122589, 23891469, 32622824, 29511670; Phenotypes: Ciliary dyskinesia, primary, 19, MIM# 614935; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5026 GAS8 Zornitza Stark Gene: gas8 has been classified as Green List (High Evidence).
Mendeliome v0.5026 GAS8 Zornitza Stark Phenotypes for gene: GAS8 were changed from to Ciliary dyskinesia, primary, 33, MIM#616726
Mendeliome v0.5023 GAS8 Zornitza Stark reviewed gene: GAS8: Rating: GREEN; Mode of pathogenicity: None; Publications: 26387594, 27120127; Phenotypes: Ciliary dyskinesia, primary, 33, mIM# 616726; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5023 DNAI2 Zornitza Stark Gene: dnai2 has been classified as Green List (High Evidence).
Mendeliome v0.5023 DNAI2 Zornitza Stark Phenotypes for gene: DNAI2 were changed from to Ciliary dyskinesia, primary, 9, with or without situs inversus, MIM# 612444
Mendeliome v0.5020 DNAI2 Zornitza Stark reviewed gene: DNAI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18950741, 23261302; Phenotypes: Ciliary dyskinesia, primary, 9, with or without situs inversus, MIM# 612444; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5020 DNAI1 Zornitza Stark Gene: dnai1 has been classified as Green List (High Evidence).
Mendeliome v0.5020 DNAI1 Zornitza Stark Phenotypes for gene: DNAI1 were changed from to Ciliary dyskinesia, primary, 1, with or without situs inversus, MIM# 244400
Mendeliome v0.5017 DNAI1 Zornitza Stark reviewed gene: DNAI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10577904, 11231901, 32502479, 31765523, 30622330; Phenotypes: Ciliary dyskinesia, primary, 1, with or without situs inversus, MIM# 244400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5016 DNAH11 Zornitza Stark reviewed gene: DNAH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 12142464, 18022865, 22102620, 32633470, 31879361, 31765523, 31040315; Phenotypes: Ciliary dyskinesia, primary, 7, with or without situs inversus, MIM#611884; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5016 DNAAF5 Zornitza Stark Gene: dnaaf5 has been classified as Green List (High Evidence).
Mendeliome v0.5016 DNAAF5 Zornitza Stark Phenotypes for gene: DNAAF5 were changed from to Ciliary dyskinesia, primary, 18, MIM# 614874
Mendeliome v0.5013 DNAAF5 Zornitza Stark reviewed gene: DNAAF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23040496, 29363216, 25232951; Phenotypes: Ciliary dyskinesia, primary, 18, MIM# 614874; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5013 DNAAF3 Zornitza Stark Gene: dnaaf3 has been classified as Green List (High Evidence).
Mendeliome v0.5013 DNAAF3 Zornitza Stark Phenotypes for gene: DNAAF3 were changed from to Ciliary dyskinesia, primary, 2, MIM# 606763
Mendeliome v0.5010 DNAAF3 Zornitza Stark reviewed gene: DNAAF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22387996, 32622824, 31186518; Phenotypes: Ciliary dyskinesia, primary, 2, MIM# 606763; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5010 RAB27A Zornitza Stark Gene: rab27a has been classified as Green List (High Evidence).
Mendeliome v0.5007 DNAAF2 Zornitza Stark Gene: dnaaf2 has been classified as Green List (High Evidence).
Mendeliome v0.5007 DNAAF2 Zornitza Stark Phenotypes for gene: DNAAF2 were changed from to Ciliary dyskinesia, primary, 10, MIM# 612518
Mendeliome v0.5004 DNAAF2 Zornitza Stark reviewed gene: DNAAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19052621, 32638265, 31107948; Phenotypes: Ciliary dyskinesia, primary, 10, MIM# 612518; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.5004 PPP1R13L Zornitza Stark Gene: ppp1r13l has been classified as Green List (High Evidence).
Mendeliome v0.5004 PPP1R13L Zornitza Stark Classified gene: PPP1R13L as Green List (high evidence)
Mendeliome v0.5004 PPP1R13L Zornitza Stark Gene: ppp1r13l has been classified as Green List (High Evidence).
Mendeliome v0.5003 PPP1R13L Zornitza Stark gene: PPP1R13L was added
gene: PPP1R13L was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PPP1R13L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R13L were set to 32666529; 28864777
Phenotypes for gene: PPP1R13L were set to Dilated cardiomyopathy, onset in infancy
Review for gene: PPP1R13L was set to GREEN
Added comment: Four families reported in PMID 28864777, but same homozygous variant, identity by descent. Five unrelated families reported in PMID 32666529. Severe progressive DCM with onset in infancy.
Sources: Expert list
Mendeliome v0.5002 CCNO Zornitza Stark Gene: ccno has been classified as Green List (High Evidence).
Mendeliome v0.5002 CCNO Zornitza Stark Phenotypes for gene: CCNO were changed from to Ciliary dyskinesia, primary, 29, MIM# 615872
Mendeliome v0.4999 CCNO Zornitza Stark reviewed gene: CCNO: Rating: GREEN; Mode of pathogenicity: None; Publications: 24747639, 31765523, 28801648; Phenotypes: Ciliary dyskinesia, primary, 29, MIM# 615872; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4999 CSNK1G1 Zornitza Stark Gene: csnk1g1 has been classified as Green List (High Evidence).
Mendeliome v0.4999 CSNK1G1 Zornitza Stark Classified gene: CSNK1G1 as Green List (high evidence)
Mendeliome v0.4999 CSNK1G1 Zornitza Stark Gene: csnk1g1 has been classified as Green List (High Evidence).
Mendeliome v0.4998 CSNK1G1 Zornitza Stark gene: CSNK1G1 was added
gene: CSNK1G1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSNK1G1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CSNK1G1 were set to 33009664
Phenotypes for gene: CSNK1G1 were set to Global developmental delay; Intellectual disability; Autism; Seizures
Review for gene: CSNK1G1 was set to GREEN
Added comment: Borderline Green/Amber rating.

Gold et al (2020 - PMID: 33009664) report 5 individuals with CSNK1G1 variants, including updated information on a previously reported subject (Martin et al 2014 - PMID: 24463883).

Features included DD (5/5) with associated expressive language delay, ASD (in at least 3/5), seizures (2/5), dysmorphic facial features (4/5 arched eyebrows, 3/5 prominent central incisors, 2/5 epicanthus) and limb anomalies (2/5 - proximally placed thumb, 5th f. clinodactyly, asymmetric overgrowth - the other individual had tapering fingers). GI problems were observed in 4/5. Two individuals had macrocephaly and one had microcephaly. There was no formal developmental assessment although ID might be implied in at least 3 individuals (p1: 20y - single words/regression in walking following a seizure episode, p2: 8y - first words at 5y, assistance to feed, dress and bathe, ASD, p4: 13y - regression, assistance to feed and dress).

CSNK1G1 encodes the gamma-1 isoform of casein kinase 1, a protein involved in growth and cell morphogenesis. The gene has ubiquitous expression, incl. brain. As commented, in brain it regulates phosphorylation of NMDA receptors, playing a role in synaptic transmission (4 articles cited).

One individual had a 1.2 kb deletion spanning exon 3 of CSNK1G1 [chr15:64550952-64552120 - GRCh37]. Parental samples were unavailable for this individual. Four individuals were found to harbor de novo CSNK1G1 variants [NM_022048.3: c.688C>T - p.(Arg230Trp) dn | c.1255C>T - p.(Gln419*) dn | c.1214+5G>A dn with in silico predictions in favor of splice disruption | c.419C>T - p.(Thr140Met) dn].

Arg230Trp is however present once in gnomAD. The stopgain variant is located in the last exon and predicted to skip NMD.

There were no variant studies performed.

The Drosophila gish gene encodes a CK1γ homolog with preferential expression in the mushroom body. Heterozygous and homozygous mutants exhibit impairment in memory retention, more severe in homozygous flies. gish was also identified as a seizure modifier in a fly epilepsy model (heterozygous para mt flies).
Sources: Literature
Mendeliome v0.4997 LMNB2 Zornitza Stark Gene: lmnb2 has been classified as Green List (High Evidence).
Mendeliome v0.4993 SREBF1 Zornitza Stark Phenotypes for gene: SREBF1 were changed from IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016 to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016; Mucoepithelial dysplasia, hereditary, MIM#158310
Mendeliome v0.4991 SREBF1 Zornitza Stark edited their review of gene: SREBF1: Added comment: HMD phenotype: 5 unrelated families reported with heterozygous variants at same residue (p.Arg557Cys and p.Arg557His) and a panepithelial defect involving the oral, nasal, conjunctival, vaginal, cervical, perineal, urethral, and bladder mucosa. Individuals developed cataracts, blindness, nonscarring alopecia, perineal psoriasiform lesions, and follicular keratoses.; Changed publications: 32497488, 31790666, 32902915; Changed phenotypes: IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016, Mucoepithelial dysplasia, hereditary, MIM#158310
Mendeliome v0.4991 CCDC40 Zornitza Stark Gene: ccdc40 has been classified as Green List (High Evidence).
Mendeliome v0.4991 CCDC40 Zornitza Stark Phenotypes for gene: CCDC40 were changed from to Ciliary dyskinesia, primary, 15, MIM#613808
Mendeliome v0.4988 CCDC40 Zornitza Stark reviewed gene: CCDC40: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131974, 23255504, 31879361, 31765523, 31650533; Phenotypes: Ciliary dyskinesia, primary, 15, MIM#613808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4988 CCDC39 Zornitza Stark Gene: ccdc39 has been classified as Green List (High Evidence).
Mendeliome v0.4988 CCDC39 Zornitza Stark Phenotypes for gene: CCDC39 were changed from to Ciliary dyskinesia, primary, 14, MIM# 613807
Mendeliome v0.4985 CCDC39 Zornitza Stark reviewed gene: CCDC39: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131972, 23255504; Phenotypes: Ciliary dyskinesia, primary, 14, MIM# 613807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4985 CCDC151 Zornitza Stark Gene: ccdc151 has been classified as Green List (High Evidence).
Mendeliome v0.4985 CCDC151 Zornitza Stark Phenotypes for gene: CCDC151 were changed from to Ciliary dyskinesia, primary, 30, MIM# 616037
Mendeliome v0.4982 CCDC151 Zornitza Stark reviewed gene: CCDC151: Rating: GREEN; Mode of pathogenicity: None; Publications: 25192045, 25224326, 32490514, 32286033, 30504913; Phenotypes: Ciliary dyskinesia, primary, 30, MIM# 616037; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4982 CCDC114 Zornitza Stark Gene: ccdc114 has been classified as Green List (High Evidence).
Mendeliome v0.4982 CCDC114 Zornitza Stark Phenotypes for gene: CCDC114 were changed from to Ciliary dyskinesia, primary, 20, MIM# 615067
Mendeliome v0.4979 CCDC114 Zornitza Stark reviewed gene: CCDC114: Rating: GREEN; Mode of pathogenicity: None; Publications: 23261303, 23261302, 32855706, 23506398; Phenotypes: Ciliary dyskinesia, primary, 20, MIM# 615067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4979 CCDC103 Zornitza Stark Gene: ccdc103 has been classified as Green List (High Evidence).
Mendeliome v0.4979 CCDC103 Zornitza Stark Phenotypes for gene: CCDC103 were changed from to Ciliary dyskinesia, primary, 17, MIM# 614679
Mendeliome v0.4976 CCDC103 Zornitza Stark reviewed gene: CCDC103: Rating: GREEN; Mode of pathogenicity: None; Publications: 22581229, 32447765, 31858719, 28790179; Phenotypes: Ciliary dyskinesia, primary, 17, MIM# 614679; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4976 GARS Zornitza Stark Gene: gars has been classified as Green List (High Evidence).
Mendeliome v0.4973 SELENON Zornitza Stark Gene: selenon has been classified as Green List (High Evidence).
Mendeliome v0.4970 TNNT1 Zornitza Stark Gene: tnnt1 has been classified as Green List (High Evidence).
Mendeliome v0.4968 TNNT3 Zornitza Stark Gene: tnnt3 has been classified as Green List (High Evidence).
Mendeliome v0.4968 TNNT3 Zornitza Stark Phenotypes for gene: TNNT3 were changed from to Arthrogryposis, distal, type 2B2, MIM# 618435
Mendeliome v0.4964 TNNT3 Zornitza Stark reviewed gene: TNNT3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 12865991, 19142688, 21402185, 25337069, 17194691; Phenotypes: Arthrogryposis, distal, type 2B2, MIM# 618435; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4964 STAC3 Zornitza Stark Gene: stac3 has been classified as Green List (High Evidence).
Mendeliome v0.4961 SPEG Zornitza Stark Gene: speg has been classified as Green List (High Evidence).
Mendeliome v0.4958 TPM3 Zornitza Stark Gene: tpm3 has been classified as Green List (High Evidence).
Mendeliome v0.4958 TPM3 Zornitza Stark Phenotypes for gene: TPM3 were changed from to CAP myopathy 1, MIM# 609284; Myopathy, congenital, with fiber-type disproportion, MIM# 255310; Nemaline myopathy 1, autosomal dominant or recessive, MIM# 609284; Congenital muscle stiffness
Mendeliome v0.4954 TPM3 Zornitza Stark reviewed gene: TPM3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 26418456, 7704029, 17376686, 18382475, 19487656; Phenotypes: CAP myopathy 1, MIM# 609284, Myopathy, congenital, with fiber-type disproportion, MIM# 255310, Nemaline myopathy 1, autosomal dominant or recessive, MIM# 609284, Congenital muscle stiffness; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4954 MICU1 Zornitza Stark Gene: micu1 has been classified as Green List (High Evidence).
Mendeliome v0.4954 MICU1 Zornitza Stark Phenotypes for gene: MICU1 were changed from to Myopathy with extrapyramidal signs, MIM# 615673
Mendeliome v0.4951 MICU1 Zornitza Stark reviewed gene: MICU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24336167, 29721912, 32395406; Phenotypes: Myopathy with extrapyramidal signs, MIM# 615673; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4951 LMOD3 Zornitza Stark Gene: lmod3 has been classified as Green List (High Evidence).
Mendeliome v0.4947 MYH2 Zornitza Stark Gene: myh2 has been classified as Green List (High Evidence).
Mendeliome v0.4944 KLHL41 Zornitza Stark Gene: klhl41 has been classified as Green List (High Evidence).
Mendeliome v0.4941 KLHL40 Zornitza Stark Gene: klhl40 has been classified as Green List (High Evidence).
Mendeliome v0.4941 KLHL40 Zornitza Stark Phenotypes for gene: KLHL40 were changed from to Nemaline myopathy 8, autosomal recessive, MIM# 615348
Mendeliome v0.4938 KLHL40 Zornitza Stark reviewed gene: KLHL40: Rating: GREEN; Mode of pathogenicity: None; Publications: 23746549, 24960163, 32352246, 31908664, 27528495; Phenotypes: Nemaline myopathy 8, autosomal recessive, MIM# 615348; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4938 MYO18B Zornitza Stark Gene: myo18b has been classified as Green List (High Evidence).
Mendeliome v0.4938 MYO18B Zornitza Stark Phenotypes for gene: MYO18B were changed from to Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism, MIM# 616549
Mendeliome v0.4935 MYO18B Zornitza Stark reviewed gene: MYO18B: Rating: GREEN; Mode of pathogenicity: None; Publications: 25748484, 27858739, 32637634, 32184166, 27879346; Phenotypes: Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism, MIM# 616549; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4935 MEGF10 Zornitza Stark Gene: megf10 has been classified as Green List (High Evidence).
Mendeliome v0.4931 WDPCP Zornitza Stark Classified gene: WDPCP as Green List (high evidence)
Mendeliome v0.4931 WDPCP Zornitza Stark Gene: wdpcp has been classified as Green List (High Evidence).
Mendeliome v0.4930 WDPCP Zornitza Stark Gene: wdpcp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4927 WDPCP Zornitza Stark Classified gene: WDPCP as Amber List (moderate evidence)
Mendeliome v0.4927 WDPCP Zornitza Stark Gene: wdpcp has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4926 TUBGCP4 Zornitza Stark Gene: tubgcp4 has been classified as Green List (High Evidence).
Mendeliome v0.4926 TUBGCP4 Zornitza Stark Phenotypes for gene: TUBGCP4 were changed from to Microcephaly and chorioretinopathy, autosomal recessive, 3, MIM# 616335
Mendeliome v0.4923 TUBGCP4 Zornitza Stark reviewed gene: TUBGCP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25817018, 32270730; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 3, MIM# 616335; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4923 DYNC2LI1 Zornitza Stark Gene: dync2li1 has been classified as Green List (High Evidence).
Mendeliome v0.4923 DYNC2LI1 Zornitza Stark Phenotypes for gene: DYNC2LI1 were changed from to Short-rib thoracic dysplasia 15 with polydactyly (MIM#617088)
Mendeliome v0.4917 DYNC2LI1 Ain Roesley reviewed gene: DYNC2LI1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33030252; Phenotypes: Short-rib thoracic dysplasia 15 with polydactyly (MIM#617088); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4916 GPC6 Elena Savva reviewed gene: GPC6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19481194, 32655339; Phenotypes: Omodysplasia 1 MIM#258315; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4916 FKBP14 Zornitza Stark Gene: fkbp14 has been classified as Green List (High Evidence).
Mendeliome v0.4913 EPG5 Zornitza Stark Gene: epg5 has been classified as Green List (High Evidence).
Mendeliome v0.4910 LMX1B Zornitza Stark Gene: lmx1b has been classified as Green List (High Evidence).
Mendeliome v0.4907 SEMA4A Zornitza Stark Gene: sema4a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4904 SEMA4A Zornitza Stark Classified gene: SEMA4A as Amber List (moderate evidence)
Mendeliome v0.4904 SEMA4A Zornitza Stark Gene: sema4a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4903 JPH2 Zornitza Stark Gene: jph2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4900 JPH2 Zornitza Stark Classified gene: JPH2 as Amber List (moderate evidence)
Mendeliome v0.4900 JPH2 Zornitza Stark Gene: jph2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4899 RGR Zornitza Stark Gene: rgr has been classified as Red List (Low Evidence).
Mendeliome v0.4896 RGR Zornitza Stark Classified gene: RGR as Red List (low evidence)
Mendeliome v0.4896 RGR Zornitza Stark Gene: rgr has been classified as Red List (Low Evidence).
Mendeliome v0.4895 RDH11 Zornitza Stark Gene: rdh11 has been classified as Red List (Low Evidence).
Mendeliome v0.4895 RDH11 Zornitza Stark gene: RDH11 was added
gene: RDH11 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RDH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH11 were set to 24916380; 15634683; 30731079; 18326732
Phenotypes for gene: RDH11 were set to Retinal dystrophy, juvenile cataracts, and short stature syndrome, MIM# 616108
Review for gene: RDH11 was set to RED
Added comment: Single family reported with compound heterozygous LOF variants segregating with disease in three siblings. Some functional data, but note mouse KO did not have eye phenotype.
Sources: Expert list
Mendeliome v0.4894 CEP112 Zornitza Stark Gene: cep112 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4892 GPC6 Zornitza Stark Gene: gpc6 has been classified as Green List (High Evidence).
Mendeliome v0.4892 GPC6 Zornitza Stark Phenotypes for gene: GPC6 were changed from to Omodysplasia 1 (MIM#258315), AR
Mendeliome v0.4889 GPC6 Kristin Rigbye reviewed gene: GPC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 19481194; Phenotypes: Omodysplasia 1 (MIM#258315), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4889 SPATA7 Zornitza Stark Gene: spata7 has been classified as Green List (High Evidence).
Mendeliome v0.4889 SPATA7 Zornitza Stark Phenotypes for gene: SPATA7 were changed from to Leber congenital amaurosis 3, MIM#604232; Autosomal recessive juvenile retinitis pigmentosa, MIM#604232
Mendeliome v0.4886 SPATA7 Chern Lim reviewed gene: SPATA7: Rating: GREEN; Mode of pathogenicity: None; Publications: 31908400, 32799588; Phenotypes: Leber congenital amaurosis 3, MIM#604232, Autosomal recessive juvenile retinitis pigmentosa, MIM#604232; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.4886 KIRREL3 Zornitza Stark Gene: kirrel3 has been classified as Red List (Low Evidence).
Mendeliome v0.4886 KIRREL3 Zornitza Stark gene: KIRREL3 was added
gene: KIRREL3 was added to Mendeliome. Sources: Expert list
refuted tags were added to gene: KIRREL3.
Mode of inheritance for gene: KIRREL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIRREL3 were set to 19012874
Phenotypes for gene: KIRREL3 were set to Intellectual disability
Review for gene: KIRREL3 was set to RED
Added comment: Variants associated with ID have now been re-classified based on population frequency.
Sources: Expert list
Mendeliome v0.4885 NEUROD1 Zornitza Stark Gene: neurod1 has been classified as Green List (High Evidence).
Mendeliome v0.4882 DNAAF4 Zornitza Stark Gene: dnaaf4 has been classified as Green List (High Evidence).
Mendeliome v0.4882 DNAAF4 Zornitza Stark Phenotypes for gene: DNAAF4 were changed from to Ciliary dyskinesia, primary, 25, MIM# 615482
Mendeliome v0.4879 DNAAF4 Zornitza Stark reviewed gene: DNAAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23872636; Phenotypes: Ciliary dyskinesia, primary, 25, MIM# 615482; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4879 MAG Zornitza Stark Phenotypes for gene: MAG were changed from Spastic paraplegia 75, autosomal recessive, MIM# 616680 to Spastic paraplegia 75, autosomal recessive, MIM# 616680; Cerebellar ataxia
Mendeliome v0.4878 MAG Zornitza Stark changed review comment from: Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood. Eight unrelated families reported.; to: Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood. Eight unrelated families reported with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms.
Mendeliome v0.4878 GZF1 Zornitza Stark Gene: gzf1 has been classified as Green List (High Evidence).
Mendeliome v0.4875 ITFG2 Zornitza Stark Gene: itfg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4875 ITFG2 Zornitza Stark Classified gene: ITFG2 as Amber List (moderate evidence)
Mendeliome v0.4875 ITFG2 Zornitza Stark Gene: itfg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4874 ITFG2 Zornitza Stark gene: ITFG2 was added
gene: ITFG2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITFG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Phenotypes for gene: ITFG2 were set to Neurodevelopmental abnormality; Intellectual disability; Developmental regression; Ataxia
Review for gene: ITFG2 was set to AMBER
Added comment: ITFG2 was suggested to be a candidate gene for autosomal recessive ID in the study by Harripaul et al (2018 - PMID: 28397838). The authors performed microarray and exome sequencing in 192 consanguineous families and identified a homozygous ITGF2 stopgain variant (NM_018463.3:c.472G>T / p.Glu158*) along with 3 additional variants segregating with ID within an investigated family (PK51). Cheema et al (2020 - https://doi.org/10.1038/s41525-020-00150-z) report briefly on a male, born to consanguineous parents presenting with NDD, seizures, regression and ataxia. There was a similarly affected female sibling. Evaluation of ROH revealed a homozygous ITFG2 nonsense variant [NM_018463.3:c.361C>T / p.(Gln121*)]. Families in this study were investigated by trio WES or WGS. Evaluation of data of the same lab revealed 3 additional unrelated subjects with overlapping phenotypes, notably NDD and ataxia. These individuals were - each - homozygous for pLoF variants [NM_018463.3:c.848-1G>A; NM_018463.3:c.704dupC, p.(Ala236fs), NM_018463.3:c.1000_1001delAT, p.(Ile334fs)]. As discussed in OMIM, ITFG2 encodes a subunit of the KICSTOR protein complex, having a role in regulating nutrient sensing by MTOR complex-1 (Wolfson et al 2017 - PMID : 28199306).

Rated Amber as Cheema et al report on diagnostic outcomes and multiple candidate genes as part of a heterogenous cohort and details are therefore limited.
Sources: Literature
Mendeliome v0.4873 SHMT2 Zornitza Stark Gene: shmt2 has been classified as Green List (High Evidence).
Mendeliome v0.4873 SHMT2 Zornitza Stark Classified gene: SHMT2 as Green List (high evidence)
Mendeliome v0.4873 SHMT2 Zornitza Stark Gene: shmt2 has been classified as Green List (High Evidence).
Mendeliome v0.4872 SHMT2 Zornitza Stark gene: SHMT2 was added
gene: SHMT2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly
Review for gene: SHMT2 was set to GREEN
Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).
Sources: Literature
Mendeliome v0.4871 DHX38 Zornitza Stark Gene: dhx38 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4868 DHX38 Zornitza Stark Classified gene: DHX38 as Amber List (moderate evidence)
Mendeliome v0.4868 DHX38 Zornitza Stark Gene: dhx38 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4867 CCT2 Zornitza Stark Gene: cct2 has been classified as Red List (Low Evidence).
Mendeliome v0.4867 CCT2 Zornitza Stark gene: CCT2 was added
gene: CCT2 was added to Mendeliome. Sources: NHS GMS
Mode of inheritance for gene: CCT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCT2 were set to 27645772; 29450543
Phenotypes for gene: CCT2 were set to Leber's congenital amaurosis
Review for gene: CCT2 was set to RED
Added comment: Single family reported with compound het missense variants, functional data, including animal model.
Sources: NHS GMS
Mendeliome v0.4866 CA4 Zornitza Stark Gene: ca4 has been classified as Red List (Low Evidence).
Mendeliome v0.4863 CA4 Zornitza Stark Classified gene: CA4 as Red List (low evidence)
Mendeliome v0.4863 CA4 Zornitza Stark Gene: ca4 has been classified as Red List (Low Evidence).
Mendeliome v0.4862 VPS41 Zornitza Stark Gene: vps41 has been classified as Red List (Low Evidence).
Mendeliome v0.4862 VPS41 Zornitza Stark gene: VPS41 was added
gene: VPS41 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683
Phenotypes for gene: VPS41 were set to Dystonia; intellectual disability
Review for gene: VPS41 was set to RED
Added comment: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.
Sources: Literature
Mendeliome v0.4861 VPS16 Zornitza Stark Gene: vps16 has been classified as Green List (High Evidence).
Mendeliome v0.4861 VPS16 Zornitza Stark Classified gene: VPS16 as Green List (high evidence)
Mendeliome v0.4861 VPS16 Zornitza Stark Gene: vps16 has been classified as Green List (High Evidence).
Mendeliome v0.4860 VPS16 Zornitza Stark gene: VPS16 was added
gene: VPS16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS16 were set to 32808683
Phenotypes for gene: VPS16 were set to Dystonia
Added comment: 18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood. Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals.
Sources: Literature
Mendeliome v0.4859 KRIT1 Zornitza Stark Gene: krit1 has been classified as Green List (High Evidence).
Mendeliome v0.4856 SH3TC2 Zornitza Stark Gene: sh3tc2 has been classified as Green List (High Evidence).
Mendeliome v0.4853 ABCC6 Zornitza Stark Added comment: Comment when marking as ready: Evidence for mono-allelic variants causing disease is limited.
Mendeliome v0.4853 ABCC6 Zornitza Stark Gene: abcc6 has been classified as Green List (High Evidence).
Mendeliome v0.4853 CAPN3 Zornitza Stark Gene: capn3 has been classified as Green List (High Evidence).
Mendeliome v0.4853 CAPN3 Zornitza Stark Phenotypes for gene: CAPN3 were changed from to Muscular dystrophy, limb-girdle, autosomal dominant 4, MIM# 618129; Muscular dystrophy, limb-girdle, autosomal recessive 1, MIM# 253600
Mendeliome v0.4850 CAPN3 Zornitza Stark reviewed gene: CAPN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31937337, 28881388, 32342993, 32557990; Phenotypes: Muscular dystrophy, limb-girdle, autosomal dominant 4, MIM# 618129, Muscular dystrophy, limb-girdle, autosomal recessive 1, MIM# 253600; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4850 SLC6A5 Zornitza Stark Gene: slc6a5 has been classified as Green List (High Evidence).
Mendeliome v0.4846 ARX Zornitza Stark Gene: arx has been classified as Green List (High Evidence).
Mendeliome v0.4843 ABCC6 Kristin Rigbye changed review comment from: All conditions are regarded as a single disorder at variable ends of the phenotypic spectrum. The same variants have been reported in all three conditions, however reports for AD PE are consistently from older papers (pre-2005) and may have missed a 2nd hit (OMIM). More recent papers consistently report this condition as autosomal recessive (PMID: 28102862).; to: All conditions are regarded as a single disorder at variable ends of the phenotypic spectrum. The same variants have been reported in all three conditions, however reports for AD PXE are consistently from older papers (pre-2005) and may have missed a 2nd hit (OMIM). More recent papers consistently report this condition as autosomal recessive (PMID: 28102862).

In addition to missense, PTCs and splice variants, deletions and duplications in this gene comprise a significant proportion of variants and are a recognised mechanism / cause of PXE.
Mendeliome v0.4842 MCM2 Zornitza Stark Gene: mcm2 has been classified as Red List (Low Evidence).
Mendeliome v0.4842 MCM2 Zornitza Stark gene: MCM2 was added
gene: MCM2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MCM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MCM2 were set to 26196677
Phenotypes for gene: MCM2 were set to Deafness, autosomal dominant 70, MIM# 616968
Review for gene: MCM2 was set to RED
Added comment: One family, expression studies.
Sources: Expert Review
Mendeliome v0.4841 ATP1A4 Zornitza Stark Gene: atp1a4 has been classified as Red List (Low Evidence).
Mendeliome v0.4841 ATP1A4 Zornitza Stark gene: ATP1A4 was added
gene: ATP1A4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP1A4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP1A4 were set to 32549268
Phenotypes for gene: ATP1A4 were set to Hemiplegic migraine
Review for gene: ATP1A4 was set to RED
Added comment: Single family reported where missense variant segregated with hemiplegic migraine in four affected individuals.
Sources: Literature
Mendeliome v0.4840 BSND Zornitza Stark Gene: bsnd has been classified as Green List (High Evidence).
Mendeliome v0.4837 LTBP2 Zornitza Stark Gene: ltbp2 has been classified as Green List (High Evidence).
Mendeliome v0.4832 NEK9 Zornitza Stark Phenotypes for gene: NEK9 were changed from Lethal congenital contracture syndrome 10, MIM# 617022; Skeletal dysplasia to Lethal congenital contracture syndrome 10, MIM# 617022; Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262; Skeletal dysplasia
Mendeliome v0.4830 NEK9 Zornitza Stark Classified gene: NEK9 as Amber List (moderate evidence)
Mendeliome v0.4830 NEK9 Zornitza Stark Gene: nek9 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4829 NEK9 Zornitza Stark edited their review of gene: NEK9: Added comment: Another Saudi family described with which 2 sisters and a female cousin who had a similar disorder characterised by arthrogryposis apparent since early childhood, avascular necrosis of the hip (Perthes disease), and upward gaze palsy. Homozygous missense variant segregated with the phenotype. Given the small number of reports, it is unclear whether this represents a distinct association is part of a spectrum with includes the more severe phenotype described in the Irish traveller families.; Changed publications: 26908619, 21271645; Changed phenotypes: Lethal congenital contracture syndrome 10, MIM# 617022, Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262, Skeletal dysplasia
Mendeliome v0.4829 IL11RA Zornitza Stark Gene: il11ra has been classified as Green List (High Evidence).
Mendeliome v0.4829 IL11RA Zornitza Stark Phenotypes for gene: IL11RA were changed from to Craniosynostosis and dental anomalies, MIM# 614188
Mendeliome v0.4826 IL11RA Zornitza Stark reviewed gene: IL11RA: Rating: GREEN; Mode of pathogenicity: None; Publications: 21741611, 32277509, 30811827, 29926465, 24498618; Phenotypes: Craniosynostosis and dental anomalies, MIM# 614188; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4825 EFNB1 Zornitza Stark Gene: efnb1 has been classified as Green List (High Evidence).
Mendeliome v0.4825 EFNB1 Zornitza Stark Phenotypes for gene: EFNB1 were changed from to Craniofrontonasal dysplasia, MIM# 304110
Mendeliome v0.4822 EFNB1 Zornitza Stark reviewed gene: EFNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15166289, 18627045, 23335590; Phenotypes: Craniofrontonasal dysplasia, MIM# 304110; Mode of inheritance: Other
Mendeliome v0.4822 AGAP1 Zornitza Stark Gene: agap1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4822 AGAP1 Zornitza Stark Classified gene: AGAP1 as Amber List (moderate evidence)
Mendeliome v0.4822 AGAP1 Zornitza Stark Gene: agap1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4820 SMN1 Zornitza Stark Gene: smn1 has been classified as Green List (High Evidence).
Mendeliome v0.4817 BUB1B Zornitza Stark Gene: bub1b has been classified as Green List (High Evidence).
Mendeliome v0.4814 ROM1 Zornitza Stark Gene: rom1 has been classified as Green List (High Evidence).
Mendeliome v0.4811 FOXC1 Zornitza Stark Gene: foxc1 has been classified as Green List (High Evidence).
Mendeliome v0.4808 ALG14 Zornitza Stark Phenotypes for gene: ALG14 were changed from Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Disorder of N-glycosylation to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036; Disorder of N-glycosylation
Mendeliome v0.4807 ALG14 Zornitza Stark edited their review of gene: ALG14: Changed phenotypes: Myasthenic syndrome, congenital, 15, without tubular aggregates 616227, Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031, Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036, Disorder of N-glycosylation
Mendeliome v0.4807 ACER3 Zornitza Stark Gene: acer3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4804 ACER3 Zornitza Stark Classified gene: ACER3 as Amber List (moderate evidence)
Mendeliome v0.4804 ACER3 Zornitza Stark Gene: acer3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4802 TRPV1 Bryony Thompson Classified gene: TRPV1 as Amber List (moderate evidence)
Mendeliome v0.4802 TRPV1 Bryony Thompson Gene: trpv1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4796 AP1S1 Zornitza Stark Gene: ap1s1 has been classified as Green List (High Evidence).
Mendeliome v0.4791 AP1S1 Ee Ming Wong changed review comment from: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants; to: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants
Mendeliome v0.4791 AP1S1 Ee Ming Wong changed review comment from: - 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants; to: - Established green gene in Ichthyosis, Palmoplantar Keratoderma and Erythrokeratoderma, ID and Hereditary Neuropathy (complex) panels associated with MEDNIK syndrome
- PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease

- 2 consanguineous families, each carrying a homozygous missense AP1S1 variant
- AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense mutants
Mendeliome v0.4791 AKNA Seb Lunke Gene: akna has been classified as Red List (Low Evidence).
Mendeliome v0.4791 GOLGA3 Zornitza Stark Gene: golga3 has been classified as Red List (Low Evidence).
Mendeliome v0.4791 GOLGA3 Zornitza Stark Classified gene: GOLGA3 as Red List (low evidence)
Mendeliome v0.4791 GOLGA3 Zornitza Stark Gene: golga3 has been classified as Red List (Low Evidence).
Mendeliome v0.4790 AKNA Seb Lunke Classified gene: AKNA as Red List (low evidence)
Mendeliome v0.4790 AKNA Seb Lunke Gene: akna has been classified as Red List (Low Evidence).
Mendeliome v0.4789 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and in mouse it induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the hypomorphic thoc1 in mouse induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4789 GOLGA3 Elena Savva gene: GOLGA3 was added
gene: GOLGA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GOLGA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOLGA3 were set to PMID: 23495255
Phenotypes for gene: GOLGA3 were set to Primary ciliary dyskinesia
Review for gene: GOLGA3 was set to RED
Added comment: https://link.springer.com/article/10.1007/s00439-020-02170-2
Two siblings with a homozygous missense and PCD

PMID: 23495255; null mice have failed spermatogenesis
Sources: Literature
Mendeliome v0.4789 PRICKLE3 Seb Lunke Gene: prickle3 has been classified as Red List (Low Evidence).
Mendeliome v0.4789 PRICKLE3 Seb Lunke Classified gene: PRICKLE3 as Red List (low evidence)
Mendeliome v0.4789 PRICKLE3 Seb Lunke Added comment: Comment on list classification: Single variant only and questionable association due to uncertainty of role around ND4.
Mendeliome v0.4789 PRICKLE3 Seb Lunke Gene: prickle3 has been classified as Red List (Low Evidence).
Mendeliome v0.4788 AKNA Elena Savva gene: AKNA was added
gene: AKNA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AKNA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AKNA were set to PMID: 21606955
Phenotypes for gene: AKNA were set to Primary ciliary dyskinesia
Review for gene: AKNA was set to RED
Added comment: https://link.springer.com/article/10.1007/s00439-020-02170-2
Two siblings with homozygous PTCs with PCD. Carrier parents and mutation negative siblings (5) was normal.

PMID: 21606955: Null mice have neonatal death with systemic inflammation and alveolar loss
Sources: Literature
Mendeliome v0.4788 THOC1 Zornitza Stark Gene: thoc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4788 THOC1 Zornitza Stark Classified gene: THOC1 as Amber List (moderate evidence)
Mendeliome v0.4788 THOC1 Zornitza Stark Gene: thoc1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4787 GBF1 Seb Lunke Gene: gbf1 has been classified as Green List (High Evidence).
Mendeliome v0.4787 GBF1 Seb Lunke Classified gene: GBF1 as Green List (high evidence)
Mendeliome v0.4787 GBF1 Seb Lunke Gene: gbf1 has been classified as Green List (High Evidence).
Mendeliome v0.4786 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and in mouse it induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4786 NUAK2 Seb Lunke Classified gene: NUAK2 as Amber List (moderate evidence)
Mendeliome v0.4786 NUAK2 Seb Lunke Gene: nuak2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4785 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4785 RNPC3 Zornitza Stark Classified gene: RNPC3 as Amber List (moderate evidence)
Mendeliome v0.4785 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4784 RNPC3 Zornitza Stark gene: RNPC3 was added
gene: RNPC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 29866761; 32462814
Phenotypes for gene: RNPC3 were set to Growth hormone deficiency
Review for gene: RNPC3 was set to AMBER
Added comment: Two families reported. PMID 29866761: isolated growth deficiency and pituitary hypoplasia. PMID 32462814: growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. Full spectrum of phenotype unclear at present.
Sources: Literature
Mendeliome v0.4783 THOC1 Melanie Marty changed review comment from: Missense variant identified and segregated with adulthood-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature; to: Missense variant identified and segregated with adult-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4783 PRICKLE3 Teresa Zhao gene: PRICKLE3 was added
gene: PRICKLE3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRICKLE3 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: PRICKLE3 were set to 32516135
Phenotypes for gene: PRICKLE3 were set to Leber’s hereditary optic neuropathy MIM#535000
Review for gene: PRICKLE3 was set to AMBER
Added comment: Reported as X-linked LHON modifier (c.157C>T, p.Arg53Trp) in PRICKLE3 in 3 Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only a single mutation exhibited normal vision.

Defective assembly, stability, and function of ATP synthase observed using Lymphoblastoid cell lines from one of the families.

This finding indicated that the p.Arg53Trp mutation acted in synergy with the m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON.

Prickle3-deficient mice exhibited pronounced ATPase deficiencies.
Sources: Literature
Mendeliome v0.4783 NUAK2 Seb Lunke Gene: nuak2 has been classified as Red List (Low Evidence).
Mendeliome v0.4783 NUAK2 Seb Lunke gene: NUAK2 was added
gene: NUAK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUAK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NUAK2 were set to 32845958
Phenotypes for gene: NUAK2 were set to ANENCEPHALY (OMIM#206500)
Review for gene: NUAK2 was set to AMBER
Added comment: Novel gene described in single consanguineous family with three FDIU and extensive anencephaly. Hom inframe del affecting functional kinase domain, parents confirmed carriers. Good functional data showing loss of enzyme function and mouse model with 40% anencephaly after knock-out.
Sources: Literature
Mendeliome v0.4782 THOC1 Melanie Marty gene: THOC1 was added
gene: THOC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THOC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THOC1 were set to 32776944
Phenotypes for gene: THOC1 were set to Nonsyndromic hearing loss
Review for gene: THOC1 was set to AMBER
Added comment: Missense variant identified and segregated with adulthood-onset hearing loss in 9 affected family members. 12 unaffected individuals also tested.
Functional studies showed THOC1 was expressed in mouse and zebrafish hair cells. Furthermore, thoc1 deficiency caused the reduction of hair cell numbers in zebrafish and the induced hair cell apoptosis.
Sources: Literature
Mendeliome v0.4782 MBTPS1 Zornitza Stark Gene: mbtps1 has been classified as Green List (High Evidence).
Mendeliome v0.4782 MBTPS1 Zornitza Stark Classified gene: MBTPS1 as Green List (high evidence)
Mendeliome v0.4782 MBTPS1 Zornitza Stark Gene: mbtps1 has been classified as Green List (High Evidence).
Mendeliome v0.4781 MBTPS1 Zornitza Stark gene: MBTPS1 was added
gene: MBTPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MBTPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBTPS1 were set to 32857899; 32420688; 30046013
Phenotypes for gene: MBTPS1 were set to Skeletal dysplasia
Review for gene: MBTPS1 was set to GREEN
Added comment: Three unrelated individuals reported with bi-allelic variants in this gene and a skeletal dysplasia, one described with SRS-like features. Elevated blood lysosomal enzymes are also a feature.
Sources: Literature
Mendeliome v0.4780 ALS2 Ain Roesley gene: ALS2 was added
gene: ALS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ALS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALS2 were set to 32214227
Phenotypes for gene: ALS2 were set to Tetraparesis with affection of upper and lower motor neuron
Penetrance for gene: ALS2 were set to unknown
Review for gene: ALS2 was set to RED
Added comment: In a cohort of Palestinian and Israeli Arabs with neurological disorders, a family with 2 affecteds were homozygous for a nonsense variant. Authors classified as likely path by ACMG guidelines
Sources: Literature
Mendeliome v0.4780 QRICH1 Zornitza Stark Gene: qrich1 has been classified as Green List (High Evidence).
Mendeliome v0.4777 GREB1L Zornitza Stark Gene: greb1l has been classified as Green List (High Evidence).
Mendeliome v0.4777 GREB1L Zornitza Stark Phenotypes for gene: GREB1L were changed from to Renal hypodysplasia/aplasia 3, OMIM# 617805
Mendeliome v0.4774 GREB1L Zornitza Stark reviewed gene: GREB1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100091; Phenotypes: Renal hypodysplasia/aplasia 3, OMIM# 617805; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4774 IL1RAP Zornitza Stark Gene: il1rap has been classified as Red List (Low Evidence).
Mendeliome v0.4774 IL1RAP Zornitza Stark gene: IL1RAP was added
gene: IL1RAP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL1RAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL1RAP were set to 31954058
Phenotypes for gene: IL1RAP were set to Steroid-sensitive nephrotic syndrome
Review for gene: IL1RAP was set to RED
Added comment: A pair of siblings with compound heterozygous variants in this gene and steroid-sensitive nephrotic syndrome. Functional effect of variants demonstrated but mouse model does not have proteinuria.
Sources: Literature
Mendeliome v0.4770 NEMF Zornitza Stark changed review comment from: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.
Sources: Literature; to: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.

Single individual with de novo variant reported, postulated dominant negative effect. Evidence for mono allelic variants causing disease is limited.
Sources: Literature
Mendeliome v0.4769 HOMER2 Zornitza Stark Gene: homer2 has been classified as Green List (High Evidence).
Mendeliome v0.4766 TPRN Zornitza Stark Gene: tprn has been classified as Green List (High Evidence).
Mendeliome v0.4766 TPRN Zornitza Stark Phenotypes for gene: TPRN were changed from to Deafness, autosomal recessive 79, MIM# 613307
Mendeliome v0.4763 TPRN Zornitza Stark reviewed gene: TPRN: Rating: GREEN; Mode of pathogenicity: None; Publications: 19603065, 20170898, 20170899, 23340767, 25129962, 20170899, 20170899, 27693694, 24285636; Phenotypes: Deafness, autosomal recessive 79, MIM# 613307; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4763 TMC1 Zornitza Stark Gene: tmc1 has been classified as Green List (High Evidence).
Mendeliome v0.4763 TMC1 Zornitza Stark Phenotypes for gene: TMC1 were changed from to Deafness, autosomal dominant 36, MIM# 606705; Deafness, autosomal recessive 7, MIM# 600974
Mendeliome v0.4760 TMC1 Zornitza Stark reviewed gene: TMC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11850618, 17250663, 18616530, 24827932, 11850623, 22105175; Phenotypes: Deafness, autosomal dominant 36, MIM# 606705, Deafness, autosomal recessive 7, MIM# 600974; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4760 TMIE Zornitza Stark Gene: tmie has been classified as Green List (High Evidence).
Mendeliome v0.4760 TMIE Zornitza Stark Phenotypes for gene: TMIE were changed from to Deafness, autosomal recessive 6, MIM# 600971
Mendeliome v0.4757 TMIE Zornitza Stark reviewed gene: TMIE: Rating: GREEN; Mode of pathogenicity: None; Publications: 12145746, 19438934, 24416283, 25467981, 25475183, 19934034, 12140191; Phenotypes: Deafness, autosomal recessive 6, MIM# 600971; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4757 TRIOBP Zornitza Stark Gene: triobp has been classified as Green List (High Evidence).
Mendeliome v0.4757 TRIOBP Zornitza Stark Phenotypes for gene: TRIOBP were changed from to Deafness, autosomal recessive 28, MIM# 609823
Mendeliome v0.4754 TRIOBP Zornitza Stark reviewed gene: TRIOBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 16385458, 16385457, 23226338, 27014650, 24853665, 27344577, 20510926; Phenotypes: Deafness, autosomal recessive 28, MIM# 609823; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4754 STRC Zornitza Stark Gene: strc has been classified as Green List (High Evidence).
Mendeliome v0.4754 STRC Zornitza Stark Phenotypes for gene: STRC were changed from to Deafness, autosomal recessive 16, MIM# 603720
Mendeliome v0.4751 STRC Zornitza Stark reviewed gene: STRC: Rating: GREEN; Mode of pathogenicity: None; Publications: 11687802, 26011646, 26746617, 20301780; Phenotypes: Deafness, autosomal recessive 16, MIM# 603720; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4750 SETD1A Zornitza Stark Gene: setd1a has been classified as Green List (High Evidence).
Mendeliome v0.4750 SETD1A Zornitza Stark Classified gene: SETD1A as Green List (high evidence)
Mendeliome v0.4750 SETD1A Zornitza Stark Gene: setd1a has been classified as Green List (High Evidence).
Mendeliome v0.4748 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome to Spastic paraplegia-83 (SPG83), MIM#619027; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome
Mendeliome v0.4747 HPDL Zornitza Stark edited their review of gene: HPDL: Added comment: Although two distinct distinct disease associations have been assigned by OMIM, these clinical presentations likely represent a continuum of severity for an underlying mitochondrial disorder.; Changed phenotypes: Spastic paraplegia-83 (SPG83), MIM#619027, Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026
Mendeliome v0.4747 HPDL Zornitza Stark commented on gene: HPDL: 17 individuals from 13 families, with a spectrum of neurologic impairment ranging from a severe congenital form without any neurological development (n = 2/17, 12%) to infantile-onset presentations (n = 10/17, 59%) with moderate to severe neurodevelopmental issues, partly with a pathology reminiscent of mitochondrial disease (Leigh-like syndrome), to juvenile-onset spastic paraplegia (n = 5/17, 29%).

Frequently observed clinical findings included chronic progression of neurological signs (n = 16/17, 94%), motor developmental delay (n = 12/17, 71%), intellectual impairment (n = 11/17, 65%), microcephaly (n = 9/16, 56%), and seizures/epilepsy (n = 9/17, 53%). Other relevant clinical findings were visual disturbances/strabismus (n = 9/17, 53%) and loss of developmental milestones (n = 6/17, 35%).

Acute central respiratory failure leading to life-threatening events requiring partly mechanically assisted ventilation occurred in half of individuals with infantile presentation (n = 5/10, 50%), respectively one third of all individuals (n = 5/17, 29%).

Demyelinating neuropathy was present in three individuals (n = 3/11, 27%), with reduced sensory nerve conduction velocity (NCV) in all and severely reduced motor NCV in one.
Mendeliome v0.4747 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Progressive neurological disorder; Leigh-like syndrome to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome
Mendeliome v0.4746 HPDL Zornitza Stark reviewed gene: HPDL: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Mode of inheritance: None
Mendeliome v0.4745 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208 to Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208; Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome; Febrile seizures; Arthrogryposis multiplex congenita
Mendeliome v0.4743 SCN1A Zornitza Stark edited their review of gene: SCN1A: Added comment: Note we have reported the association with AMC previously in PMID 29543227 (Supplementary info) in an infant presenting with AMC and severe EE, and de novo p.(Ile1347Asn) variant which at the time was thought to only partially explain the phenotype, but in light of this new report, likely fully explains the phenotype. Given the presence of severe seizure disorder in the two infants who were phenotyped in the newborn period, this likely represents the severe end of the spectrum of SCN1A-related disorders rather than a distinct association.; Changed phenotypes: Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208, Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome, Febrile seizures, Arthrogryposis multiplex congenita
Mendeliome v0.4743 PRKD1 Zornitza Stark changed review comment from: PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.

c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.; to: PMID: 27479907 (2016): three individuals reported, two with the c.1774G>A variant and one with the c.896T>G variant. All had congenital heart disease, two had some developmental delay, and two had variable features of ectodermal dysplasia, including sparse hair, dry skin, thin skin, fragile nails, premature loss of primary teeth, and small widely spaced teeth; the third individuals had a 'disorganized eyebrow.'

PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.

c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.
Mendeliome v0.4742 PRKD1 Zornitza Stark reviewed gene: PRKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479907, 32817298; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4742 SCN1A Arina Puzriakova reviewed gene: SCN1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 32928894; Phenotypes: Arthrogryposis multiplex congenita; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4742 SIX1 Zornitza Stark Marked gene: SIX1 as ready
Mendeliome v0.4742 SIX1 Zornitza Stark Gene: six1 has been classified as Green List (High Evidence).
Mendeliome v0.4742 SIX1 Zornitza Stark Phenotypes for gene: SIX1 were changed from to Deafness, autosomal dominant 23, MIM# 605192; Branchiootic syndrome 3, MIM# 608389
Mendeliome v0.4741 SIX1 Zornitza Stark Publications for gene: SIX1 were set to
Mendeliome v0.4740 SIX1 Zornitza Stark Mode of inheritance for gene: SIX1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4739 SIX1 Zornitza Stark reviewed gene: SIX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15141091, 18330911, 21254961, 17637804, 29500469, 21700001, 24164807; Phenotypes: Deafness, autosomal dominant 23, MIM# 605192, Branchiootic syndrome 3, MIM# 608389; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4739 PTPRQ Zornitza Stark Gene: ptprq has been classified as Green List (High Evidence).
Mendeliome v0.4739 PTPRQ Zornitza Stark Phenotypes for gene: PTPRQ were changed from to Deafness, autosomal recessive 84A, MIM# 613391; Deafness, autosomal dominant 73, MIM# 617663
Mendeliome v0.4736 PTPRQ Zornitza Stark reviewed gene: PTPRQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 20346435, 20472657, 25919374, 14534255, 22357859, 29849575, 29309402, 31655630; Phenotypes: Deafness, autosomal recessive 84A, MIM# 613391, Deafness, autosomal dominant 73, MIM# 617663; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4736 POU4F3 Zornitza Stark Gene: pou4f3 has been classified as Green List (High Evidence).
Mendeliome v0.4733 KPTN Zornitza Stark Gene: kptn has been classified as Green List (High Evidence).
Mendeliome v0.4733 KPTN Zornitza Stark Phenotypes for gene: KPTN were changed from to Mental retardation, autosomal recessive 41 (MIM#615637)
Mendeliome v0.4730 NPHS1 Zornitza Stark Gene: nphs1 has been classified as Green List (High Evidence).
Mendeliome v0.4728 TTI2 Zornitza Stark Gene: tti2 has been classified as Green List (High Evidence).
Mendeliome v0.4728 TTI2 Zornitza Stark Phenotypes for gene: TTI2 were changed from to Mental retardation, autosomal recessive 39, MIM#615541
Mendeliome v0.4725 TTI2 Zornitza Stark reviewed gene: TTI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32061250, 23956177, 31737043; Phenotypes: Mental retardation, autosomal recessive 39, MIM#615541; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4725 IGSF10 Bryony Thompson Gene: igsf10 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4725 IGSF10 Bryony Thompson Classified gene: IGSF10 as Amber List (moderate evidence)
Mendeliome v0.4725 IGSF10 Bryony Thompson Gene: igsf10 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4724 IGSF10 Bryony Thompson gene: IGSF10 was added
gene: IGSF10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IGSF10 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: IGSF10 were set to 27137492; 31042289
Phenotypes for gene: IGSF10 were set to delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency
Review for gene: IGSF10 was set to AMBER
Added comment: PMID: 27137492 - 4 Finnish families segregating p.Glu161Lys, but Finnish MAF in ExAC is 2%. Another six additional families with a possible missense, but variants are seen in ExAC suggesting incomplete penetrance. Supporting in vitro functional assays and zebrafish model. PMID: 31042289 - 2 unrelated consanguineous families with homozygous variants and family with a heterozygous frameshift and apparent incomplete penetrance.
Sources: Literature
Mendeliome v0.4723 KPTN Melanie Marty reviewed gene: KPTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 24239382, 32358097, 32808430; Phenotypes: Mental retardation, autosomal recessive 41 (MIM#615637); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4723 PFN1 Zornitza Stark Gene: pfn1 has been classified as Green List (High Evidence).
Mendeliome v0.4722 PFN1 Zornitza Stark Phenotypes for gene: PFN1 were changed from to Amyotrophic lateral sclerosis 18 (MIM# 614808); Paget’s disease of bone
Mendeliome v0.4720 PFN1 Zornitza Stark reviewed gene: PFN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31802421, 31611772, 31401564, 30203378, 28040732, 22801503; Phenotypes: Amyotrophic lateral sclerosis 18, MIM# 614808; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4720 PCDH15 Zornitza Stark Gene: pcdh15 has been classified as Green List (High Evidence).
Mendeliome v0.4720 PCDH15 Zornitza Stark Phenotypes for gene: PCDH15 were changed from to Usher syndrome, type 1F, MIM# 602083; Deafness, autosomal recessive 23, MIM# 609533
Mendeliome v0.4717 PCDH15 Zornitza Stark reviewed gene: PCDH15: Rating: GREEN; Mode of pathogenicity: None; Publications: 11398101, 11487575, 11138007, 12782354, 16260500, 14570705, 25930172, 28281779; Phenotypes: Usher syndrome, type 1F, MIM# 602083, Deafness, autosomal recessive 23, MIM# 609533; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4717 WHRN Zornitza Stark Gene: whrn has been classified as Green List (High Evidence).
Mendeliome v0.4717 WHRN Zornitza Stark Phenotypes for gene: WHRN were changed from to Usher syndrome, type 2D, MIM# 611383; Deafness, autosomal recessive 31, MIM# 607084
Mendeliome v0.4714 WHRN Zornitza Stark reviewed gene: WHRN: Rating: GREEN; Mode of pathogenicity: None; Publications: 17171570, 21738389, 22147658, 26338283, 12833159, 20502675, 28254438, 27117407, 12833159, 29270100, 15841483; Phenotypes: Usher syndrome, type 2D, MIM# 611383, Deafness, autosomal recessive 31, MIM# 607084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4714 PFN1 Ain Roesley reviewed gene: PFN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23141414, 22801503, 25499087, 24309268, 22801503, 26908597; Phenotypes: Amyotrophic lateral sclerosis 18 (MIM# 614808); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4714 OTOGL Zornitza Stark Gene: otogl has been classified as Green List (High Evidence).
Mendeliome v0.4714 OTOGL Zornitza Stark Phenotypes for gene: OTOGL were changed from to Deafness, autosomal recessive 84B, MIM# 614944
Mendeliome v0.4711 OTOGL Zornitza Stark reviewed gene: OTOGL: Rating: GREEN; Mode of pathogenicity: None; Publications: 23122586, 23850727, 25829320, ​25719458, 28426234; Phenotypes: Deafness, autosomal recessive 84B, MIM# 614944; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4711 RDX Zornitza Stark Gene: rdx has been classified as Green List (High Evidence).
Mendeliome v0.4711 RDX Zornitza Stark Phenotypes for gene: RDX were changed from to Deafness, autosomal recessive 24, MIM# 611022
Mendeliome v0.4708 RDX Zornitza Stark reviewed gene: RDX: Rating: GREEN; Mode of pathogenicity: None; Publications: 17226784, 19215054, 22567349, 26226137, 15314067; Phenotypes: Deafness, autosomal recessive 24, MIM# 611022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4708 OTOA Zornitza Stark Gene: otoa has been classified as Green List (High Evidence).
Mendeliome v0.4708 OTOA Zornitza Stark Phenotypes for gene: OTOA were changed from to Deafness, autosomal recessive 22, MIM# 607039
Mendeliome v0.4705 OTOA Zornitza Stark reviewed gene: OTOA: Rating: GREEN; Mode of pathogenicity: None; Publications: 11972037, 19888295, 23173898, 16460646, 26029705, 26969326, 23129639; Phenotypes: Deafness, autosomal recessive 22, MIM# 607039; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4705 MYO7A Zornitza Stark Gene: myo7a has been classified as Green List (High Evidence).
Mendeliome v0.4705 MYO7A Zornitza Stark Phenotypes for gene: MYO7A were changed from to Deafness, autosomal dominant 11, MIM# 601317; Deafness, autosomal recessive 2, 600060; Usher syndrome, type 1B, MIM# 276900
Mendeliome v0.4702 MYO7A Zornitza Stark reviewed gene: MYO7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 9354784, 15300860, 15121790, 15221449, 16449806, 21150918, 23451214, 23383098, 28802369, 29400105, 23559863, 18181211, 25211151; Phenotypes: Deafness, autosomal dominant 11, MIM# 601317, Deafness, autosomal recessive 2, 600060, Usher syndrome, type 1B, MIM# 276900; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4702 SMPX Zornitza Stark Gene: smpx has been classified as Green List (High Evidence).
Mendeliome v0.4699 MYO6 Zornitza Stark Gene: myo6 has been classified as Green List (High Evidence).
Mendeliome v0.4699 MYO6 Zornitza Stark Phenotypes for gene: MYO6 were changed from to Deafness, autosomal dominant 22, MIM# 606346; Deafness, autosomal recessive 37, MIM# 607821
Mendeliome v0.4696 MYO6 Zornitza Stark reviewed gene: MYO6: Rating: GREEN; Mode of pathogenicity: None; Publications: 24105371, 11468689, 25999546, 25227905, 18348273, 27171474; Phenotypes: Deafness, autosomal dominant 22, MIM# 606346, Deafness, autosomal recessive 37, MIM# 607821; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4696 MYO15A Zornitza Stark Gene: myo15a has been classified as Green List (High Evidence).
Mendeliome v0.4696 MYO15A Zornitza Stark Phenotypes for gene: MYO15A were changed from to Deafness, autosomal recessive 3, MIM# 600316
Mendeliome v0.4693 MYO15A Zornitza Stark reviewed gene: MYO15A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27375115, 26226137, 23208854, 19309289, 9603735, 10915760; Phenotypes: Deafness, autosomal recessive 3, MIM# 600316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4693 MYH9 Zornitza Stark Gene: myh9 has been classified as Green List (High Evidence).
Mendeliome v0.4693 MYH9 Zornitza Stark Phenotypes for gene: MYH9 were changed from to Deafness, autosomal dominant 17, MIM# 603622; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100; MYH9-related disorders
Mendeliome v0.4690 MYH9 Zornitza Stark reviewed gene: MYH9: Rating: GREEN; Mode of pathogenicity: None; Publications: 9390828, 24890873, 17146397, 25505834, 16630581, 16162639, 23976996, 21908426; Phenotypes: Deafness, autosomal dominant 17, MIM# 603622, Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, MIM# 155100, MYH9-related disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4690 MARVELD2 Zornitza Stark Gene: marveld2 has been classified as Green List (High Evidence).
Mendeliome v0.4690 MARVELD2 Zornitza Stark Phenotypes for gene: MARVELD2 were changed from to Deafness, autosomal recessive 49, MIM# 610153
Mendeliome v0.4687 MARVELD2 Zornitza Stark reviewed gene: MARVELD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17186462, 18084694, 22903915, 27344577, 26677943, 23979167; Phenotypes: Deafness, autosomal recessive 49, MIM# 610153; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4687 RPL9 Zornitza Stark Gene: rpl9 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4686 RPL9 Zornitza Stark Classified gene: RPL9 as Amber List (moderate evidence)
Mendeliome v0.4686 RPL9 Zornitza Stark Gene: rpl9 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4685 RPL9 Arina Puzriakova changed review comment from: PMID: 31799629 (2020) - One individual diagnosed with Diamond Blackfan anaemia carrying a de novo variant (c.-2+1G>C) in the 5′UTR of RPL9, predicted to affect the donor splice site of exon 1. Functional studies showed the variant impairs processing of pre-rRNA during ribosome biogenesis, stabilises TP53 and impairs the proliferation and differentiation of erythroid cells. Zebrafish models of RPL9 LoF recapitulate the anaemia phenotype.; to: PMID: 31799629 (2020) - Female infant diagnosed with Diamond-Blackfan anaemia carrying a de novo variant (c.-2+1G>C) in the 5′UTR of RPL9, predicted to affect the donor splice site of exon 1. Phenotypic overlap can be seen with the previously reported case with the same variant, including colitis, thumb anomaly, and microcephaly. Functional studies showed the variant impairs processing of pre-rRNA during ribosome biogenesis, stabilises TP53 and impairs the proliferation and differentiation of erythroid cells. Zebrafish models of RPL9 LoF recapitulate the anaemia phenotype.
Mendeliome v0.4685 LRTOMT Zornitza Stark Gene: lrtomt has been classified as Green List (High Evidence).
Mendeliome v0.4685 LRTOMT Zornitza Stark Phenotypes for gene: LRTOMT were changed from to Deafness, autosomal recessive 63, MIM# 611451
Mendeliome v0.4682 LRTOMT Zornitza Stark reviewed gene: LRTOMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 18953341, 18794526, 21739586, 18794526; Phenotypes: Deafness, autosomal recessive 63, MIM# 611451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4682 LHFPL5 Zornitza Stark Gene: lhfpl5 has been classified as Green List (High Evidence).
Mendeliome v0.4682 LHFPL5 Zornitza Stark Phenotypes for gene: LHFPL5 were changed from to Deafness, autosomal recessive 67, MIM# 610265
Mendeliome v0.4679 LHFPL5 Zornitza Stark reviewed gene: LHFPL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 16459341, 16752389, 21816241, 19888295, 26437881, 26029705, 15905332, 19102128, 25550511; Phenotypes: Deafness, autosomal recessive 67, MIM# 610265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4679 GYS1 Zornitza Stark Gene: gys1 has been classified as Green List (High Evidence).
Mendeliome v0.4676 PIGT Zornitza Stark Gene: pigt has been classified as Green List (High Evidence).
Mendeliome v0.4672 ALG13 Zornitza Stark Gene: alg13 has been classified as Green List (High Evidence).
Mendeliome v0.4669 BLOC1S5 Zornitza Stark Gene: bloc1s5 has been classified as Green List (High Evidence).
Mendeliome v0.4669 BLOC1S5 Zornitza Stark Classified gene: BLOC1S5 as Green List (high evidence)
Mendeliome v0.4669 BLOC1S5 Zornitza Stark Gene: bloc1s5 has been classified as Green List (High Evidence).
Mendeliome v0.4668 BLOC1S5 Zornitza Stark gene: BLOC1S5 was added
gene: BLOC1S5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BLOC1S5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S5 were set to 32565547
Phenotypes for gene: BLOC1S5 were set to Hermansky–Pudlak syndrome
Review for gene: BLOC1S5 was set to GREEN
Added comment: 2 unrelated patients with mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Identified distinct homozygous variants in the BLOC1S5 gene (patient 1: deletion of exons 3 and 4, patient 2: 1-bp deletion in exon 4). Parental segregation confirmatory in patient 1, quantitative PCR analysis confirmatory in patient 2). Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5-/- melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele. Pathogenic variants in the genes encoding three other BLOC-1 subunits (DTNBP1, BLOC1S3, and BLOC1S6) underlie HPS types 7, 8, and 9 respectively.
Sources: Literature
Mendeliome v0.4667 FOXL2 Zornitza Stark Gene: foxl2 has been classified as Green List (High Evidence).
Mendeliome v0.4667 FOXL2 Zornitza Stark Phenotypes for gene: FOXL2 were changed from to Blepharophimosis, epicanthus inversus, and ptosis, type 1 with premature ovarian insufficiency (POI) and type II without POI (MIM# 110100)
Mendeliome v0.4664 FOXL2 Ain Roesley changed review comment from: PMID: 31077882; 19x probands reported, AD.

PMID: 18642388;
BPES type I : Mutations predicted to result in proteins with truncation before the poly-Ala tract
BPES type II: poly-Ala expansions (WT poly-Ala is between aa 221-234)
Exceptions: Truncated proteins with complete forkhead and poly-Ala domains, can be either Type I and II

NOTE: only 1 family reported for AR (PMID: 17089161); to: PMID: 31077882; >100 probands reported, AD.

PMID: 18642388;
BPES type I : Mutations predicted to result in proteins with truncation before the poly-Ala tract
BPES type II: poly-Ala expansions (WT poly-Ala is between aa 221-234)
Exceptions: Truncated proteins with complete forkhead and poly-Ala domains, can be either Type I and II

NOTE: only 1 family reported for AR (PMID: 17089161)
Mendeliome v0.4664 FOXL2 Ain Roesley reviewed gene: FOXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31077882, 18642388, 17089161; Phenotypes: Blepharophimosis, epicanthus inversus, and ptosis, type 1 with premature ovarian insufficiency (POI) and type II without POI (MIM# 110100); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4664 ILDR1 Zornitza Stark Gene: ildr1 has been classified as Green List (High Evidence).
Mendeliome v0.4664 ILDR1 Zornitza Stark Phenotypes for gene: ILDR1 were changed from to Deafness, autosomal recessive 42, MIM# 609646
Mendeliome v0.4661 ILDR1 Zornitza Stark reviewed gene: ILDR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21255762, 23226338, 22903915, 27344577, 21255762, 23239027, 25822906, 25819842, 24990150; Phenotypes: Deafness, autosomal recessive 42, MIM# 609646; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4661 HOXA2 Zornitza Stark Gene: hoxa2 has been classified as Green List (High Evidence).
Mendeliome v0.4658 GRXCR1 Zornitza Stark Gene: grxcr1 has been classified as Green List (High Evidence).
Mendeliome v0.4658 GRXCR1 Zornitza Stark Phenotypes for gene: GRXCR1 were changed from to Deafness, autosomal recessive 25, MIM# 613285
Mendeliome v0.4655 GRXCR1 Zornitza Stark reviewed gene: GRXCR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20137778, 25802247, 26226137, 26445815, 26969326, 20137774; Phenotypes: Deafness, autosomal recessive 25, MIM# 613285; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4655 GPSM2 Zornitza Stark Gene: gpsm2 has been classified as Green List (High Evidence).
Mendeliome v0.4652 GIPC3 Zornitza Stark Gene: gipc3 has been classified as Green List (High Evidence).
Mendeliome v0.4652 GIPC3 Zornitza Stark Phenotypes for gene: GIPC3 were changed from to Deafness, autosomal recessive 15, MIM# 601869
Mendeliome v0.4649 GIPC3 Zornitza Stark reviewed gene: GIPC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21326233, 21660509; Phenotypes: Deafness, autosomal recessive 15, MIM# 601869; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4649 COCH Zornitza Stark Phenotypes for gene: COCH were changed from Deafness, autosomal dominant 9, MIM# 601369 to Deafness, autosomal dominant 9, MIM# 601369; Deafness, autosomal recessive 110, MIM# 618094
Mendeliome v0.4647 COCH Zornitza Stark changed review comment from: Over 50 affected individuals from more than 10 families reported, mouse model. Single family with two siblings reported with bi-allelic variants in this gene and deafness (homozygous LOF) in PMID 29449721, evidence for bi-allelic disease is limited.; to: Mono-allelic variants: Over 50 affected individuals from more than 10 families reported, mouse model. Dominant negative effect postulated.

Bi-allelic variants: three families reported with bi-allelic variants in this gene and deafness. All variants are LOF, some functional data. PMIDs 29449721, 32939038, 32562050.
Mendeliome v0.4647 COCH Zornitza Stark edited their review of gene: COCH: Changed phenotypes: Deafness, autosomal dominant 9, MIM# 601369, Deafness, autosomal recessive 110, MIM# 618094
Mendeliome v0.4647 CNOT1 Zornitza Stark Phenotypes for gene: CNOT1 were changed from Holoprosencephaly 12, with or without pancreatic agenesis; OMIM# 618500 to Vissers-Bodmer syndrome, MIM#619033; Holoprosencephaly 12, with or without pancreatic agenesis; OMIM# 618500
Mendeliome v0.4643 GATA3 Zornitza Stark Gene: gata3 has been classified as Green List (High Evidence).
Mendeliome v0.4643 GATA3 Zornitza Stark Phenotypes for gene: GATA3 were changed from to Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255
Mendeliome v0.4640 GATA3 Zornitza Stark reviewed gene: GATA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10935639, 11389161, 21120445, 26316437, 25771973, 27387476, 30396722; Phenotypes: Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4639 FGF3 Zornitza Stark reviewed gene: FGF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21480479, 21306635, 18435799, 17236138, 21306635, 18701883, 8223243, 26995070, 29902227, 30504125; Phenotypes: Deafness, congenital with inner ear agenesis, microtia, and microdontia, MIM# 610706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4636 ESPN Zornitza Stark Gene: espn has been classified as Green List (High Evidence).
Mendeliome v0.4636 ESPN Zornitza Stark Phenotypes for gene: ESPN were changed from to Deafness, autosomal recessive 36, MIM# 609006; Deafness, neurosensory, without vestibular involvement, autosomal dominant, MIM# 609006
Mendeliome v0.4633 ESPN Zornitza Stark reviewed gene: ESPN: Rating: GREEN; Mode of pathogenicity: None; Publications: 15286153, 18973245, 26445815, 28281779, 10975527, 15930085; Phenotypes: Deafness, autosomal recessive 36, MIM# 609006, Deafness, neurosensory, without vestibular involvement, autosomal dominant, MIM# 609006; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4633 DFNB59 Zornitza Stark Gene: dfnb59 has been classified as Green List (High Evidence).
Mendeliome v0.4633 DFNB59 Zornitza Stark Phenotypes for gene: DFNB59 were changed from to Deafness, autosomal recessive 59, MIM# 610220
Mendeliome v0.4630 DFNB59 Zornitza Stark reviewed gene: DFNB59: Rating: GREEN; Mode of pathogenicity: None; Publications: 16804542, 26166082, 22617256, 28964305, 17373699, 25631766, 28209736; Phenotypes: Deafness, autosomal recessive 59, MIM# 610220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4630 DFNA5 Zornitza Stark Gene: dfna5 has been classified as Green List (High Evidence).
Mendeliome v0.4627 RIC3 Bryony Thompson Gene: ric3 has been classified as Red List (Low Evidence).
Mendeliome v0.4627 RIC3 Bryony Thompson Classified gene: RIC3 as Red List (low evidence)
Mendeliome v0.4627 RIC3 Bryony Thompson Gene: ric3 has been classified as Red List (Low Evidence).
Mendeliome v0.4626 PRIMPOL Zornitza Stark Classified gene: PRIMPOL as Red List (low evidence)
Mendeliome v0.4626 PRIMPOL Zornitza Stark Gene: primpol has been classified as Red List (Low Evidence).
Mendeliome v0.4625 MIEF2 Zornitza Stark Phenotypes for gene: MIEF2 were changed from Progressive muscle weakness; Exercise intolerance; Ragged red and COX negative fibres; Complex I and IV deficiency to Combined oxidative phosphorylation deficiency 49, MIM# 619024; Progressive muscle weakness; Exercise intolerance; Ragged red and COX negative fibres; Complex I and IV deficiency
Mendeliome v0.4624 MRPS25 Zornitza Stark Phenotypes for gene: MRPS25 were changed from Dyskinetic cerebral palsy; Mitochondrial myopathy; Partial agenesis of the corpus callosum to Combined oxidative phosphorylation deficiency 50, MIM# 619025; Dyskinetic cerebral palsy; Mitochondrial myopathy; Partial agenesis of the corpus callosum
Mendeliome v0.4623 MRPS25 Zornitza Stark edited their review of gene: MRPS25: Changed phenotypes: Combined oxidative phosphorylation deficiency 50, MIM# 619025, Dyskinetic cerebral palsy, Mitochondrial myopathy, Partial agenesis of the corpus callosum
Mendeliome v0.4623 MIEF2 Zornitza Stark edited their review of gene: MIEF2: Changed phenotypes: Combined oxidative phosphorylation deficiency 49, MIM# 619024, Progressive muscle weakness, Exercise intolerance, Ragged red and COX negative fibres, Complex I and IV deficiency
Mendeliome v0.4623 COL4A5 Zornitza Stark Gene: col4a5 has been classified as Green List (High Evidence).
Mendeliome v0.4621 COCH Zornitza Stark Gene: coch has been classified as Green List (High Evidence).
Mendeliome v0.4618 CLRN1 Zornitza Stark Gene: clrn1 has been classified as Green List (High Evidence).
Mendeliome v0.4615 CLPP Zornitza Stark Gene: clpp has been classified as Green List (High Evidence).
Mendeliome v0.4612 CLDN14 Zornitza Stark Gene: cldn14 has been classified as Green List (High Evidence).
Mendeliome v0.4612 CLDN14 Zornitza Stark Phenotypes for gene: CLDN14 were changed from to Deafness, autosomal recessive 29, MIM# 614035
Mendeliome v0.4609 CLDN14 Zornitza Stark reviewed gene: CLDN14: Rating: GREEN; Mode of pathogenicity: None; Publications: 11163249, 20811388, 22246673, 23235333, 27870113, 27838790, 12913076; Phenotypes: Deafness, autosomal recessive 29, MIM# 614035; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4609 CIB2 Zornitza Stark Gene: cib2 has been classified as Green List (High Evidence).
Mendeliome v0.4609 CIB2 Zornitza Stark Phenotypes for gene: CIB2 were changed from to Deafness, autosomal recessive 48, MIM# 609439
Mendeliome v0.4606 CIB2 Zornitza Stark reviewed gene: CIB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23023331, 23023331, 26173970, 26473954, 27344577, 26226137, 26445815; Phenotypes: Deafness, autosomal recessive 48, MIM# 609439; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4606 GCM2 Zornitza Stark Gene: gcm2 has been classified as Green List (High Evidence).
Mendeliome v0.4602 SECISBP2 Zornitza Stark Gene: secisbp2 has been classified as Green List (High Evidence).
Mendeliome v0.4599 UBA1 Zornitza Stark Gene: uba1 has been classified as Green List (High Evidence).
Mendeliome v0.4596 TRIP4 Zornitza Stark Gene: trip4 has been classified as Green List (High Evidence).
Mendeliome v0.4593 EXOSC9 Zornitza Stark Gene: exosc9 has been classified as Green List (High Evidence).
Mendeliome v0.4593 EXOSC9 Zornitza Stark Phenotypes for gene: EXOSC9 were changed from to Pontocerebellar hypoplasia, type 1D, MIM# 618065
Mendeliome v0.4590 EXOSC9 Zornitza Stark reviewed gene: EXOSC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 30690203, 29727687; Phenotypes: Pontocerebellar hypoplasia, type 1D, MIM# 618065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4590 SLC7A14 Zornitza Stark Gene: slc7a14 has been classified as Red List (Low Evidence).
Mendeliome v0.4587 SLC7A14 Zornitza Stark Classified gene: SLC7A14 as Red List (low evidence)
Mendeliome v0.4587 SLC7A14 Zornitza Stark Gene: slc7a14 has been classified as Red List (Low Evidence).
Mendeliome v0.4586 ATP6V1B1 Zornitza Stark Gene: atp6v1b1 has been classified as Green List (High Evidence).
Mendeliome v0.4586 ATP6V1B1 Zornitza Stark Phenotypes for gene: ATP6V1B1 were changed from to Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300
Mendeliome v0.4583 ATP6V1B1 Zornitza Stark reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916796, 12414817, 16611712, 18798332; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4583 ATP2B2 Zornitza Stark reviewed gene: ATP2B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30535804, 15829536; Phenotypes: Dominant progressive sensorineural deafness, {Deafness, autosomal recessive 12, modifier of}, MIM# 601386; Mode of inheritance: None
Mendeliome v0.4581 ALB Zornitza Stark Gene: alb has been classified as Green List (High Evidence).
Mendeliome v0.4578 TREM2 Zornitza Stark Gene: trem2 has been classified as Green List (High Evidence).
Mendeliome v0.4578 TREM2 Zornitza Stark Phenotypes for gene: TREM2 were changed from to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193
Mendeliome v0.4575 TREM2 Zornitza Stark reviewed gene: TREM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 12080485, 15883308; Phenotypes: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4575 SPG21 Zornitza Stark Gene: spg21 has been classified as Green List (High Evidence).
Mendeliome v0.4572 LMX1A Zornitza Stark Gene: lmx1a has been classified as Green List (High Evidence).
Mendeliome v0.4569 RPS20 Bryony Thompson Gene: rps20 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4569 RPS20 Bryony Thompson Classified gene: RPS20 as Amber List (moderate evidence)
Mendeliome v0.4569 RPS20 Bryony Thompson Gene: rps20 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4568 RPS20 Bryony Thompson gene: RPS20 was added
gene: RPS20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RPS20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS20 were set to 32790018
Phenotypes for gene: RPS20 were set to Diamond Blackfan anaemia
Mode of pathogenicity for gene: RPS20 was set to Other
Review for gene: RPS20 was set to AMBER
Added comment: Two unrelated cases where a de novo variant involving Ile84 (Ile84Ser and Ile84Asn), and reduce the RPS20 protein level in patient cells. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. Loss of function may not be the mechanism of disease, because loss of function variants appear to be exclusively associated with familial colorectal cancer without the DBA phenotype.
Sources: Literature
Mendeliome v0.4566 SPAST Zornitza Stark Gene: spast has been classified as Green List (High Evidence).
Mendeliome v0.4563 TRRAP Zornitza Stark Gene: trrap has been classified as Green List (High Evidence).
Mendeliome v0.4560 UPF3B Zornitza Stark Gene: upf3b has been classified as Green List (High Evidence).
Mendeliome v0.4557 XPR1 Zornitza Stark Gene: xpr1 has been classified as Green List (High Evidence).
Mendeliome v0.4554 VPS13C Zornitza Stark Gene: vps13c has been classified as Green List (High Evidence).
Mendeliome v0.4551 KIAA1161 Zornitza Stark Phenotypes for gene: KIAA1161 were changed from Basal ganglia calcification, idiopathic, 7, autosomal recessive; OMIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome to Basal ganglia calcification, idiopathic, 7, MIM #618317; primary familial brain calcifications (PFBC); ataxia; dysarthria; cerebellar atrophy; akinetic-hypertonic syndrome
Mendeliome v0.4548 KIAA1161 Zornitza Stark edited their review of gene: KIAA1161: Added comment: In a cohort study comprising 435 individuals with primary brain calcification, 38 individuals identified with mono-allelic variants in this gene, in addition to 14 with bi-allelic variants. Clinical and imaging penetrance of individuals with bi-allelic variants were 100%, whereas among individuals with heterozygous variants, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG variants, individuals with heterozygous variants had brain calcifications with much lower calcification scores (P < 2e-16). HGNC approved name is MYORG.; Changed publications: 30656188, 30649222, 30460687, 29910000, 31951047; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4548 ALG14 Zornitza Stark Gene: alg14 has been classified as Green List (High Evidence).
Mendeliome v0.4545 TCF12 Zornitza Stark Gene: tcf12 has been classified as Green List (High Evidence).
Mendeliome v0.4545 TCF12 Zornitza Stark Phenotypes for gene: TCF12 were changed from to Craniosynostosis 3, MIM# 615314; Kallman syndrome
Mendeliome v0.4542 TCF12 Zornitza Stark reviewed gene: TCF12: Rating: GREEN; Mode of pathogenicity: None; Publications: 23354436, 32620954; Phenotypes: Craniosynostosis 3, MIM# 615314, Kallman syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4542 RP1L1 Zornitza Stark Gene: rp1l1 has been classified as Green List (High Evidence).
Mendeliome v0.4539 CYP11B2 Zornitza Stark Gene: cyp11b2 has been classified as Green List (High Evidence).
Mendeliome v0.4536 HPS5 Zornitza Stark Gene: hps5 has been classified as Green List (High Evidence).
Mendeliome v0.4533 IBA57 Zornitza Stark Phenotypes for gene: IBA57 were changed from Multiple mitochondrial dysfunctions syndrome 3, MIM#615330 to Multiple mitochondrial dysfunctions syndrome 3, MIM#615330; Spastic paraplegia 74, autosomal recessive MIM#616451
Mendeliome v0.4531 IBA57 Zornitza Stark changed review comment from: More than 15 families reported with bi-allelic variants in this gene and a severe neurodegenerative disorder characterised by loss of previously acquired developmental milestones in the first months or years of life. Some affected individuals have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some individuals die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some individuals may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable.; to: MMDS3: More than 15 families reported with bi-allelic variants in this gene and a severe neurodegenerative disorder characterised by loss of previously acquired developmental milestones in the first months or years of life. Some affected individuals have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some individuals die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some individuals may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable.

SPG74: Three families with spastic paraparesis as a feature of the condition.
Mendeliome v0.4531 IBA57 Zornitza Stark edited their review of gene: IBA57: Changed phenotypes: Multiple mitochondrial dysfunctions syndrome 3, MIM#615330, Spastic paraplegia 74, autosomal recessive MIM#616451
Mendeliome v0.4531 IBA57 Zornitza Stark Gene: iba57 has been classified as Green List (High Evidence).
Mendeliome v0.4525 PAX7 Zornitza Stark Gene: pax7 has been classified as Green List (High Evidence).
Mendeliome v0.4525 PAX7 Zornitza Stark Phenotypes for gene: PAX7 were changed from to Myopathy, congenital, progressive, with scoliosis, MIM# 618578
Mendeliome v0.4522 PAX7 Zornitza Stark reviewed gene: PAX7: Rating: GREEN; Mode of pathogenicity: None; Publications: 31092906, 11030621, 24065826, 31092906, 8631261, 11030621, 24065826; Phenotypes: Myopathy, congenital, progressive, with scoliosis, MIM# 618578; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4521 MADD Zornitza Stark edited their review of gene: MADD: Added comment: OMIM have assigned two disease entities to this gene.

DEEAH syndrome: 12 families.
NEDDISH syndrome: 8 families.; Changed phenotypes: DEEAH syndrome, MIM#619004 (Developmental Delay With Endocrine, Exocrine, Autonomic, and Hematologic Abnormalities), Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (NEDDISH), MIM# 619005
Mendeliome v0.4520 SLC12A2 Zornitza Stark edited their review of gene: SLC12A2: Added comment: Monoallelic :
DD/ID was a feature in >= 6 individuals with monoallelic de novo SLC12A2. An individual with an exon 22 truncating variant was reported to have normal milestones and cognitive function. Exon 21 variants have been described in individuals with rather isolated hearing impairment (possibly some associated motor delay, but normal cognition). Hearing impairment was also reported in 2/6 patients with variants in other exons (1 missense / 1 frameshift).

Biallelic :
DD/ID was reported in at least 3 individuals in literature. Hearing impairment has been reported on 2 occasions (although this was not probably evaluated in all subjects).

---

Monoallelic SLC12A2 mutations :

► Individuals with de novo mutations and developmental disorder were first identified by the DDD study (2017 - PMID: 28135719). 5 of them have been reported in detail by McNeill et al (below).

► McNeill et al (2020 - PMID: 32658972) report on 6 individuals with neurodevelopmental disorder due to de novo SLC12A2 mutation. All presented DD or ID ranging from mild to severe. ASD was reported in 3/6. Sensorineural hearing loss was a feature in 2/6 with the remaining having normal formal evaluations. Brain, cardiac and/or additional malformations were reported in a single individual. Following non-diagnostic prior work-up (CMA, FMR1 or other investigations) trio exome sequencing revealed missense (4/6) or truncating variants (2/6).

Three additional individuals (incl. a father and his son) with missense variants in exon 21 (NM_001046.3 / p.Glu979Lys and p.Glu980Lys) presented with bilateral sensorineural hearing loss. Speech and/or motor delay reported in these cases were attributed to the hearing impairment/vestibular arreflexia (cognitive abilities not tested).

SLC12A2 encodes sodium-potassium-chloride transporter 1 (also NKCC1).

The GTEx project has identified 8 isoforms. In brain both exon 21-containing/deleted isoforms are expressed (cited Morita et al 2014 - PMID: 24695712). As the authors discuss, RNA-seq of the developing mouse cochlea suggests that the exon 21 containing isoform is the single transcript expressed. Evidence from RNA-seq data (BrainSpan project) and literature suggests that the significant amounts of exon 21 lacking isoforms in fetal brain compensate for the deleterious effects of exon 21 variants and explain the lack of NDD in relevant patients.

Slc12a2 (NKCC1) null mouse model has demonstrated that the transporter plays a role in accumulation of the potassium rich endolymph in the inner ear, with NKCC1 absence causing sensorineural deafness and imbalance. Slc12a2 display cochlear malformations, loss of hair cells and hearing impairment (cited Delpire et al 1999 - PMID: 10369265). The brain phenotype has not been studied extensively, although loss of Slc12a2 has been shown to inhibit neurogenesis (cited: Magalhães and Rivera et al. - PMID: 27582690).

Slc12a2 null zebrafish display a collapse of the otic vesicle and reduced endolymph (Abbas and Whitfield, 2009 - PMID: 19633174) relevant to the human hearing disorder.

In vitro assessment of NKCC1 ion transporter function in Xenopus laevis, supported the deleterious effect of the identified variants (significant reduction in K+ influx). Using available single cell RNA-seq data the authors further demonstrated that SLC12A2 expressing cells display transcriptomic profiles reflective of active neurogenesis.

► Delpire et al (2016 - PMID: 27900370 - not reviewed in detail) described a 13 y.o. girl harboring a de novo 11-bp deletion in SLC12A2 exon 22. This individual reached developmental milestones on time and had a NORMAL cognitive function. Hearing was seemingly normal. Features included orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency and multiorgan failure incl. gut and bladder. Exome in the proband, parents and 3 unaffected sibs suggested SLC12A2 as the only candidate for her phenotype. Functional analyses in Xenopus laevis oocytes suggested that a non functional transporter was expressed and trafficked to the membrane as the wt. Detection of the truncated protein at higher molecular sizes suggested either enhanced dimerization or misfolded aggregate. There was no dominant-negative effect of mutant NKCC1. In patient fibroblasts a reduced total and NKCC1-mediated K+ influx.

► Mutai et al (2020 - PMID: 32294086) report on several individuals from 4 families, harboring variants within exon 21 or - in one case - at it's 3' splice-site (leading to skipping oe this exon at the mRNA level). All subjects were investigated for severe/profound hearing loss (in line with the role of exon 21-included isoforms in cochlea. The variant segregated with hearing impairment in 3 generations of a family while in all other subjects the variant had occured as de novo event. Despite motor delays (e.g. the subject from fam2 could not hold head or sit at the age of 10m / the proband in Fam3 was able to hold his head and walk at 6 and 20 m respectively) behavior and cognition were commented to be within normal range.


-----

Biallelic SLC12A2 mutations:

► Anazi et al (2017 - PMID: 29288388) briefly reported on a 3 y.o. boy (17DG0776) with central hypotonia, neonatal respiratory distress, failure to thrive, global DD and microcephaly and a skeletal survey suggestive of osteopenia. After non-diagnostic prior investigations (CMA revealing a 1p duplication classified as VUS, extensive metabolic workup), WES revealed a homozygous SLC12A2 splicing variant [NM_001046.2:c.2617-2A>G].

► Macnamara et al (2019 - PMID: 30740830) described a 5.5 y.o. male with sensorineural hearing loss, profound delays in all developmental areas among several other features (choanal atresia, failure to thrive, respiratory problems, absent sweat and tear production or salivation, GI abnormalities). Genetic testing for several disorders considered (cystic fibrosis, spinal muscular atrophy, sequencing and del/dup analysis of mtDNA) was normal. CMA revealed paternal uniparental isodisomy for chr. 5 and WGS a homozygous 22kb deletion in SLC12A2. This was followed by confirmation of homozygosity in the proband, heterozygosity of the unaffected father, delineation of breakpoints (chr5:127441491-127471419). mRNA studies in patient fibroblasts confirmed deletion of ex2-7, splicing of ex1 directly to ex8 and introduction of a premature stop codon in ex9. qRT-PCR confirmed that mRNA is likely subjected to NMD (expression ~80% of control). Western blot confirmed absence of the protein in the patient's fibroblasts. Again mouse models are thought to recapitulate the hearing defect but also the deficient saliva production (cited Evans et al 2000 - PMID: 10831596). Again the authors speculate a role of SLC12A2 in brain development based on evidence from murine models (migration, dendritic growth, increse in neuron density through regulation of GABAergic signalling (Young et al 2012 - PMID: 23015452). Hypotheses are also made on a regulatory relationship between NKCC1 and CFTR based on mRNA data from the ko mouse model.

► Stödberg et al (2020 - PMID: 32754646) reported 2 sibs with a complex neurodevelopmental disorder due to compound heterozygosity for a frameshift SLC12A2 variant and a splicing one (NM_001046:c.1431delT and c.2006-1G>A). Both presented hypotonia, neonatal S. aureus parotitis and respiratory problems (incl. apneas). While the older sib died at the age of 22 days, the younger one had persistent respiratory issues incl. a dry respiratory mucosa motivating metabolic, immunology investigations and testing for CF. She displayed microcephaly (OFC -2.5 SD, H was also -3.5SD), severe intellectual disability. MRI was suggestive of white matter and basal ganglia abnormalities. Other features incl. hearing impairment, and lack of tears,saliva and sweat, constipation and intestinal malrotation. There was facial dysmorphism. The variants were the only retained following WGS of the 2 affected sisters, parents and an unaffected brother. The splicing variant was shown to result in skipping of exon 13, while the indel in NMD. Again the authors discuss that the deficient saliva production, impaired hearing and GI problems are recapitulated in the mouse model (several refs provided).; Changed rating: GREEN; Changed publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Changed phenotypes: Kilquist syndrome, deafness, intellectual disability, dysmorphic features, absent salivation, ectodermal dysplasia, constipation, intestinal malrotation, multiple congenital anomalies; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4520 VPS37A Zornitza Stark Gene: vps37a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4520 VPS37A Zornitza Stark Phenotypes for gene: VPS37A were changed from to Spastic paraplegia 53, autosomal recessive, MIM# 614898
Mendeliome v0.4517 VPS37A Zornitza Stark Classified gene: VPS37A as Amber List (moderate evidence)
Mendeliome v0.4517 VPS37A Zornitza Stark Gene: vps37a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4516 VPS37A Zornitza Stark reviewed gene: VPS37A: Rating: AMBER; Mode of pathogenicity: None; Publications: 22717650; Phenotypes: Spastic paraplegia 53, autosomal recessive, MIM# 614898; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4516 TECPR2 Zornitza Stark Gene: tecpr2 has been classified as Green List (High Evidence).
Mendeliome v0.4516 TECPR2 Zornitza Stark Phenotypes for gene: TECPR2 were changed from to Spastic paraplegia 49, autosomal recessive, MIM# 615031; Autonomic-sensory neuropathy
Mendeliome v0.4513 TECPR2 Zornitza Stark reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176824, 26542466; Phenotypes: Spastic paraplegia 49, autosomal recessive, MIM# 615031, Autonomic-sensory neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4513 SMOC2 Zornitza Stark Gene: smoc2 has been classified as Green List (High Evidence).
Mendeliome v0.4513 SMOC2 Zornitza Stark Phenotypes for gene: SMOC2 were changed from to Dentin dysplasia, type I, with microdontia and misshapen teeth, MIM# 125400
Mendeliome v0.4510 SMOC2 Zornitza Stark reviewed gene: SMOC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22152679, 23317772, 32908163; Phenotypes: Dentin dysplasia, type I, with microdontia and misshapen teeth, MIM# 125400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4510 MAG Zornitza Stark Gene: mag has been classified as Green List (High Evidence).
Mendeliome v0.4510 MAG Zornitza Stark Phenotypes for gene: MAG were changed from to Spastic paraplegia 75, autosomal recessive, MIM# 616680
Mendeliome v0.4507 MAG Zornitza Stark reviewed gene: MAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 26179919, 31402626, 32629324; Phenotypes: Spastic paraplegia 75, autosomal recessive, MIM# 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4507 DSTYK Zornitza Stark Gene: dstyk has been classified as Green List (High Evidence).
Mendeliome v0.4504 ZMYM2 Zornitza Stark Gene: zmym2 has been classified as Green List (High Evidence).
Mendeliome v0.4504 ZMYM2 Zornitza Stark Classified gene: ZMYM2 as Green List (high evidence)
Mendeliome v0.4504 ZMYM2 Zornitza Stark Gene: zmym2 has been classified as Green List (High Evidence).
Mendeliome v0.4503 ZMYM2 Zornitza Stark gene: ZMYM2 was added
gene: ZMYM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Congenital anomalies of kidney and urinary tract; Neurodevelopmental disorder
Review for gene: ZMYM2 was set to GREEN
Added comment: Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features.

--

Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants.

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Mendeliome v0.4502 MTX2 Zornitza Stark Gene: mtx2 has been classified as Green List (High Evidence).
Mendeliome v0.4502 MTX2 Zornitza Stark Classified gene: MTX2 as Green List (high evidence)
Mendeliome v0.4502 MTX2 Zornitza Stark Gene: mtx2 has been classified as Green List (High Evidence).
Mendeliome v0.4501 MTX2 Zornitza Stark gene: MTX2 was added
gene: MTX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTX2 were set to 32917887
Phenotypes for gene: MTX2 were set to Mandibuloacral dysplasia; lipodystrophy; arterial calcification
Review for gene: MTX2 was set to GREEN
Added comment: Seven individuals from 5 unrelated families reported with severe progeroid form of MAD with growth retardation, small viscerocranium with mandibular underdevelopment, distal acro-osteolyses, lipodystrophy, altered skin pigmentation, renal focal glomerulosclerosis, and extremely severe hypertension in most cases, eventually associated with disseminated arterial calcification. Loss of MTX2 in patients' primary fibroblasts led to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts were resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation.
Sources: Literature
Mendeliome v0.4500 RREB1 Zornitza Stark Gene: rreb1 has been classified as Red List (Low Evidence).
Mendeliome v0.4500 RREB1 Zornitza Stark gene: RREB1 was added
gene: RREB1 was added to Mendeliome. Sources: Literature
SV/CNV tags were added to gene: RREB1.
Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RREB1 were set to 32938917
Phenotypes for gene: RREB1 were set to Noonan syndrome-like disorder
Review for gene: RREB1 was set to RED
Added comment: Single individual reported with Noonan syndrome-like features and a deletion encompassing RREB1. Overlapping deletions in publicly reported databases examined, and RREB1 postulated to be the key gene. Rreb1 hemizygous mice display orbital hypertelorism and age dependent cardiac hypertrophy. RREB1 recruits SIN3A and KDM1A to an RRE in target promoters in human and murine cells to control histone H3K4 methylation of MAPK pathway genes.

In summary, single well phenotyped individual with a CNV and experimental data to support gene-disease association.
Sources: Literature
Mendeliome v0.4499 FNIP1 Zornitza Stark Gene: fnip1 has been classified as Green List (High Evidence).
Mendeliome v0.4499 FNIP1 Zornitza Stark Classified gene: FNIP1 as Green List (high evidence)
Mendeliome v0.4499 FNIP1 Zornitza Stark Gene: fnip1 has been classified as Green List (High Evidence).
Mendeliome v0.4498 NEMF Zornitza Stark Gene: nemf has been classified as Green List (High Evidence).
Mendeliome v0.4498 NEMF Zornitza Stark Classified gene: NEMF as Green List (high evidence)
Mendeliome v0.4498 NEMF Zornitza Stark Gene: nemf has been classified as Green List (High Evidence).
Mendeliome v0.4497 NEMF Zornitza Stark gene: NEMF was added
gene: NEMF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NEMF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEMF were set to 32934225
Phenotypes for gene: NEMF were set to Intellectual disability; neuropathy
Review for gene: NEMF was set to GREEN
Added comment: Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.
Sources: Literature
Mendeliome v0.4496 TAOK1 Zornitza Stark Gene: taok1 has been classified as Green List (High Evidence).
Mendeliome v0.4493 CSF1R Zornitza Stark Gene: csf1r has been classified as Green List (High Evidence).
Mendeliome v0.4493 CSF1R Zornitza Stark Phenotypes for gene: CSF1R were changed from to Brain abnormalities, neurodegeneration, and dysosteosclerosis, (MIM#618476); Leukoencephalopathy, diffuse hereditary, with spheroids, (MIM#221820)
Mendeliome v0.4489 L2HGDH Zornitza Stark Gene: l2hgdh has been classified as Green List (High Evidence).
Mendeliome v0.4486 CSF1R Elena Savva reviewed gene: CSF1R: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 31330095, 24336230; Phenotypes: Brain abnormalities, neurodegeneration, and dysosteosclerosis, (MIM#618476), Leukoencephalopathy, diffuse hereditary, with spheroids, (MIM#221820); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4486 LMNB1 Zornitza Stark Gene: lmnb1 has been classified as Green List (High Evidence).
Mendeliome v0.4483 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from to Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500
Mendeliome v0.4482 LMNB1 Zornitza Stark reviewed gene: LMNB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32910914, 16951681, 19151023; Phenotypes: Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis, Leukodystrophy, adult-onset, autosomal dominant, MIM#169500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4482 MAPK8 Zornitza Stark reviewed gene: MAPK8: Rating: AMBER; Mode of pathogenicity: None; Publications: 31784499; Phenotypes: Chronic mucocutaneous candidiasis, Connective tissue disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4482 MAPK8 Zornitza Stark Gene: mapk8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4482 MAPK8 Zornitza Stark Classified gene: MAPK8 as Amber List (moderate evidence)
Mendeliome v0.4482 MAPK8 Zornitza Stark Gene: mapk8 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4481 CTNNBL1 Zornitza Stark Gene: ctnnbl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4481 CTNNBL1 Zornitza Stark Classified gene: CTNNBL1 as Amber List (moderate evidence)
Mendeliome v0.4481 CTNNBL1 Zornitza Stark Gene: ctnnbl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4480 MAPK8 Arina Puzriakova gene: MAPK8 was added
gene: MAPK8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAPK8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK8 were set to 31784499
Phenotypes for gene: MAPK8 were set to Chronic mucocutaneous candidiasis; Connective tissue disorders
Added comment: PMID: 31784499 (2020) - Three cases in a single family with chronic mucocutaneous candidiasis and a connective tissue disorder that clinically overlaps with hEDS. WES revealed a splice-site variant (c.311+1G>A) in the MAPK8 gene that segregated with the disorder. Includes supportive functional data using patient-derived fibroblasts, showing that the variant impairs IL-17A/F immunity and the development of Th17 cells.
Sources: Literature
Mendeliome v0.4480 CTNNBL1 Arina Puzriakova gene: CTNNBL1 was added
gene: CTNNBL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CTNNBL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTNNBL1 were set to 32484799
Phenotypes for gene: CTNNBL1 were set to Primary Immunodeficiency; Autoimmune Cytopenias; Common variable immunodeficiency
Added comment: PMID: 32484799 (2020) - One patient with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC), associated with a homozygous missense M466V variant in the CTNNBL1 gene. Functional studies showed that the variant impaired interaction with AID, in turn disrupting AID-mediated antibody diversification in activated B-cells.
Sources: Literature
Mendeliome v0.4480 PDIA5 Zornitza Stark Gene: pdia5 has been classified as Red List (Low Evidence).
Mendeliome v0.4480 PDIA5 Zornitza Stark Classified gene: PDIA5 as Red List (low evidence)
Mendeliome v0.4480 PDIA5 Zornitza Stark Gene: pdia5 has been classified as Red List (Low Evidence).
Mendeliome v0.4479 TNNI2 Zornitza Stark Gene: tnni2 has been classified as Green List (High Evidence).
Mendeliome v0.4479 TNNI2 Zornitza Stark Phenotypes for gene: TNNI2 were changed from to Arthrogryposis, distal, type 2B1 (MIM#601680)
Mendeliome v0.4475 TNNI2 Michelle Torres reviewed gene: TNNI2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 17194691, 25340332; Phenotypes: Arthrogryposis, distal, type 2B1 (MIM#601680); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4475 MMP23A Bryony Thompson Gene: mmp23a has been classified as Red List (Low Evidence).
Mendeliome v0.4475 MMP23A Bryony Thompson Classified gene: MMP23A as Red List (low evidence)
Mendeliome v0.4475 MMP23A Bryony Thompson Gene: mmp23a has been classified as Red List (Low Evidence).
Mendeliome v0.4474 MMP23A Bryony Thompson reviewed gene: MMP23A: Rating: RED; Mode of pathogenicity: None; Publications: 15483646, 18924166; Phenotypes: Craniosynostosis; Mode of inheritance: Unknown
Mendeliome v0.4473 TAF2 Elena Savva reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24084144, 21937992, 22633631, 26350204; Phenotypes: Mental retardation, autosomal recessive 40 615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4473 VPS11 Zornitza Stark Gene: vps11 has been classified as Green List (High Evidence).
Mendeliome v0.4470 GGT1 Zornitza Stark Gene: ggt1 has been classified as Red List (Low Evidence).
Mendeliome v0.4467 GGT1 Zornitza Stark Classified gene: GGT1 as Red List (low evidence)
Mendeliome v0.4467 GGT1 Zornitza Stark Gene: ggt1 has been classified as Red List (Low Evidence).
Mendeliome v0.4466 GGT1 Elena Savva edited their review of gene: GGT1: Added comment: PMID: 29483667 - 1 family (2 sibs) w/ a homozygous 16.9kb deletion spanning part of the gene and no others. Carrier parents were normal.

PMID: 23615310 - homozygous mutant mouse model have dwarfism, cataracts and coat colour abnormalities. Protein activity reduced to 4% of wildtype. Noted it was for use as a GGT deficiency model.

PMID: 31520399 - 2 families with AD inheritance showing GGT1 deficiency but NO clinical symptoms. Authors call GGTemia a benign condition.; Changed publications: PMID: 29483667, 23615310, 31520399
Mendeliome v0.4466 NAXE Zornitza Stark Gene: naxe has been classified as Green List (High Evidence).
Mendeliome v0.4466 NAXE Zornitza Stark Phenotypes for gene: NAXE were changed from to Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186
Mendeliome v0.4463 NAXE Zornitza Stark changed review comment from: Early-onset progressive encephalopathy with brain edema 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.; to: 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.
Mendeliome v0.4463 NAXE Zornitza Stark reviewed gene: NAXE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27122014, 27616477, 31758406; Phenotypes: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4463 NAXD Zornitza Stark Gene: naxd has been classified as Green List (High Evidence).
Mendeliome v0.4463 NAXD Zornitza Stark Phenotypes for gene: NAXD were changed from to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321
Mendeliome v0.4460 NAXD Zornitza Stark reviewed gene: NAXD: Rating: GREEN; Mode of pathogenicity: None; Publications: 30576410, 31755961, 32462209; Phenotypes: Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4460 ISCA2 Zornitza Stark Gene: isca2 has been classified as Green List (High Evidence).
Mendeliome v0.4457 PRIMPOL Zornitza Stark Gene: primpol has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4454 PRIMPOL Zornitza Stark Classified gene: PRIMPOL as Amber List (moderate evidence)
Mendeliome v0.4454 PRIMPOL Zornitza Stark Gene: primpol has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4453 KCNN4 Zornitza Stark Gene: kcnn4 has been classified as Green List (High Evidence).
Mendeliome v0.4453 KCNN4 Zornitza Stark Classified gene: KCNN4 as Green List (high evidence)
Mendeliome v0.4453 KCNN4 Zornitza Stark Gene: kcnn4 has been classified as Green List (High Evidence).
Mendeliome v0.4452 KCNN4 Zornitza Stark gene: KCNN4 was added
gene: KCNN4 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNN4 were set to 26148990; 26198474; 26178367
Phenotypes for gene: KCNN4 were set to Dehydrated hereditary stomatocytosis 2, MIM# 616689
Review for gene: KCNN4 was set to GREEN
Added comment: At least three families reported.
Sources: Expert list
Mendeliome v0.4451 C15orf41 Zornitza Stark Gene: c15orf41 has been classified as Green List (High Evidence).
Mendeliome v0.4451 C15orf41 Zornitza Stark Classified gene: C15orf41 as Green List (high evidence)
Mendeliome v0.4451 C15orf41 Zornitza Stark Gene: c15orf41 has been classified as Green List (High Evidence).
Mendeliome v0.4449 XRCC2 Zornitza Stark Gene: xrcc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4446 XRCC2 Zornitza Stark Classified gene: XRCC2 as Amber List (moderate evidence)
Mendeliome v0.4446 XRCC2 Zornitza Stark Gene: xrcc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4445 TSR2 Zornitza Stark Gene: tsr2 has been classified as Red List (Low Evidence).
Mendeliome v0.4445 TSR2 Zornitza Stark Phenotypes for gene: TSR2 were changed from to Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, MIM# 300946
Mendeliome v0.4442 TSR2 Zornitza Stark Classified gene: TSR2 as Red List (low evidence)
Mendeliome v0.4442 TSR2 Zornitza Stark Gene: tsr2 has been classified as Red List (Low Evidence).
Mendeliome v0.4441 TSR2 Zornitza Stark reviewed gene: TSR2: Rating: RED; Mode of pathogenicity: None; Publications: 24942156; Phenotypes: Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, MIM# 300946; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.4441 SRP72 Zornitza Stark Gene: srp72 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4438 SRP72 Zornitza Stark Classified gene: SRP72 as Amber List (moderate evidence)
Mendeliome v0.4438 SRP72 Zornitza Stark Gene: srp72 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4437 SLC25A38 Zornitza Stark Gene: slc25a38 has been classified as Green List (High Evidence).
Mendeliome v0.4437 SLC25A38 Zornitza Stark Phenotypes for gene: SLC25A38 were changed from to Anemia, sideroblastic, 2, pyridoxine-refractory, MIM# 205950
Mendeliome v0.4434 SLC25A38 Zornitza Stark reviewed gene: SLC25A38: Rating: GREEN; Mode of pathogenicity: None; Publications: 19412178; Phenotypes: Anemia, sideroblastic, 2, pyridoxine-refractory, MIM# 205950; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4434 SLC19A2 Zornitza Stark Gene: slc19a2 has been classified as Green List (High Evidence).
Mendeliome v0.4434 SLC19A2 Zornitza Stark Phenotypes for gene: SLC19A2 were changed from to Thiamine-responsive megaloblastic anemia syndrome, MIM# 249270
Mendeliome v0.4431 SLC19A2 Zornitza Stark reviewed gene: SLC19A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10391221, 10978358; Phenotypes: Thiamine-responsive megaloblastic anemia syndrome, MIM# 249270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4431 SEC23B Zornitza Stark Gene: sec23b has been classified as Green List (High Evidence).
Mendeliome v0.4428 RPS27 Zornitza Stark Gene: rps27 has been classified as Red List (Low Evidence).
Mendeliome v0.4425 RPS27 Zornitza Stark Classified gene: RPS27 as Red List (low evidence)
Mendeliome v0.4425 RPS27 Zornitza Stark Gene: rps27 has been classified as Red List (Low Evidence).
Mendeliome v0.4424 RPS17 Zornitza Stark Gene: rps17 has been classified as Green List (High Evidence).
Mendeliome v0.4421 RPL9 Zornitza Stark Gene: rpl9 has been classified as Red List (Low Evidence).
Mendeliome v0.4421 RPL9 Zornitza Stark gene: RPL9 was added
gene: RPL9 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: RPL9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL9 were set to 29114930; 20116044
Phenotypes for gene: RPL9 were set to Diamond Blackfan anaemia
Review for gene: RPL9 was set to RED
Added comment: PMID: 29114930, de novo splice site variant, c.-2+1G>C, functional impact of this variant is likely deleterious but not proven. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad.
Sources: Expert list
Mendeliome v0.4420 RPL31 Zornitza Stark Gene: rpl31 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4417 RPL31 Zornitza Stark Classified gene: RPL31 as Amber List (moderate evidence)
Mendeliome v0.4417 RPL31 Zornitza Stark Gene: rpl31 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4416 PUS1 Zornitza Stark Gene: pus1 has been classified as Green List (High Evidence).
Mendeliome v0.4416 PUS1 Zornitza Stark Phenotypes for gene: PUS1 were changed from to Myopathy, lactic acidosis, and sideroblastic anemia 1, MIM# 600462
Mendeliome v0.4413 PUS1 Zornitza Stark reviewed gene: PUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25227147, 17056637, 15108122, 32287105, 31641589, 28832011; Phenotypes: Myopathy, lactic acidosis, and sideroblastic anemia 1, MIM# 600462; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4413 OXSR1 Zornitza Stark Gene: oxsr1 has been classified as Red List (Low Evidence).
Mendeliome v0.4413 OXSR1 Zornitza Stark Classified gene: OXSR1 as Red List (low evidence)
Mendeliome v0.4413 OXSR1 Zornitza Stark Gene: oxsr1 has been classified as Red List (Low Evidence).
Mendeliome v0.4412 NHP2 Zornitza Stark Gene: nhp2 has been classified as Green List (High Evidence).
Mendeliome v0.4412 NHP2 Zornitza Stark Phenotypes for gene: NHP2 were changed from to Dyskeratosis congenita, autosomal recessive 2, MIM# 613987
Mendeliome v0.4409 NHP2 Zornitza Stark reviewed gene: NHP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18523010, 31985013; Phenotypes: Dyskeratosis congenita, autosomal recessive 2, MIM# 613987; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4409 LIG4 Zornitza Stark Gene: lig4 has been classified as Green List (High Evidence).
Mendeliome v0.4406 HOXA11 Zornitza Stark Gene: hoxa11 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4406 HOXA11 Zornitza Stark Phenotypes for gene: HOXA11 were changed from to Radioulnar synostosis with amegakaryocytic thrombocytopenia 1, MIM# 605432
Mendeliome v0.4403 HOXA11 Zornitza Stark Classified gene: HOXA11 as Amber List (moderate evidence)
Mendeliome v0.4403 HOXA11 Zornitza Stark Gene: hoxa11 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4402 HOXA11 Zornitza Stark reviewed gene: HOXA11: Rating: AMBER; Mode of pathogenicity: None; Publications: 11101832, 16765069; Phenotypes: Radioulnar synostosis with amegakaryocytic thrombocytopenia 1, MIM# 605432; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4402 TGM6 Zornitza Stark Gene: tgm6 has been classified as Red List (Low Evidence).
Mendeliome v0.4399 TGM6 Zornitza Stark Classified gene: TGM6 as Red List (low evidence)
Mendeliome v0.4399 TGM6 Zornitza Stark Gene: tgm6 has been classified as Red List (Low Evidence).
Mendeliome v0.4398 SVBP Zornitza Stark changed review comment from: 5 unrelated families with homozygous mutations in SVBP. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Literature; to: 5 unrelated families with homozygous mutations in SVBP. Some shared the same founder variant, p.Q28*. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Literature
Mendeliome v0.4398 SQSTM1 Zornitza Stark Gene: sqstm1 has been classified as Green List (High Evidence).
Mendeliome v0.4395 SQSTM1 Zornitza Stark changed review comment from: Four unrelated families, presenting feature of this progressive neurological disorder was ataxia.; to: Nine individuals from four unrelated families.
Mendeliome v0.4395 SLC25A46 Zornitza Stark Gene: slc25a46 has been classified as Green List (High Evidence).
Mendeliome v0.4392 SLC25A46 Zornitza Stark changed review comment from: Age of onset is variable, but childhood onset described. Ataxia is a feature.; to: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus.

At least 10 unrelated families reported, supportive functional data.
Mendeliome v0.4392 RORA Zornitza Stark Gene: rora has been classified as Green List (High Evidence).
Mendeliome v0.4389 LARS2 Zornitza Stark Gene: lars2 has been classified as Green List (High Evidence).
Mendeliome v0.4389 LARS2 Zornitza Stark Phenotypes for gene: LARS2 were changed from to Perrault syndrome 4; Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021; Leukodystrophy
Mendeliome v0.4386 LARS2 Zornitza Stark reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29205794, 32423379, 30737337, 26537577, 23541342; Phenotypes: Perrault syndrome 4, Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021, Leukodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4386 LAMA1 Zornitza Stark Gene: lama1 has been classified as Green List (High Evidence).
Mendeliome v0.4383 KCNA2 Zornitza Stark Gene: kcna2 has been classified as Green List (High Evidence).
Mendeliome v0.4380 KCNA2 Zornitza Stark commented on gene: KCNA2: Review of 23 affected individuals in PMID 29050392: some variants are LoF and others GoF, and some genotype-phenotype correlations made. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalised and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations.
Mendeliome v0.4380 HARS2 Zornitza Stark Gene: hars2 has been classified as Green List (High Evidence).
Mendeliome v0.4377 EBF3 Zornitza Stark Gene: ebf3 has been classified as Green List (High Evidence).
Mendeliome v0.4374 DOCK3 Zornitza Stark Gene: dock3 has been classified as Green List (High Evidence).
Mendeliome v0.4371 ATP8A2 Zornitza Stark Gene: atp8a2 has been classified as Green List (High Evidence).
Mendeliome v0.4368 ATP8A2 Zornitza Stark changed review comment from: Multiple individuals from unrelated families reported with bi-allelic variants in this gene and neurological phenotypes including intellectual disability.
Sources: Expert list; to: 10 individuals from six unrelated families reported with bi-allelic variants in this gene and neurological phenotypes including intellectual disability.
Sources: Expert list
Mendeliome v0.4368 ADPRHL2 Zornitza Stark Gene: adprhl2 has been classified as Green List (High Evidence).
Mendeliome v0.4368 CNGB3 Zornitza Stark Gene: cngb3 has been classified as Green List (High Evidence).
Mendeliome v0.4368 CNGB3 Zornitza Stark Phenotypes for gene: CNGB3 were changed from to Achromatopsia 3, MIM# 262300
Mendeliome v0.4365 CNGB3 Zornitza Stark reviewed gene: CNGB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17265047; Phenotypes: Achromatopsia 3, MIM# 262300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4365 CNGA3 Zornitza Stark Gene: cnga3 has been classified as Green List (High Evidence).
Mendeliome v0.4365 CNGA3 Zornitza Stark Phenotypes for gene: CNGA3 were changed from to Achromatopsia 2, MIM# 216900
Mendeliome v0.4362 CNGA3 Zornitza Stark reviewed gene: CNGA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9662398, 11536077, 17265047; Phenotypes: Achromatopsia 2, MIM# 216900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4362 SPRED1 Zornitza Stark Gene: spred1 has been classified as Green List (High Evidence).
Mendeliome v0.4355 SOS1 Zornitza Stark edited their review of gene: SOS1: Added comment: Over 50 individuals reported with SOS1 variants and a Noonan syndrome phenotype. Pulmonic stenosis tends to be more frequent compared to those with PTPN11 mutations, and atrial septal defect is relatively rare. Ectodermal features including keratosis pilaris and curly hair are significantly more prevalent compared with the general Noonan population. Height below the third percentile and learning disability are observed in fewer individuals compared with Noonan syndrome in general. In contrast, macrocephaly is overrepresented among those with SOS1 mutations.; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 17143285, 17143282, 28884940, 17586837; Changed phenotypes: Noonan syndrome 4, MIM# 610733; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4355 SHOC2 Zornitza Stark Gene: shoc2 has been classified as Green List (High Evidence).
Mendeliome v0.4351 RIT1 Zornitza Stark Gene: rit1 has been classified as Green List (High Evidence).
Mendeliome v0.4347 NRAS Zornitza Stark Gene: nras has been classified as Green List (High Evidence).
Mendeliome v0.4343 MAP2K2 Zornitza Stark Gene: map2k2 has been classified as Green List (High Evidence).
Mendeliome v0.4339 MAP2K1 Zornitza Stark Gene: map2k1 has been classified as Green List (High Evidence).
Mendeliome v0.4335 HRAS Zornitza Stark Gene: hras has been classified as Green List (High Evidence).
Mendeliome v0.4331 CBL Zornitza Stark Gene: cbl has been classified as Green List (High Evidence).
Mendeliome v0.4327 CSNK1D Zornitza Stark Gene: csnk1d has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4324 CSNK1D Zornitza Stark Classified gene: CSNK1D as Amber List (moderate evidence)
Mendeliome v0.4324 CSNK1D Zornitza Stark Gene: csnk1d has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4323 CACNA1E Zornitza Stark Gene: cacna1e has been classified as Green List (High Evidence).
Mendeliome v0.4320 ATAD1 Zornitza Stark Gene: atad1 has been classified as Green List (High Evidence).
Mendeliome v0.4317 ATAD1 Zornitza Stark changed review comment from: Severe progressive neurological disorder, severe/profound intellectual disability is a feature; to: Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Three unrelated families reported. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures. Severe progressive neurological disorder, severe/profound intellectual disability is a feature.
Mendeliome v0.4316 ADAT1 Zornitza Stark Gene: adat1 has been classified as Green List (High Evidence).
Mendeliome v0.4316 ADAT1 Zornitza Stark Classified gene: ADAT1 as Green List (high evidence)
Mendeliome v0.4316 ADAT1 Zornitza Stark Gene: adat1 has been classified as Green List (High Evidence).
Mendeliome v0.4315 ADAT1 Zornitza Stark gene: ADAT1 was added
gene: ADAT1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ADAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAT1 were set to 28180185; 29390050; 29659736
Phenotypes for gene: ADAT1 were set to Hyperekplexia 4, MIM#618011
Review for gene: ADAT1 was set to GREEN
Added comment: Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Three unrelated families reported. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures.
Sources: Expert list
Mendeliome v0.4312 OCA2 Zornitza Stark Gene: oca2 has been classified as Green List (High Evidence).
Mendeliome v0.4309 OCA2 Elena Savva changed review comment from: Single variant found causing AD OCA - p.G780S in two families (Lee, 2020) -> GOF suggested

Complete penetrance for oculocutaneous albininism but variable expressivity (PMID: 24518832). No variable expressivity or incomplete penetrance reported in GeneReviews.

Loss of function; to: Single variant found causing AD OCA - p.G780S in two families (Lee, 2020) -> GOF suggested

Complete penetrance for oculocutaneous albininism but variable expressivity (PMID: 24518832). No variable expressivity or incomplete penetrance reported in GeneReviews.

Loss of function

2.7kb deletion is very common in sub-Saharan African populations (GeneReviews)
Mendeliome v0.4309 ZSWIM6 Zornitza Stark changed review comment from: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp; to: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X) identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp
Mendeliome v0.4309 ZSWIM6 Zornitza Stark changed review comment from: MIM #617865 A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671: recurrent missense identified in 6 unrelated families, p.Arg1163Trp; to: MIM #617865 (NEDMAGA): A recurrent de novo heterozygous truncating mutation in the ZSWIM6 gene (R913X)identified in 7 unrelated patients. Analysis of patient cells indicated that the mutant transcript escaped nonsense-mediated mRNA decay, and most likely produced a truncated protein, although antibody studies were unable to detect a truncated protein. Possible dominant-negative effect. NB a more proximal nonsense variant was also reported inherited in a family with an unaffected mother: loss of function variants may not cause a phenotype.
MIM#603671 (acromelic frontonasal dysplasia): recurrent missense identified in 6 unrelated families, p.Arg1163Trp
Mendeliome v0.4309 SREBF1 Zornitza Stark Phenotypes for gene: SREBF1 were changed from IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome to IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016
Mendeliome v0.4308 SREBF1 Zornitza Stark reviewed gene: SREBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome 2, MIM619016; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4308 VPS13D Zornitza Stark Gene: vps13d has been classified as Green List (High Evidence).
Mendeliome v0.4308 VPS13D Zornitza Stark Phenotypes for gene: VPS13D were changed from to Spinocerebellar ataxia, autosomal recessive 4, MIM# 607317
Mendeliome v0.4304 FARSA Zornitza Stark Gene: farsa has been classified as Red List (Low Evidence).
Mendeliome v0.4304 FARSA Zornitza Stark gene: FARSA was added
gene: FARSA was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to Rajab interstitial lung disease with brain calcifications 2, MIM# 619013
Review for gene: FARSA was set to RED
Added comment: Autosomal recessive disorder characterized by growth delay, interstitial lung disease, liver disease, and abnormal brain MRI findings, including brain calcifications and periventricular cysts. Single affected individual reported, but FARSA interacts with FARSB, which causes a similar disorder.
Sources: Expert list
Mendeliome v0.4303 SLC1A3 Zornitza Stark Gene: slc1a3 has been classified as Green List (High Evidence).
Mendeliome v0.4300 ANGPT2 Zornitza Stark Gene: angpt2 has been classified as Green List (High Evidence).
Mendeliome v0.4300 ANGPT2 Zornitza Stark Classified gene: ANGPT2 as Green List (high evidence)
Mendeliome v0.4300 ANGPT2 Zornitza Stark Gene: angpt2 has been classified as Green List (High Evidence).
Mendeliome v0.4298 UBR4 Zornitza Stark changed review comment from: Episodic ataxia reported in two families, but another molecular diagnosis present in the second, so suggested as a modifier. Only one individual reported with childhood-onset progressive neurological disorder as part of a large paper proposing multiple candidate genes.; to: Episodic ataxia reported in four families, but another molecular diagnosis present in the some, so suggested as a modifier. Variants are missense, with no supportive segregation or functional data, some are present at a low level in population databases. Only one individual reported with childhood-onset progressive neurological disorder as part of a large paper proposing multiple candidate genes.
Mendeliome v0.4298 SLC20A2 Zornitza Stark Gene: slc20a2 has been classified as Green List (High Evidence).
Mendeliome v0.4295 SLC16A2 Zornitza Stark Gene: slc16a2 has been classified as Green List (High Evidence).
Mendeliome v0.4289 HSP90B2P Bryony Thompson Gene: hsp90b2p has been classified as Red List (Low Evidence).
Mendeliome v0.4289 HSP90B2P Bryony Thompson Classified gene: HSP90B2P as Red List (low evidence)
Mendeliome v0.4289 HSP90B2P Bryony Thompson Gene: hsp90b2p has been classified as Red List (Low Evidence).
Mendeliome v0.4288 NOBOX Zornitza Stark Gene: nobox has been classified as Green List (High Evidence).
Mendeliome v0.4282 TET2 Zornitza Stark Classified gene: TET2 as Green List (high evidence)
Mendeliome v0.4282 TET2 Zornitza Stark Gene: tet2 has been classified as Green List (High Evidence).
Mendeliome v0.4281 TLR7 Zornitza Stark Gene: tlr7 has been classified as Green List (High Evidence).
Mendeliome v0.4278 EXOSC5 Zornitza Stark Gene: exosc5 has been classified as Green List (High Evidence).
Mendeliome v0.4278 EXOSC5 Zornitza Stark Phenotypes for gene: EXOSC5 were changed from to Short stature; Motor developmental delays; Cerebellar hypoplasia; Ataxia
Mendeliome v0.4275 EXOSC5 Arina Puzriakova changed review comment from: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXCOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXCOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.; to: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.
Mendeliome v0.4275 EXOSC5 Arina Puzriakova reviewed gene: EXOSC5: Rating: ; Mode of pathogenicity: None; Publications: 32504085, 29302074; Phenotypes: Short stature, Motor developmental delays, Cerebellar hypoplasia, Ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4275 SLC20A1 Zornitza Stark Gene: slc20a1 has been classified as Green List (High Evidence).
Mendeliome v0.4272 PNPLA8 Zornitza Stark Gene: pnpla8 has been classified as Green List (High Evidence).
Mendeliome v0.4272 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from to Mitochondrial myopathy with lactic acidosis (MIM#251950), AR
Mendeliome v0.4269 NR2F1 Zornitza Stark Gene: nr2f1 has been classified as Green List (High Evidence).
Mendeliome v0.4266 RAD50 Zornitza Stark Gene: rad50 has been classified as Green List (High Evidence).
Mendeliome v0.4262 KMT2D Zornitza Stark edited their review of gene: KMT2D: Added comment: Four further individuals with KMT2D-associated neurodevelopmental syndrome reported. Features include: athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. Two of the four individuals had severe interstitial lung disease.; Changed publications: 31949313, 32083401
Mendeliome v0.4261 CFAP58 Zornitza Stark Gene: cfap58 has been classified as Green List (High Evidence).
Mendeliome v0.4261 CFAP58 Zornitza Stark Classified gene: CFAP58 as Green List (high evidence)
Mendeliome v0.4261 CFAP58 Zornitza Stark Gene: cfap58 has been classified as Green List (High Evidence).
Mendeliome v0.4260 WASHC4 Zornitza Stark Gene: washc4 has been classified as Green List (High Evidence).
Mendeliome v0.4260 WASHC4 Zornitza Stark Classified gene: WASHC4 as Green List (high evidence)
Mendeliome v0.4260 WASHC4 Zornitza Stark Gene: washc4 has been classified as Green List (High Evidence).
Mendeliome v0.4259 WASHC4 Zornitza Stark gene: WASHC4 was added
gene: WASHC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WASHC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASHC4 were set to 31953988; 21498477
Phenotypes for gene: WASHC4 were set to Mental retardation, autosomal recessive 43, MIM #615817
Review for gene: WASHC4 was set to GREEN
Added comment: Three unrelated families reported.
Sources: Literature
Mendeliome v0.4258 DNAJC7 Seb Lunke Gene: dnajc7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4258 DNAJC7 Seb Lunke Classified gene: DNAJC7 as Amber List (moderate evidence)
Mendeliome v0.4258 DNAJC7 Seb Lunke Gene: dnajc7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4257 DNAJC7 Seb Lunke gene: DNAJC7 was added
gene: DNAJC7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAJC7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DNAJC7 were set to 31768050
Phenotypes for gene: DNAJC7 were set to amyotrophic lateral sclerosis
Review for gene: DNAJC7 was set to AMBER
Added comment: Two cohort studies in ALS patients identified 11 and 1 patient, respectively, with variants in DNAJC7. Seven of these are putative PTVs. However gene described as risk factor, unclear why.

DOI: https://doi.org/10.1212/NXG.0000000000000503
Sources: Literature
Mendeliome v0.4256 SVIL Melanie Marty edited their review of gene: SVIL: Added comment: Four patients from two unrelated consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. Functional studies on muscle biopsies showed complete loss protein in muscle fibres by western blot.; Changed rating: AMBER
Mendeliome v0.4256 HSPA9 Zornitza Stark Gene: hspa9 has been classified as Green List (High Evidence).
Mendeliome v0.4256 HSPA9 Zornitza Stark Phenotypes for gene: HSPA9 were changed from to Anemia, sideroblastic, 4, MIM# 182170; Even-plus syndrome, MIM#616854; skeletal anomalies; congenital cardiac and renal anomalies: marked small nose
Mendeliome v0.4252 SVIL Zornitza Stark Gene: svil has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4252 SVIL Zornitza Stark Classified gene: SVIL as Amber List (moderate evidence)
Mendeliome v0.4252 SVIL Zornitza Stark Gene: svil has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4250 CFAP57 Zornitza Stark reviewed gene: CFAP57: Rating: AMBER; Mode of pathogenicity: None; Publications: 21574244, 32764743; Phenotypes: Van der Woude Syndrome, Primary ciliary dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4250 SVIL Melanie Marty gene: SVIL was added
gene: SVIL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SVIL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVIL were set to 32779703
Phenotypes for gene: SVIL were set to myopathy
Penetrance for gene: SVIL were set to unknown
Review for gene: SVIL was set to GREEN
Added comment: Four patients from two unrelated consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. Functional studies on muscle biopsies showed complete loss protein in muscle fibres by western blot.
Sources: Literature
Mendeliome v0.4250 HSPA9 Zornitza Stark reviewed gene: HSPA9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Anemia, sideroblastic, 4, MIM# 182170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4249 MYT1L Zornitza Stark edited their review of gene: MYT1L: Added comment: Over 50 individuals reported with deletions and SNVs affecting MYT1L, and variable phenotype comprising intellectual disability, obesity, and behavioral problems.; Changed publications: 28859103, 32065501
Mendeliome v0.4249 ARID1A Zornitza Stark Gene: arid1a has been classified as Green List (High Evidence).
Mendeliome v0.4249 ARID1A Zornitza Stark Phenotypes for gene: ARID1A were changed from to Coffin-Siris syndrome 2 (MIM#614607)
Mendeliome v0.4246 PDE10A Zornitza Stark Gene: pde10a has been classified as Green List (High Evidence).
Mendeliome v0.4246 PDE10A Zornitza Stark Phenotypes for gene: PDE10A were changed from to Dyskinesia, limb and orofacial, infantile-onset, MIM#616921; Striatal degeneration, autosomal dominant, MIM# 616922
Mendeliome v0.4243 PDE10A Zornitza Stark reviewed gene: PDE10A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27058446, 27058447; Phenotypes: Dyskinesia, limb and orofacial, infantile-onset, MIM#616921, Striatal degeneration, autosomal dominant, MIM# 616922; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.4242 PNPLA8 Kristin Rigbye reviewed gene: PNPLA8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29681094, 25512002; Phenotypes: Mitochondrial myopathy with lactic acidosis (MIM#251950), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4242 ARID1A Crystle Lee reviewed gene: ARID1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23929686, 22426308, 25168959; Phenotypes: Coffin-Siris syndrome 2 (MIM#614607); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.4241 KIF1C Zornitza Stark Gene: kif1c has been classified as Green List (High Evidence).
Mendeliome v0.4241 KIF1C Zornitza Stark Phenotypes for gene: KIF1C were changed from to Spastic ataxia 2, autosomal recessive, MIM# 611302
Mendeliome v0.4238 KIF1C Zornitza Stark reviewed gene: KIF1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 24319291, 31413903, 29544888; Phenotypes: Spastic ataxia 2, autosomal recessive, MIM# 611302; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4238 GTPBP2 Zornitza Stark Gene: gtpbp2 has been classified as Green List (High Evidence).
Mendeliome v0.4235 GNB1 Zornitza Stark Gene: gnb1 has been classified as Green List (High Evidence).
Mendeliome v0.4232 NDUFB10 Zornitza Stark Phenotypes for gene: NDUFB10 were changed from fatal infantile lactic acidosis; cardiomyopathy to fatal infantile lactic acidosis; cardiomyopathy; Mitochondrial complex I deficiency nuclear type 35 (MC1DN35), MIM#619003
Mendeliome v0.4231 NDUFB10 Zornitza Stark edited their review of gene: NDUFB10: Changed phenotypes: fatal infantile lactic acidosis, cardiomyopathy, Mitochondrial complex I deficiency nuclear type 35 (MC1DN35), MIM#619003
Mendeliome v0.4230 MCM10 Zornitza Stark Gene: mcm10 has been classified as Red List (Low Evidence).
Mendeliome v0.4229 TET2 Zornitza Stark changed review comment from: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.; to: Mono-allelic variants: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.
Mendeliome v0.4229 TET2 Zornitza Stark changed review comment from: No evidence for Mendelian gene-disease association. Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.; to: Somatic TET2 variants are commonly found in cancers. One Finnish family reported where germline variant present 7 individuals, of whom 3 had lymphoma. Another French family reported with three sibs: frameshift variant and myeloid malignancies. Contribution of germline variants to malignancy risk to be established.
Mendeliome v0.4229 FDXR Zornitza Stark Gene: fdxr has been classified as Green List (High Evidence).
Mendeliome v0.4226 FDXR Zornitza Stark edited their review of gene: FDXR: Added comment: Four families reported with bi-allelic variants in FDXR causing an autosomal recessive neurologic disorder characterised by onset of visual and hearing impairment in the first or second decades. Two individuals described with a more severe progressive neurological phenotype. Mouse model exhibits neurodegeneration.; Changed rating: GREEN; Changed publications: 30250212, 28965846
Mendeliome v0.4226 EXOC7 Zornitza Stark Gene: exoc7 has been classified as Green List (High Evidence).
Mendeliome v0.4226 EXOC7 Zornitza Stark Classified gene: EXOC7 as Green List (high evidence)
Mendeliome v0.4226 EXOC7 Zornitza Stark Gene: exoc7 has been classified as Green List (High Evidence).
Mendeliome v0.4225 EIF2S3 Zornitza Stark Gene: eif2s3 has been classified as Green List (High Evidence).
Mendeliome v0.4220 TRAPPC6B Zornitza Stark Gene: trappc6b has been classified as Green List (High Evidence).
Mendeliome v0.4217 TRAPPC12 Zornitza Stark Phenotypes for gene: TRAPPC12 were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669
Mendeliome v0.4214 TRAPPC12 Zornitza Stark reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837, 28777934; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4214 TPRKB Zornitza Stark Gene: tprkb has been classified as Green List (High Evidence).
Mendeliome v0.4211 TP53RK Zornitza Stark Gene: tp53rk has been classified as Green List (High Evidence).
Mendeliome v0.4208 TBC1D20 Zornitza Stark Gene: tbc1d20 has been classified as Green List (High Evidence).
Mendeliome v0.4205 DHX34 Zornitza Stark Gene: dhx34 has been classified as Red List (Low Evidence).
Mendeliome v0.4205 DHX34 Zornitza Stark gene: DHX34 was added
gene: DHX34 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX34 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DHX34 were set to 31256877
Phenotypes for gene: DHX34 were set to Intellectual disability; congenital anomalies
Review for gene: DHX34 was set to RED
Added comment: Three families reported. Two with bi-allelic variants and ID/multiple congenital anomalies but another molecular diagnosis present in both (variants in established genes). Single de novo missense in another individual with ID and dysmorphism. No supporting functional data. Overall RED rating for both MOI.
Sources: Literature
Mendeliome v0.4204 DDX54 Zornitza Stark Gene: ddx54 has been classified as Red List (Low Evidence).
Mendeliome v0.4204 DDX54 Zornitza Stark gene: DDX54 was added
gene: DDX54 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX54 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DDX54 were set to 31256877
Phenotypes for gene: DDX54 were set to Intellectual disability; congenital anomalies
Review for gene: DDX54 was set to RED
Added comment: Three individuals reported with different MOIs and different phenotypes. One with de novo variant and ID, another with bi-allelic variants and ID, and a third with bi-allelic variants and CAKUT. All variants are missense, no functional data. Overall, Red rating given inconsistent phenotypes and modes of inheritance, each one is essentially treated separately for now until further cases identified.
Sources: Literature
Mendeliome v0.4203 DHX16 Zornitza Stark Gene: dhx16 has been classified as Green List (High Evidence).
Mendeliome v0.4203 DHX16 Zornitza Stark Classified gene: DHX16 as Green List (high evidence)
Mendeliome v0.4203 DHX16 Zornitza Stark Gene: dhx16 has been classified as Green List (High Evidence).
Mendeliome v0.4202 DHX16 Zornitza Stark gene: DHX16 was added
gene: DHX16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, MIM# 618733
Review for gene: DHX16 was set to GREEN
Added comment: Four unrelated individuals reported with de novo missense variants in this gene. Three of the individuals died in infancy, so phenotypic spectrum difficult to discern. Two had seizures. Individual with long-term survival had a progressive course, evidence of myopathy, loss of hearing and vision, and normal IQ.
Sources: Literature
Mendeliome v0.4201 DHX37 Zornitza Stark Phenotypes for gene: DHX37 were changed from 46,XY gonadal dysgenesis; testicular regression syndrome (TRS) to 46,XY gonadal dysgenesis; testicular regression syndrome (TRS); Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731
Mendeliome v0.4198 DHX37 Zornitza Stark changed review comment from: Seventeen individuals with 46,XY gonadal dysgenesis reported in two studies.
Sources: Literature; to: Mono-allelic disease: Seventeen individuals with 46,XY gonadal dysgenesis reported in two studies.
Sources: Literature
Mendeliome v0.4198 DHX37 Zornitza Stark edited their review of gene: DHX37: Added comment: Bi-allelic disease: 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype, which also includes congenital anomalies particularly affecting the vertebrae and heart, but also some with microcephaly, brain anomalies.; Changed publications: 31337883, 31745530, 26539891, 31256877; Changed phenotypes: 46,XY gonadal dysgenesis, testicular regression syndrome (TRS), Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4198 CFL2 Zornitza Stark Gene: cfl2 has been classified as Green List (High Evidence).
Mendeliome v0.4198 CFL2 Zornitza Stark Phenotypes for gene: CFL2 were changed from to Nemaline myopathy 7, autosomal recessive, MIM# 610687
Mendeliome v0.4195 CFL2 Zornitza Stark reviewed gene: CFL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17160903, 22560515, 32697999, 29457652, 24610938; Phenotypes: Nemaline myopathy 7, autosomal recessive, MIM# 610687; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4195 TDRD7 Zornitza Stark Gene: tdrd7 has been classified as Green List (High Evidence).
Mendeliome v0.4195 TDRD7 Zornitza Stark Phenotypes for gene: TDRD7 were changed from Cataract 36 613887; glaucoma; nonobstructive azoospermia; arrested spermatogenesis to Cataract 36, 613887; glaucoma; nonobstructive azoospermia; arrested spermatogenesis
Mendeliome v0.4193 PAK3 Zornitza Stark Gene: pak3 has been classified as Green List (High Evidence).
Mendeliome v0.4190 CLTC Zornitza Stark Gene: cltc has been classified as Green List (High Evidence).
Mendeliome v0.4187 SLC1A4 Zornitza Stark reviewed gene: SLC1A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25930971, 26138499, 26041762, 27193218, 29989513; Phenotypes: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4187 RPL10 Zornitza Stark Gene: rpl10 has been classified as Green List (High Evidence).
Mendeliome v0.4184 IFT122 Zornitza Stark Gene: ift122 has been classified as Green List (High Evidence).
Mendeliome v0.4184 IFT122 Zornitza Stark Phenotypes for gene: IFT122 were changed from to Cranioectodermal dysplasia 1, MIM# MIM#218330
Mendeliome v0.4181 IFT122 Zornitza Stark reviewed gene: IFT122: Rating: GREEN; Mode of pathogenicity: None; Publications: 26792575, 28370949, 29037998; Phenotypes: Cranioectodermal dysplasia 1, MIM# MIM#218330; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4181 JAK1 Zornitza Stark edited their review of gene: JAK1: Changed phenotypes: Eosinophilia, Eosinophilic enteritis, Thyroid disease, Poor growth, Viral infections, Susceptibility to mycobacteria and viruses, Autoinflammation, immunde dysregulation, and eosinophilia, MIM# 618999
Mendeliome v0.4181 RC3H1 Zornitza Stark Phenotypes for gene: RC3H1 were changed from Relapsing HLH to Relapsing HLH; Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v0.4180 RC3H1 Zornitza Stark edited their review of gene: RC3H1: Changed phenotypes: Relapsing HLH, Hemophagocytic lymphohistiocytosis, familial, 6, MIM# 618998
Mendeliome v0.4180 KIAA0319 Zornitza Stark Gene: kiaa0319 has been classified as Red List (Low Evidence).
Mendeliome v0.4179 KIAA0319 Zornitza Stark Classified gene: KIAA0319 as Red List (low evidence)
Mendeliome v0.4179 KIAA0319 Zornitza Stark Gene: kiaa0319 has been classified as Red List (Low Evidence).
Mendeliome v0.4178 RARS2 Zornitza Stark Gene: rars2 has been classified as Green List (High Evidence).
Mendeliome v0.4178 RARS2 Zornitza Stark Phenotypes for gene: RARS2 were changed from Pontocerebellar hypoplasia, type 6, MIM# 611523 to Pontocerebellar hypoplasia, type 6, MIM# 611523; early onset cerebellar ataxia
Mendeliome v0.4176 RARS2 Zornitza Stark Phenotypes for gene: RARS2 were changed from to Pontocerebellar hypoplasia, type 6, MIM# 611523
Mendeliome v0.4172 RAB3GAP2 Zornitza Stark Gene: rab3gap2 has been classified as Green List (High Evidence).
Mendeliome v0.4169 RAB3GAP1 Zornitza Stark Gene: rab3gap1 has been classified as Green List (High Evidence).
Mendeliome v0.4166 RAB18 Zornitza Stark Gene: rab18 has been classified as Green List (High Evidence).
Mendeliome v0.4163 PTPN23 Zornitza Stark Gene: ptpn23 has been classified as Green List (High Evidence).
Mendeliome v0.4160 PRUNE1 Zornitza Stark Gene: prune1 has been classified as Green List (High Evidence).
Mendeliome v0.4157 POGZ Zornitza Stark Gene: pogz has been classified as Green List (High Evidence).
Mendeliome v0.4154 POC1A Zornitza Stark Gene: poc1a has been classified as Green List (High Evidence).
Mendeliome v0.4154 POC1A Zornitza Stark Phenotypes for gene: POC1A were changed from to Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis, MIM# 614813
Mendeliome v0.4151 POC1A Zornitza Stark reviewed gene: POC1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22840364, 22840363, 26374189, 26162852, 26791357; Phenotypes: Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis, MIM# 614813; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4151 PLK4 Zornitza Stark Gene: plk4 has been classified as Green List (High Evidence).
Mendeliome v0.4151 PLK4 Zornitza Stark Phenotypes for gene: PLK4 were changed from to Microcephaly and chorioretinopathy, autosomal recessive, 2, MIM# 616171
Mendeliome v0.4148 PLK4 Zornitza Stark reviewed gene: PLK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25344692, 25320347, 27650967; Phenotypes: Microcephaly and chorioretinopathy, autosomal recessive, 2, MIM# 616171; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4148 PIGH Zornitza Stark Gene: pigh has been classified as Green List (High Evidence).
Mendeliome v0.4148 PIGH Zornitza Stark Phenotypes for gene: PIGH were changed from to Glycosylphosphatidylinositol biosynthesis defect 17, MIM# 618010
Mendeliome v0.4145 PIGH Zornitza Stark reviewed gene: PIGH: Rating: GREEN; Mode of pathogenicity: None; Publications: 29573052, 29603516; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 17, MIM# 618010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4145 PCYT2 Zornitza Stark Gene: pcyt2 has been classified as Green List (High Evidence).
Mendeliome v0.4145 PCYT2 Zornitza Stark Phenotypes for gene: PCYT2 were changed from to Spastic paraplegia 82, autosomal recessive 618770; global developmental delay; regression; spastic parapesis or tetraparesis; epilepsy; progressive cerebral and cerebellar atrophy
Mendeliome v0.4143 PCYT2 Zornitza Stark reviewed gene: PCYT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31637422; Phenotypes: Spastic paraplegia 82, autosomal recessive 618770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4143 TRAPPC2L Zornitza Stark Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4143 TRAPPC2L Zornitza Stark Classified gene: TRAPPC2L as Amber List (moderate evidence)
Mendeliome v0.4143 TRAPPC2L Zornitza Stark Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4141 TIMM8A Zornitza Stark Gene: timm8a has been classified as Green List (High Evidence).
Mendeliome v0.4139 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Red List (Low Evidence).
Mendeliome v0.4139 TOGARAM1 Zornitza Stark Classified gene: TOGARAM1 as Red List (low evidence)
Mendeliome v0.4139 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Red List (Low Evidence).
Mendeliome v0.4138 DPP6 Zornitza Stark Gene: dpp6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4135 DPP6 Zornitza Stark Classified gene: DPP6 as Amber List (moderate evidence)
Mendeliome v0.4135 DPP6 Zornitza Stark Gene: dpp6 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4134 TRAPPC2L Arina Puzriakova changed review comment from: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature; to: Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications. Rating Amber as additional cases required to delineate the genotype-phenotype relationship.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.

Sources: Literature
Mendeliome v0.4134 TRAPPC2L Arina Puzriakova gene: TRAPPC2L was added
gene: TRAPPC2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC2L were set to 30120216; 32843486
Phenotypes for gene: TRAPPC2L were set to Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331
Review for gene: TRAPPC2L was set to AMBER
Added comment: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature
Mendeliome v0.4134 TOGARAM1 Arina Puzriakova gene: TOGARAM1 was added
gene: TOGARAM1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TOGARAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOGARAM1 were set to 32747439
Phenotypes for gene: TOGARAM1 were set to Cleft of the lip and palate; Microphthalmia; Cerebral dysgenesis; Hydrocephalus
Added comment: PMID: 32747439 (2020) - Novel gene-disease association. In two sibling fetuses with a malformation disorder characterised by microcephaly, severe cleft lip and palate, microphthalmia, and brain anomalies, WES revealed compound heterozygous variants ([c.1102C>T, p.Arg368Trp] and [c.3619C>T, p.Arg1207*]) in the TOGARAM1 gene.

Functional analysis of the missense variant in a C. elegans model showed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. In vitro analysis revealed faster microtubule polymerisation compared to wild-type, suggesting aberrant tubulin binding.
Sources: Literature
Mendeliome v0.4134 PCGF2 Zornitza Stark Gene: pcgf2 has been classified as Green List (High Evidence).
Mendeliome v0.4131 TRIT1 Zornitza Stark Gene: trit1 has been classified as Green List (High Evidence).
Mendeliome v0.4128 CRIPT Zornitza Stark Gene: cript has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4128 CRIPT Zornitza Stark Classified gene: CRIPT as Amber List (moderate evidence)
Mendeliome v0.4128 CRIPT Zornitza Stark Gene: cript has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4125 CRIPT Ain Roesley gene: CRIPT was added
gene: CRIPT was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRIPT were set to 24389050; 27250922
Phenotypes for gene: CRIPT were set to Short stature with microcephaly and distinctive facies (MIM#615789)
Penetrance for gene: CRIPT were set to unknown
Review for gene: CRIPT was set to AMBER
Added comment: PMID: 24389050
- 2 unrelated probands homozygous for PTVs. However 1 was deceased and DNA was unavailable therefore parents were sequenced

PMID: 27250922
- 1x proband
- het for a missense which was maternally inherited. Because the father was negative for SNVs, they did CMA and found a small heterozygous deletion 1.6kb in size encompassing exon 1 of CRIPT. This deletion was paternally inherited

*did not find new reports since
Sources: Literature
Mendeliome v0.4125 DIAPH1 Zornitza Stark Gene: diaph1 has been classified as Green List (High Evidence).
Mendeliome v0.4123 UFC1 Seb Lunke Gene: ufc1 has been classified as Green List (High Evidence).
Mendeliome v0.4122 UFC1 Seb Lunke Classified gene: UFC1 as Green List (high evidence)
Mendeliome v0.4122 UFC1 Seb Lunke Gene: ufc1 has been classified as Green List (High Evidence).
Mendeliome v0.4121 UFC1 Paul De Fazio gene: UFC1 was added
gene: UFC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UFC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFC1 were set to 29868776; 30552426
Phenotypes for gene: UFC1 were set to Neurodevelopmental disorder with spasticity and poor growth (MIM#618076)
Review for gene: UFC1 was set to GREEN
gene: UFC1 was marked as current diagnostic
Added comment: PMID 29868776: 8 affected individuals from 4 families reported. 7 were described to be postnatally microcephalic (at or below 3rd percentile). One was -5.1SD and one was -3.6SD. SD values for the others weren't provided.

The following head circumference measurements were provided for 6 of the affecteds:

51cm at 16yo; 50cm at 19yo; 42.5cm at 12mo, 45cm at 28mo, 45.2cm at 7yo; 45cm at 4yo.

3 of the families were consanguineous Saudi families with the same homozygous missense variant.

In vitro functional expression studies showed that both mutations caused impaired thioester binding with UFM1. Patient cells also showed decreased UFC1 intermediate formation with UFM1. The decrease in function was consistent with a hypomorphic allele, and the authors suggested that complete loss of function would be embryonic lethal.

PMID 30552426: 1 more individual with epileptic encephalopathy reported with a different homozygous missense variant in UFC1. The patient had microcephaly <3rd percentile.
Sources: Literature
Mendeliome v0.4121 CENPE Seb Lunke Gene: cenpe has been classified as Red List (Low Evidence).
Mendeliome v0.4121 CENPE Seb Lunke Phenotypes for gene: CENPE were changed from to Microcephaly 13, primary, autosomal recessive (MIM#616051)
Mendeliome v0.4118 CENPE Seb Lunke Classified gene: CENPE as Red List (low evidence)
Mendeliome v0.4118 CENPE Seb Lunke Gene: cenpe has been classified as Red List (Low Evidence).
Mendeliome v0.4117 CENPE Ain Roesley reviewed gene: CENPE: Rating: RED; Mode of pathogenicity: None; Publications: 24748105, 30086807; Phenotypes: Microcephaly 13, primary, autosomal recessive (MIM#616051); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4117 CDC6 Seb Lunke Gene: cdc6 has been classified as Red List (Low Evidence).
Mendeliome v0.4114 CDC6 Seb Lunke Classified gene: CDC6 as Red List (low evidence)
Mendeliome v0.4114 CDC6 Seb Lunke Gene: cdc6 has been classified as Red List (Low Evidence).
Mendeliome v0.4113 CTNND1 Zornitza Stark Gene: ctnnd1 has been classified as Green List (High Evidence).
Mendeliome v0.4109 RIPOR2 Zornitza Stark Phenotypes for gene: RIPOR2 were changed from Deafness, autosomal recessive 104, MIM# 616515 to Deafness, autosomal recessive 104, MIM# 616515; Deafness, autosomal dominant
Mendeliome v0.4108 RIPOR2 Zornitza Stark changed review comment from: Single family and animal model data.
Sources: Expert list; to: Single family with bi-allelic variants and animal model data.
Sources: Expert list
Mendeliome v0.4108 RIPOR2 Zornitza Stark Gene: ripor2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4106 NOTCH3 Zornitza Stark Classified gene: NOTCH3 as No list
Mendeliome v0.4102 ZFYVE19 Zornitza Stark Gene: zfyve19 has been classified as Green List (High Evidence).
Mendeliome v0.4102 ZFYVE19 Zornitza Stark Classified gene: ZFYVE19 as Green List (high evidence)
Mendeliome v0.4102 ZFYVE19 Zornitza Stark Gene: zfyve19 has been classified as Green List (High Evidence).
Mendeliome v0.4101 TRPM7 Zornitza Stark Phenotypes for gene: TRPM7 were changed from {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500 to {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500; Cardiac arrhythmia, stillbirth
Mendeliome v0.4098 TRPM7 Zornitza Stark Classified gene: TRPM7 as Amber List (moderate evidence)
Mendeliome v0.4098 TRPM7 Zornitza Stark Gene: trpm7 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4097 TRPM7 Zornitza Stark edited their review of gene: TRPM7: Added comment: Ion channel expressed in the nervous and cardiac systems. The variant associated with ALS/dementia in the Guam population, p.Thr1482Ile is present in >23,000 hets in gnomad, which is out of keeping for a rare Mendelian disorder. Note recent publication associating missense variants with cardiac arrhythmia and stillbirth, with some functional data provided to substantiate effect of variant on protein function but not necessarily establish gene-disease association.; Changed rating: AMBER; Changed publications: 32503408, 31423533; Changed phenotypes: {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500, Cardiac arrhythmia, stillbirth; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4097 CHCHD10 Zornitza Stark Gene: chchd10 has been classified as Green List (High Evidence).
Mendeliome v0.4097 CHCHD10 Zornitza Stark Phenotypes for gene: CHCHD10 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 615911; Spinal muscular atrophy, Jokela type 615048; Myopathy, isolated mitochondrial, autosomal dominant 616209
Mendeliome v0.4093 CHCHD10 Zornitza Stark reviewed gene: CHCHD10: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24934289, 25428574, 25193783, 32042922, 31690696, 30877432, 30874923; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 615911, Spinal muscular atrophy, Jokela type 615048, Myopathy, isolated mitochondrial, autosomal dominant 616209; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4091 NOTCH3 Eleanor Williams gene: NOTCH3 was added
gene: NOTCH3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NOTCH3 were set to 31960911
Phenotypes for gene: NOTCH3 were set to CADASIL
Review for gene: NOTCH3 was set to AMBER
Added comment: PMID: 31960911 - Gravesteijn et al 2020 - describe a family with a unique cysteine-altering NOTCH3 variant in exon 9 in 5 individuals, which is predicted to cause natural exon 9 skipping. This mimics the therapeutic NOTCH3 cysteine correction approach and allows the effect of cysteine corrective exon skipping on NOTCH3 protein aggregation and disease severity in humans to be studied. In this family the CADASIL phenotype was mild.

Note this gene is rated green on the Neurodegenerative disorders - adult onset panel in the Genomics England instance of PanelApp https://panelapp.genomicsengland.co.uk/panels/474/gene/NOTCH3/
Sources: Literature
Mendeliome v0.4091 TRPM7 Eleanor Williams commented on gene: TRPM7: PMID: 31423533 - Cartwright et al 2020 - functional studies on four heterozygous nonsynonymous variants that were observed in TRPM7 in four individual cases of unexplained still birth which were screened for variants in 35 candidate genes in PMID: 29874177 (Munroe et al 2018). TRPM7 is a ubiquitously expressed ion channel known to regulate cardiac development and repolarization in mice. They found two variants in TRPM7, p.G179V and p.T860M, reduce ion channel current expression, which in the case of p.T860M is likely due to rapid degradation mediated by the proteasome. In addition, the p.R494Q TRPM7 variant significantly increases TRPM7 ion channel current, in a cell-type specific manner. They believe that TRPM7 may play a key role in ensuring correct cardiac development of the fetus.
Mendeliome v0.4091 ZFYVE19 Arina Puzriakova gene: ZFYVE19 was added
gene: ZFYVE19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZFYVE19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFYVE19 were set to 32737136
Phenotypes for gene: ZFYVE19 were set to Cholestasis
Review for gene: ZFYVE19 was set to GREEN
Added comment: PMID: 32737136 (2020) - Nine Han Chinese children from seven families with biallelic, predicted complete LoF variants in ZFYVE19. All patients had high-GGT intrahepatic cholestasis, portal hypertension, and histopathological features of the ductal plate malformation/congenital hepatic fibrosis.

ZFYVE19 depletion in cultured cells from one patient yielded centriolar and axonemal abnormalities, and immunostaining for two ciliary proteins DCDC2 and ACALT showed abnormal localisation in patient cholangiocytes, indicating this as a novel ciliopathy disorder.
Sources: Literature
Mendeliome v0.4091 SRD5A3 Zornitza Stark Gene: srd5a3 has been classified as Green List (High Evidence).
Mendeliome v0.4088 KIF14 Zornitza Stark Gene: kif14 has been classified as Green List (High Evidence).
Mendeliome v0.4088 KIF14 Zornitza Stark Phenotypes for gene: KIF14 were changed from to Microcephaly 20, primary, autosomal recessive, MIM# 617914; Meckel syndrome 12, MIM# 616258
Mendeliome v0.4085 KIF14 Zornitza Stark reviewed gene: KIF14: Rating: GREEN; Mode of pathogenicity: None; Publications: 28892560, 29343805, 24128419; Phenotypes: Microcephaly 20, primary, autosomal recessive, MIM# 617914, Meckel syndrome 12, MIM# 616258; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4085 KIF1BP Zornitza Stark Gene: kif1bp has been classified as Green List (High Evidence).
Mendeliome v0.4082 TRIP11 Zornitza Stark Gene: trip11 has been classified as Green List (High Evidence).
Mendeliome v0.4082 TRIP11 Zornitza Stark Phenotypes for gene: TRIP11 were changed from to Osteochondrodysplasia, 184260; Achondrogenesis, type IA, 200600
Mendeliome v0.4079 PRF1 Zornitza Stark Gene: prf1 has been classified as Green List (High Evidence).
Mendeliome v0.4079 PRF1 Zornitza Stark Phenotypes for gene: PRF1 were changed from to Aplastic anemia 609135; Hemophagocytic lymphohistiocytosis, familial, 2 603553; Lymphoma, non-Hodgkin 605027
Mendeliome v0.4076 HLCS Zornitza Stark Gene: hlcs has been classified as Green List (High Evidence).
Mendeliome v0.4073 CA5A Zornitza Stark Gene: ca5a has been classified as Green List (High Evidence).
Mendeliome v0.4067 OSR1 Zornitza Stark Gene: osr1 has been classified as Red List (Low Evidence).
Mendeliome v0.4067 OSR1 Zornitza Stark Classified gene: OSR1 as Red List (low evidence)
Mendeliome v0.4067 OSR1 Zornitza Stark Gene: osr1 has been classified as Red List (Low Evidence).
Mendeliome v0.4066 KDM1A Zornitza Stark Gene: kdm1a has been classified as Green List (High Evidence).
Mendeliome v0.4063 TRIP11 Elena Savva reviewed gene: TRIP11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31903676, 30728324; Phenotypes: Osteochondrodysplasia, 184260, Achondrogenesis, type IA, 200600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4063 COL11A1 Zornitza Stark Gene: col11a1 has been classified as Green List (High Evidence).
Mendeliome v0.4063 COL11A1 Zornitza Stark Phenotypes for gene: COL11A1 were changed from to Fibrochondrogenesis 1 (MIM#228520); Marshall syndrome (MIM#154780); Stickler syndrome, type II (MIM#604841)
Mendeliome v0.4061 PRF1 Elena Savva reviewed gene: PRF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19487666; Phenotypes: Aplastic anemia 609135, Hemophagocytic lymphohistiocytosis, familial, 2 603553, Lymphoma, non-Hodgkin 605027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4059 COL11A1 Elena Savva reviewed gene: COL11A1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID 25073711, 30245514, 32427345, 27081569, 21035103; Phenotypes: Fibrochondrogenesis 1 (MIM#228520), Marshall syndrome (MIM#154780), Stickler syndrome, type II (MIM#604841), {Lumbar disc herniation, susceptibility to}, (MIM#603932), ?Deafness, autosomal dominant 37, (MIM#618533); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v0.4059 YRDC Zornitza Stark Gene: yrdc has been classified as Green List (High Evidence).
Mendeliome v0.4059 YRDC Zornitza Stark Classified gene: YRDC as Green List (high evidence)
Mendeliome v0.4059 YRDC Zornitza Stark Gene: yrdc has been classified as Green List (High Evidence).
Mendeliome v0.4057 GON7 Zornitza Stark Gene: gon7 has been classified as Green List (High Evidence).
Mendeliome v0.4057 GON7 Zornitza Stark Classified gene: GON7 as Green List (high evidence)
Mendeliome v0.4057 GON7 Zornitza Stark Gene: gon7 has been classified as Green List (High Evidence).
Mendeliome v0.4055 LAGE3 Zornitza Stark Gene: lage3 has been classified as Green List (High Evidence).
Mendeliome v0.4052 LINGO1 Zornitza Stark Gene: lingo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4052 LINGO1 Zornitza Stark Phenotypes for gene: LINGO1 were changed from to Mental retardation, autosomal recessive 64, MIM# 618103
Mendeliome v0.4049 LINGO1 Zornitza Stark Classified gene: LINGO1 as Amber List (moderate evidence)
Mendeliome v0.4049 LINGO1 Zornitza Stark Gene: lingo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4048 LINGO1 Zornitza Stark reviewed gene: LINGO1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31668702; Phenotypes: Mental retardation, autosomal recessive 64, MIM# 618103; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4048 OSGEP Zornitza Stark Gene: osgep has been classified as Green List (High Evidence).
Mendeliome v0.4045 NUP107 Zornitza Stark Gene: nup107 has been classified as Green List (High Evidence).
Mendeliome v0.4042 NSD2 Zornitza Stark Gene: nsd2 has been classified as Green List (High Evidence).
Mendeliome v0.4039 NSD2 Zornitza Stark changed review comment from: Microcephaly reported in 6 of 7 individuals with LOF variants in this gene.; to: 7 individuals with LOF variants in this gene, gene thought to be responsible for key features of Wolf-Hirschorn syndrome.
Mendeliome v0.4039 NCAPH Zornitza Stark Gene: ncaph has been classified as Red List (Low Evidence).
Mendeliome v0.4039 NCAPH Zornitza Stark Phenotypes for gene: NCAPH were changed from to Microcephaly 23, primary, autosomal recessive 617985
Mendeliome v0.4036 NCAPH Zornitza Stark Classified gene: NCAPH as Red List (low evidence)
Mendeliome v0.4036 NCAPH Zornitza Stark Gene: ncaph has been classified as Red List (Low Evidence).
Mendeliome v0.4035 NCAPH Zornitza Stark reviewed gene: NCAPH: Rating: RED; Mode of pathogenicity: None; Publications: 27737959; Phenotypes: Microcephaly 23, primary, autosomal recessive 617985; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4035 ATRIP Zornitza Stark Gene: atrip has been classified as Red List (Low Evidence).
Mendeliome v0.4035 ATRIP Zornitza Stark Classified gene: ATRIP as Red List (low evidence)
Mendeliome v0.4035 ATRIP Zornitza Stark Gene: atrip has been classified as Red List (Low Evidence).
Mendeliome v0.4034 ATRIP Ain Roesley gene: ATRIP was added
gene: ATRIP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATRIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATRIP were set to 23144622
Phenotypes for gene: ATRIP were set to Seckel Syndrome
Penetrance for gene: ATRIP were set to unknown
Review for gene: ATRIP was set to RED
Added comment: PMID: 23144622;
- 1x proband from a consanguineous family
- progressive severe microcephaly (-9 to -10SD)
- cHet for a nonsense and a splice
Sources: Literature
Mendeliome v0.4034 AP4E1 Zornitza Stark Gene: ap4e1 has been classified as Green List (High Evidence).
Mendeliome v0.4034 AP4E1 Zornitza Stark Phenotypes for gene: AP4E1 were changed from to Spastic paraplegia 51, autosomal recessive, MIM# 613744
Mendeliome v0.4031 AP4E1 Zornitza Stark reviewed gene: AP4E1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20972249, 21620353, 21937992; Phenotypes: Spastic paraplegia 51, autosomal recessive, MIM# 613744; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4031 AP4B1 Zornitza Stark Gene: ap4b1 has been classified as Green List (High Evidence).
Mendeliome v0.4031 AP4B1 Zornitza Stark Phenotypes for gene: AP4B1 were changed from to Spastic paraplegia 47, autosomal recessive, MIM# 614066
Mendeliome v0.4028 AP4B1 Zornitza Stark reviewed gene: AP4B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21620353, 22290197, 24700674, 24781758; Phenotypes: Spastic paraplegia 47, autosomal recessive, MIM# 614066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4028 ANKLE2 Zornitza Stark reviewed gene: ANKLE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25259927, 30214071, 31735666; Phenotypes: Microcephaly 16, primary, autosomal recessive, MIM# 616681; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4028 TSEN2 Zornitza Stark Gene: tsen2 has been classified as Green List (High Evidence).
Mendeliome v0.4028 TSEN2 Zornitza Stark Phenotypes for gene: TSEN2 were changed from to Pontocerebellar hypoplasia type 2B, MIM# 612389
Mendeliome v0.4025 TSEN2 Zornitza Stark edited their review of gene: TSEN2: Added comment: At least 3 unrelated families reported.; Changed rating: GREEN; Changed publications: 23562994, 20952379; Changed phenotypes: Pontocerebellar hypoplasia type 2B, MIM# 612389
Mendeliome v0.4025 ZSWIM6 Zornitza Stark Gene: zswim6 has been classified as Green List (High Evidence).
Mendeliome v0.4025 ZSWIM6 Zornitza Stark Phenotypes for gene: ZSWIM6 were changed from to Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features, MIM# 617865; Acromelic frontonasal dysostosis, MIM# 603671
Mendeliome v0.4022 ZSWIM6 Zornitza Stark reviewed gene: ZSWIM6: Rating: GREEN; Mode of pathogenicity: None; Publications: 29198722, 25105228, 26706854; Phenotypes: Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features, MIM# 617865, Acromelic frontonasal dysostosis, MIM# 603671; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.4022 ABCB11 Zornitza Stark Gene: abcb11 has been classified as Green List (High Evidence).
Mendeliome v0.4022 ABCB11 Zornitza Stark Phenotypes for gene: ABCB11 were changed from to Cholestasis, progressive familial intrahepatic 2, MIM# 601847; Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479
Mendeliome v0.4019 ABCB11 Zornitza Stark reviewed gene: ABCB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 16871584, 23141890, 9806540, 15300568, 11172067; Phenotypes: Cholestasis, progressive familial intrahepatic 2, MIM# 601847, Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4019 ABCB1 Zornitza Stark Gene: abcb1 has been classified as Red List (Low Evidence).
Mendeliome v0.4016 ABCB1 Zornitza Stark Classified gene: ABCB1 as Red List (low evidence)
Mendeliome v0.4016 ABCB1 Zornitza Stark Gene: abcb1 has been classified as Red List (Low Evidence).
Mendeliome v0.4015 ABCA3 Zornitza Stark Gene: abca3 has been classified as Green List (High Evidence).
Mendeliome v0.4012 ABCA12 Zornitza Stark Gene: abca12 has been classified as Green List (High Evidence).
Mendeliome v0.4012 ABCA12 Zornitza Stark Phenotypes for gene: ABCA12 were changed from to Ichthyosis, congenital, autosomal recessive 4A (MIM#601277); Ichthyosis, congenital, autosomal recessive 4B (harlequin) (MIM#242500)
Mendeliome v0.4009 ABCA12 Zornitza Stark reviewed gene: ABCA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 31168818, 19664001, 31489029; Phenotypes: Ichthyosis, congenital, autosomal recessive 4A (MIM#601277), Ichthyosis, congenital, autosomal recessive 4B (harlequin) (MIM#242500); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4006 AASS Zornitza Stark Gene: aass has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4006 AASS Zornitza Stark Phenotypes for gene: AASS were changed from to Hyperlysinemia, MIM# 238700
Mendeliome v0.4003 AASS Zornitza Stark Classified gene: AASS as Amber List (moderate evidence)
Mendeliome v0.4003 AASS Zornitza Stark Gene: aass has been classified as Amber List (Moderate Evidence).
Mendeliome v0.4002 AASS Zornitza Stark changed review comment from: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. Hyperlysinemia is generally considered to be a benign metabolic variant rather than a disease entity.; to: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. It has been suggested that hyperlysinemia is a benign metabolic variant rather than a disease entity.
Mendeliome v0.4002 AASS Zornitza Stark reviewed gene: AASS: Rating: RED; Mode of pathogenicity: None; Publications: 23570448; Phenotypes: Hyperlysinemia, MIM# 238700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.4002 AARS2 Zornitza Stark Gene: aars2 has been classified as Green List (High Evidence).
Mendeliome v0.4002 AARS2 Zornitza Stark Phenotypes for gene: AARS2 were changed from to Combined oxidative phosphorylation deficiency 8 MIM#614096; Leukoencephalopathy, progressive, with ovarian failure MIM#615889; MONDO:0013570
Mendeliome v0.3999 AARS2 Zornitza Stark edited their review of gene: AARS2: Changed phenotypes: Combined oxidative phosphorylation deficiency 8 MIM#614096, Leukoencephalopathy, progressive, with ovarian failure MIM#615889, MONDO:0013570
Mendeliome v0.3999 AARS2 Zornitza Stark reviewed gene: AARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30706699, 27839525, 21549344, 25058219, 24808023; Phenotypes: Combined oxidative phosphorylation deficiency 8 MIM#614096, Leukoencephalopathy, progressive, with ovarian failure MIM#615889; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3999 AARS Zornitza Stark Gene: aars has been classified as Green List (High Evidence).
Mendeliome v0.3996 AAGAB Zornitza Stark Gene: aagab has been classified as Green List (High Evidence).
Mendeliome v0.3993 A4GALT Zornitza Stark Gene: a4galt has been classified as Red List (Low Evidence).
Mendeliome v0.3992 A4GALT Zornitza Stark Classified gene: A4GALT as Red List (low evidence)
Mendeliome v0.3992 A4GALT Zornitza Stark Gene: a4galt has been classified as Red List (Low Evidence).
Mendeliome v0.3991 PAFAH1B1 Zornitza Stark Gene: pafah1b1 has been classified as Green List (High Evidence).
Mendeliome v0.3988 LAMB1 Zornitza Stark Gene: lamb1 has been classified as Green List (High Evidence).
Mendeliome v0.3985 TMEM5 Zornitza Stark Gene: tmem5 has been classified as Green List (High Evidence).
Mendeliome v0.3982 KIF5C Zornitza Stark Gene: kif5c has been classified as Green List (High Evidence).
Mendeliome v0.3982 KIF5C Zornitza Stark Phenotypes for gene: KIF5C were changed from to Cortical dysplasia, complex, with other brain malformations 2, MIM# 615282
Mendeliome v0.3979 KIF5C Zornitza Stark reviewed gene: KIF5C: Rating: GREEN; Mode of pathogenicity: None; Publications: 23603762, 23033978, 32562872; Phenotypes: Cortical dysplasia, complex, with other brain malformations 2, MIM# 615282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3979 KIF2A Zornitza Stark Gene: kif2a has been classified as Green List (High Evidence).
Mendeliome v0.3979 KIF2A Zornitza Stark Phenotypes for gene: KIF2A were changed from to Cortical dysplasia, complex, with other brain malformations 3, MIM# 615411
Mendeliome v0.3976 KIF2A Zornitza Stark reviewed gene: KIF2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23603762, 27896282, 27747449, 29077851, 31919497; Phenotypes: Cortical dysplasia, complex, with other brain malformations 3, MIM# 615411; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3976 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Mendeliome v0.3973 DCX Zornitza Stark Gene: dcx has been classified as Green List (High Evidence).
Mendeliome v0.3970 ASPRV1 Zornitza Stark Phenotypes for gene: ASPRV1 were changed from palmoplantar keratoderma; lamellar ichthyosis to Ichthyosis, lamellar, autosomal dominant, MIM# 146750; palmoplantar keratoderma; lamellar ichthyosis
Mendeliome v0.3969 ASPRV1 Zornitza Stark reviewed gene: ASPRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ichthyosis, lamellar, autosomal dominant, MIM# 146750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3969 MRPL44 Zornitza Stark Gene: mrpl44 has been classified as Green List (High Evidence).
Mendeliome v0.3966 KBTBD13 Zornitza Stark Gene: kbtbd13 has been classified as Green List (High Evidence).
Mendeliome v0.3962 NDUFA13 Zornitza Stark Classified gene: NDUFA13 as Amber List (moderate evidence)
Mendeliome v0.3962 NDUFA13 Zornitza Stark Gene: ndufa13 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3961 LAMA2 Zornitza Stark Gene: lama2 has been classified as Green List (High Evidence).
Mendeliome v0.3961 LAMA2 Zornitza Stark Phenotypes for gene: LAMA2 were changed from to Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855; Muscular dystrophy, limb-girdle, autosomal recessive 23, MIM# 618138
Mendeliome v0.3958 LAMA2 Zornitza Stark reviewed gene: LAMA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30055037; Phenotypes: Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855, Muscular dystrophy, limb-girdle, autosomal recessive 23, MIM# 618138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3958 GRIN2B Zornitza Stark Gene: grin2b has been classified as Green List (High Evidence).
Mendeliome v0.3955 GRIN1 Zornitza Stark Gene: grin1 has been classified as Green List (High Evidence).
Mendeliome v0.3955 GRIN1 Zornitza Stark Phenotypes for gene: GRIN1 were changed from to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820
Mendeliome v0.3952 GRIN1 Zornitza Stark reviewed gene: GRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29365063, 27164704, 27164704, 28051072; Phenotypes: Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254, Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3952 BCLAF1 Zornitza Stark Gene: bclaf1 has been classified as Red List (Low Evidence).
Mendeliome v0.3952 BCLAF1 Zornitza Stark Classified gene: BCLAF1 as Red List (low evidence)
Mendeliome v0.3952 BCLAF1 Zornitza Stark Gene: bclaf1 has been classified as Red List (Low Evidence).
Mendeliome v0.3951 ALG12 Zornitza Stark Gene: alg12 has been classified as Green List (High Evidence).
Mendeliome v0.3950 SEC61A1 Zornitza Stark Gene: sec61a1 has been classified as Green List (High Evidence).
Mendeliome v0.3945 ALG11 Zornitza Stark Gene: alg11 has been classified as Green List (High Evidence).
Mendeliome v0.3942 NPRL2 Zornitza Stark Gene: nprl2 has been classified as Green List (High Evidence).
Mendeliome v0.3942 NPRL2 Zornitza Stark Phenotypes for gene: NPRL2 were changed from to Epilepsy, familial focal, with variable foci 2, MIM# 617116; focal seizures; frontal lobe epilepsy; nocturnal frontal lobe epilepsy; temporal lobe epilepsy; focal cortical dysplasia
Mendeliome v0.3939 NPRL2 Dean Phelan reviewed gene: NPRL2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26505888, 27173016, 28199897, 31594065; Phenotypes: focal seizures, frontal lobe epilepsy, nocturnal frontal lobe epilepsy, temporal lobe epilepsy, focal cortical dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3939 PDE2A Zornitza Stark Gene: pde2a has been classified as Green List (High Evidence).
Mendeliome v0.3939 PDE2A Zornitza Stark Classified gene: PDE2A as Green List (high evidence)
Mendeliome v0.3939 PDE2A Zornitza Stark Gene: pde2a has been classified as Green List (High Evidence).
Mendeliome v0.3938 PDE2A Zornitza Stark gene: PDE2A was added
gene: PDE2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDE2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE2A were set to 32467598; 32196122; 29392776
Phenotypes for gene: PDE2A were set to Paroxysmal dyskinesia
Review for gene: PDE2A was set to GREEN
Added comment: Four unrelated families reported with childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy. One of the reports characterises the disorder as 'Rett-like'.
Sources: Literature
Mendeliome v0.3937 OTULIN Zornitza Stark Gene: otulin has been classified as Green List (High Evidence).
Mendeliome v0.3937 OTULIN Zornitza Stark Phenotypes for gene: OTULIN were changed from to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099
Mendeliome v0.3934 OTULIN Zornitza Stark reviewed gene: OTULIN: Rating: GREEN; Mode of pathogenicity: None; Publications: 27523608, 27559085; Phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3933 RRAGC Zornitza Stark Gene: rragc has been classified as Red List (Low Evidence).
Mendeliome v0.3931 RRAGC Zornitza Stark Classified gene: RRAGC as Red List (low evidence)
Mendeliome v0.3931 RRAGC Zornitza Stark Gene: rragc has been classified as Red List (Low Evidence).
Mendeliome v0.3930 RANBP17 Zornitza Stark Gene: ranbp17 has been classified as Red List (Low Evidence).
Mendeliome v0.3930 RANBP17 Zornitza Stark Classified gene: RANBP17 as Red List (low evidence)
Mendeliome v0.3930 RANBP17 Zornitza Stark Gene: ranbp17 has been classified as Red List (Low Evidence).
Mendeliome v0.3929 MICA Zornitza Stark Gene: mica has been classified as Red List (Low Evidence).
Mendeliome v0.3929 MICA Zornitza Stark Classified gene: MICA as Red List (low evidence)
Mendeliome v0.3929 MICA Zornitza Stark Gene: mica has been classified as Red List (Low Evidence).
Mendeliome v0.3928 CRADD Zornitza Stark Gene: cradd has been classified as Green List (High Evidence).
Mendeliome v0.3928 CRADD Zornitza Stark Phenotypes for gene: CRADD were changed from to Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499
Mendeliome v0.3925 CRADD Zornitza Stark reviewed gene: CRADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 27773430; Phenotypes: Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3925 TDGF1 Zornitza Stark Gene: tdgf1 has been classified as Red List (Low Evidence).
Mendeliome v0.3922 TDGF1 Zornitza Stark Classified gene: TDGF1 as Red List (low evidence)
Mendeliome v0.3922 TDGF1 Zornitza Stark Gene: tdgf1 has been classified as Red List (Low Evidence).
Mendeliome v0.3921 GABRA6 Zornitza Stark Gene: gabra6 has been classified as Red List (Low Evidence).
Mendeliome v0.3920 TMTC3 Zornitza Stark Gene: tmtc3 has been classified as Green List (High Evidence).
Mendeliome v0.3917 ARFGEF2 Zornitza Stark Gene: arfgef2 has been classified as Green List (High Evidence).
Mendeliome v0.3914 SLC6A3 Zornitza Stark Gene: slc6a3 has been classified as Green List (High Evidence).
Mendeliome v0.3911 MAOA Zornitza Stark Gene: maoa has been classified as Green List (High Evidence).
Mendeliome v0.3905 GLRB Zornitza Stark Gene: glrb has been classified as Green List (High Evidence).
Mendeliome v0.3901 GLRA1 Zornitza Stark Gene: glra1 has been classified as Green List (High Evidence).
Mendeliome v0.3898 GABRG2 Zornitza Stark Gene: gabrg2 has been classified as Green List (High Evidence).
Mendeliome v0.3895 GABRB3 Zornitza Stark Gene: gabrb3 has been classified as Green List (High Evidence).
Mendeliome v0.3892 FOLR1 Zornitza Stark Gene: folr1 has been classified as Green List (High Evidence).
Mendeliome v0.3889 DBH Zornitza Stark Gene: dbh has been classified as Green List (High Evidence).
Mendeliome v0.3886 ARHGEF9 Zornitza Stark Gene: arhgef9 has been classified as Green List (High Evidence).
Mendeliome v0.3883 STAT5B Zornitza Stark Gene: stat5b has been classified as Green List (High Evidence).
Mendeliome v0.3883 STAT5B Zornitza Stark Phenotypes for gene: STAT5B were changed from to Growth hormone insensitivity with immunodeficiency, MIM# 245590
Mendeliome v0.3879 STAT5B Zornitza Stark reviewed gene: STAT5B: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29844444; Phenotypes: Growth hormone insensitivity with immunodeficiency, MIM# 245590; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3879 ALDH5A1 Zornitza Stark Gene: aldh5a1 has been classified as Green List (High Evidence).
Mendeliome v0.3876 ABAT Zornitza Stark Gene: abat has been classified as Green List (High Evidence).
Mendeliome v0.3874 ABAT Zornitza Stark edited their review of gene: ABAT: Added comment: Bi-allelic variants in ABAT are associated with a neurotransmitter disorder. However, there are also reports of families with encephalomyopathic MDS caused by bi-allelic variants in ABAT resulting in elevated GABA in subjects' brains as well as decreased mtDNA levels in subjects' fibroblasts. Nucleoside rescue and co-IP experiments demonstrate that ABAT functions in the mitochondrial nucleoside salvage pathway to facilitate conversion of dNDPs to dNTPs. Unclear whether this a distinct disorder or part of a continuum caused by the enzyme being part of two pathways.; Changed publications: 25738457, 27903293, 28411234, 27596361, 20052547, 10407778, 6148708; Changed phenotypes: GABA-transaminase deficiency, MIM# 613163, mtDNA depletion syndrome (MDS)
Mendeliome v0.3873 LMBRD2 Zornitza Stark Gene: lmbrd2 has been classified as Green List (High Evidence).
Mendeliome v0.3873 LMBRD2 Zornitza Stark Classified gene: LMBRD2 as Green List (high evidence)
Mendeliome v0.3873 LMBRD2 Zornitza Stark Gene: lmbrd2 has been classified as Green List (High Evidence).
Mendeliome v0.3872 LMBRD2 Zornitza Stark gene: LMBRD2 was added
gene: LMBRD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Mode of pathogenicity for gene: LMBRD2 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: LMBRD2 was set to GREEN
Added comment: 13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies.

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants. Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific). All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity. 5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect. There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H). The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely. As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation. It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Mendeliome v0.3867 KAT5 Zornitza Stark Classified gene: KAT5 as Green List (high evidence)
Mendeliome v0.3867 KAT5 Zornitza Stark Gene: kat5 has been classified as Green List (High Evidence).
Mendeliome v0.3866 AFG3L2 Zornitza Stark Gene: afg3l2 has been classified as Green List (High Evidence).
Mendeliome v0.3866 AFG3L2 Zornitza Stark Phenotypes for gene: AFG3L2 were changed from to Spastic ataxia 5, autosomal recessive (MIM#614487); Spinocerebellar ataxia 28 (MIM#610246); Optic atrophy 12, MIM# 618977
Mendeliome v0.3863 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29181157, 26539208, 30252181, 30389403, 32219868, 32600459, 32548275; Phenotypes: Spastic ataxia 5, autosomal recessive (MIM#614487), Spinocerebellar ataxia 28 (MIM#610246), Optic atrophy 12, MIM# 618977; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3863 MYOD1 Zornitza Stark Gene: myod1 has been classified as Green List (High Evidence).
Mendeliome v0.3863 MYOD1 Zornitza Stark Classified gene: MYOD1 as Green List (high evidence)
Mendeliome v0.3863 MYOD1 Zornitza Stark Gene: myod1 has been classified as Green List (High Evidence).
Mendeliome v0.3861 TMEM237 Zornitza Stark Gene: tmem237 has been classified as Green List (High Evidence).
Mendeliome v0.3859 NOD2 Zornitza Stark Gene: nod2 has been classified as Green List (High Evidence).
Mendeliome v0.3856 PAX3 Zornitza Stark Gene: pax3 has been classified as Green List (High Evidence).
Mendeliome v0.3850 ESRRB Zornitza Stark Gene: esrrb has been classified as Green List (High Evidence).
Mendeliome v0.3850 ESRRB Zornitza Stark Phenotypes for gene: ESRRB were changed from to Deafness, autosomal recessive 35, MIM#608565
Mendeliome v0.3847 ESRRB Zornitza Stark reviewed gene: ESRRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 18179891, 31389194, 32681043; Phenotypes: Deafness, autosomal recessive 35, MIM#608565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3847 HNRNPA2B1 Zornitza Stark Gene: hnrnpa2b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3847 HNRNPA2B1 Zornitza Stark Classified gene: HNRNPA2B1 as Amber List (moderate evidence)
Mendeliome v0.3847 HNRNPA2B1 Zornitza Stark Gene: hnrnpa2b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3846 HNRNPA2B1 Zornitza Stark gene: HNRNPA2B1 was added
gene: HNRNPA2B1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPA2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPA2B1 were set to 23455423; 30279180; 29358076; 26744327; 23635965
Phenotypes for gene: HNRNPA2B1 were set to Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 MIM#615422
Review for gene: HNRNPA2B1 was set to AMBER
Added comment: One family reported that segregates cognitive impairment as part of the phenotype, and extensive functional analysis of protein, including a drosophila model.
Sources: Literature
Mendeliome v0.3845 PSMC3 Zornitza Stark Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3845 PSMC3 Zornitza Stark Classified gene: PSMC3 as Amber List (moderate evidence)
Mendeliome v0.3845 PSMC3 Zornitza Stark Gene: psmc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3844 PSMC3 Zornitza Stark gene: PSMC3 was added
gene: PSMC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC3 were set to 32500975
Phenotypes for gene: PSMC3 were set to Deafness; cataract
Review for gene: PSMC3 was set to AMBER
Added comment: Three affected individuals from a single consanguineous family reported with homozygous intronic variant. Animal model.
Sources: Literature
Mendeliome v0.3843 SOS2 Zornitza Stark Gene: sos2 has been classified as Green List (High Evidence).
Mendeliome v0.3838 RAI1 Zornitza Stark Gene: rai1 has been classified as Green List (High Evidence).
Mendeliome v0.3835 TAF1C Zornitza Stark Gene: taf1c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3835 TAF1C Zornitza Stark Classified gene: TAF1C as Amber List (moderate evidence)
Mendeliome v0.3835 TAF1C Zornitza Stark Gene: taf1c has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3834 TAF1C Zornitza Stark gene: TAF1C was added
gene: TAF1C was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 32779182
Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology
Review for gene: TAF1C was set to AMBER
Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants. Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual). Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1). The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele. TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit. RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs). A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data). The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual).
Sources: Expert list
Mendeliome v0.3833 KALRN Zornitza Stark Gene: kalrn has been classified as Red List (Low Evidence).
Mendeliome v0.3830 KALRN Zornitza Stark Classified gene: KALRN as Red List (low evidence)
Mendeliome v0.3830 KALRN Zornitza Stark Gene: kalrn has been classified as Red List (Low Evidence).
Mendeliome v0.3829 KRT6C Zornitza Stark Gene: krt6c has been classified as Green List (High Evidence).
Mendeliome v0.3826 KRT6B Zornitza Stark Gene: krt6b has been classified as Green List (High Evidence).
Mendeliome v0.3823 KRT2 Zornitza Stark Gene: krt2 has been classified as Green List (High Evidence).
Mendeliome v0.3823 KRT2 Zornitza Stark Phenotypes for gene: KRT2 were changed from to Superficial epidermolytic ichthyosis (SEI) (MIM#146800)
Mendeliome v0.3820 KRT2 Zornitza Stark reviewed gene: KRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26581228, 22612346; Phenotypes: Superficial epidermolytic ichthyosis (SEI) (MIM#146800); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3820 KRT17 Zornitza Stark Gene: krt17 has been classified as Green List (High Evidence).
Mendeliome v0.3817 KRT17 Zornitza Stark changed review comment from: Also known as Jackson-Lawler type, the main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. PMID: 31823354; - cohort of 815 individuals, 134 patients had variants in KRT17 - approx 61.8% presented with palmar keratoderma and approx 82.8% with plantar keratoderma; to: Also known as Jackson-Lawler type, the main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. PMID: 31823354; - cohort of 815 individuals, 134 patients had variants in KRT17 - approx 61.8% presented with palmar keratoderma and approx 82.8% with plantar keratoderma. Steatocystoma multiplex is an allelic disorder.
Mendeliome v0.3817 SERPINB7 Zornitza Stark Gene: serpinb7 has been classified as Green List (High Evidence).
Mendeliome v0.3814 SLURP1 Zornitza Stark Gene: slurp1 has been classified as Green List (High Evidence).
Mendeliome v0.3811 SLURP1 Zornitza Stark changed review comment from: Over 10 families reported with Mal de Meleda, a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma, keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities.; to: Over 10 families reported with Mal de Meleda, a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma, keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities. Note single report of manifesting carriers.
Mendeliome v0.3811 ACTN4 Zornitza Stark Gene: actn4 has been classified as Green List (High Evidence).
Mendeliome v0.3811 ACTN4 Zornitza Stark Phenotypes for gene: ACTN4 were changed from to Glomerulosclerosis, focal segmental, 1, MIM#603278
Mendeliome v0.3806 VKORC1 Zornitza Stark reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14765194, 21900891, 28198005; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2, MIM# 607473, Warfarin resistance, MIM# 122700; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v0.3806 ACTN4 Elena Savva reviewed gene: ACTN4: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 26740551, 22351778, 10700177, 26301083; Phenotypes: Glomerulosclerosis, focal segmental, 1, 603278; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3806 TPM4 Zornitza Stark Gene: tpm4 has been classified as Green List (High Evidence).
Mendeliome v0.3806 TPM4 Zornitza Stark Classified gene: TPM4 as Green List (high evidence)
Mendeliome v0.3806 TPM4 Zornitza Stark Gene: tpm4 has been classified as Green List (High Evidence).
Mendeliome v0.3804 THPO Zornitza Stark Gene: thpo has been classified as Green List (High Evidence).
Mendeliome v0.3799 TBXAS1 Zornitza Stark Gene: tbxas1 has been classified as Green List (High Evidence).
Mendeliome v0.3797 SRC Zornitza Stark Gene: src has been classified as Green List (High Evidence).
Mendeliome v0.3797 SRC Zornitza Stark Classified gene: SRC as Green List (high evidence)
Mendeliome v0.3797 SRC Zornitza Stark Gene: src has been classified as Green List (High Evidence).
Mendeliome v0.3795 SLFN14 Zornitza Stark Gene: slfn14 has been classified as Green List (High Evidence).
Mendeliome v0.3795 SLFN14 Zornitza Stark Classified gene: SLFN14 as Green List (high evidence)
Mendeliome v0.3795 SLFN14 Zornitza Stark Gene: slfn14 has been classified as Green List (High Evidence).
Mendeliome v0.3793 PTPRJ Zornitza Stark Gene: ptprj has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3793 PTPRJ Zornitza Stark Classified gene: PTPRJ as Amber List (moderate evidence)
Mendeliome v0.3793 PTPRJ Zornitza Stark Gene: ptprj has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3792 PTPRJ Zornitza Stark gene: PTPRJ was added
gene: PTPRJ was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PTPRJ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPRJ were set to 30591527
Phenotypes for gene: PTPRJ were set to Thrombocytopaenia
Review for gene: PTPRJ was set to AMBER
Added comment: Two siblings reported with nonsyndromic thrombocytopenia characterised by spontaneous bleeding, small-sized platelets, and impaired platelet responses to the GPVI agonists collagen and convulxin. Supportive zebrafish model.
Sources: Expert list
Mendeliome v0.3791 PTGS1 Zornitza Stark Gene: ptgs1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3791 PTGS1 Zornitza Stark Classified gene: PTGS1 as Amber List (moderate evidence)
Mendeliome v0.3791 PTGS1 Zornitza Stark Gene: ptgs1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3790 PTGS1 Zornitza Stark gene: PTGS1 was added
gene: PTGS1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PTGS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTGS1 were set to 32299908; 11442478; 27629384; 8562397
Phenotypes for gene: PTGS1 were set to Platelet dysfunction; bleeding
Review for gene: PTGS1 was set to AMBER
Added comment: Single molecularly characterised family reported. However, note at least two previous older reports where deficiency was identified at protein rather than gene level.
Sources: Expert list
Mendeliome v0.3789 PRKACG Zornitza Stark Gene: prkacg has been classified as Red List (Low Evidence).
Mendeliome v0.3789 PRKACG Zornitza Stark gene: PRKACG was added
gene: PRKACG was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PRKACG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRKACG were set to 25061177; 30819905
Phenotypes for gene: PRKACG were set to Bleeding disorder, platelet-type, 19, MIM# 616176
Review for gene: PRKACG was set to RED
Added comment: Single family reported only. A heterozygous VOUS reported in another individual in PMID 30819905 together with several other VOUS in same individual.
Sources: Expert list
Mendeliome v0.3788 PLAU Zornitza Stark Gene: plau has been classified as Green List (High Evidence).
Mendeliome v0.3788 PLAU Zornitza Stark Classified gene: PLAU as Green List (high evidence)
Mendeliome v0.3788 PLAU Zornitza Stark Gene: plau has been classified as Green List (High Evidence).
Mendeliome v0.3786 PLA2G4A Zornitza Stark Gene: pla2g4a has been classified as Green List (High Evidence).
Mendeliome v0.3786 PLA2G4A Zornitza Stark Classified gene: PLA2G4A as Green List (high evidence)
Mendeliome v0.3786 PLA2G4A Zornitza Stark Gene: pla2g4a has been classified as Green List (High Evidence).
Mendeliome v0.3784 MPIG6B Zornitza Stark Gene: mpig6b has been classified as Green List (High Evidence).
Mendeliome v0.3784 MPIG6B Zornitza Stark Classified gene: MPIG6B as Green List (high evidence)
Mendeliome v0.3784 MPIG6B Zornitza Stark Gene: mpig6b has been classified as Green List (High Evidence).
Mendeliome v0.3783 MPIG6B Zornitza Stark gene: MPIG6B was added
gene: MPIG6B was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: MPIG6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPIG6B were set to 31276734; 29898956; 27743390
Phenotypes for gene: MPIG6B were set to Thrombocytopenia, anemia, and myelofibrosis, MIM# 617441
Review for gene: MPIG6B was set to GREEN
Added comment: Six families reported.
Sources: Expert list
Mendeliome v0.3782 MAT2A Zornitza Stark Gene: mat2a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3779 MAT2A Zornitza Stark Classified gene: MAT2A as Amber List (moderate evidence)
Mendeliome v0.3779 MAT2A Zornitza Stark Gene: mat2a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3778 LOX Zornitza Stark Gene: lox has been classified as Green List (High Evidence).
Mendeliome v0.3775 KDSR Zornitza Stark Gene: kdsr has been classified as Green List (High Evidence).
Mendeliome v0.3775 KDSR Zornitza Stark Phenotypes for gene: KDSR were changed from to Erythrokeratodermia variabilis et progressiva 4, MIM# 617526; severe thrombocytopaenia
Mendeliome v0.3772 KDSR Zornitza Stark reviewed gene: KDSR: Rating: GREEN; Mode of pathogenicity: None; Publications: 28774589, 30467204, 28575652; Phenotypes: Erythrokeratodermia variabilis et progressiva 4, MIM# 617526, severe thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3772 GGCX Zornitza Stark Gene: ggcx has been classified as Green List (High Evidence).
Mendeliome v0.3768 GPI Zornitza Stark Gene: gpi has been classified as Green List (High Evidence).
Mendeliome v0.3766 KANK2 Zornitza Stark Gene: kank2 has been classified as Green List (High Evidence).
Mendeliome v0.3763 FAM83G Zornitza Stark Gene: fam83g has been classified as Red List (Low Evidence).
Mendeliome v0.3763 FAM83G Zornitza Stark gene: FAM83G was added
gene: FAM83G was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FAM83G was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM83G were set to 29138053
Phenotypes for gene: FAM83G were set to Palmoplantar keratoderma, curly scalp hair and toenail dystrophy
Review for gene: FAM83G was set to RED
Added comment: PMID: 29138053; - 2 siblings born of consanguineous family presented with palmoplantar keratoderma and exuberant curly scalp hair - progressive development of yellowish thickened scaly skin affecting the palms and soles since 2 years of age, and toenail dystrophy in their teenage years > homozygous for a missense p.(Ala34Glu)
Sources: Expert list
Mendeliome v0.3762 LONP2 Zornitza Stark Gene: lonp2 has been classified as Red List (Low Evidence).
Mendeliome v0.3762 LONP2 Zornitza Stark Classified gene: LONP2 as Red List (low evidence)
Mendeliome v0.3762 LONP2 Zornitza Stark Gene: lonp2 has been classified as Red List (Low Evidence).
Mendeliome v0.3761 CAST Zornitza Stark Gene: cast has been classified as Green List (High Evidence).
Mendeliome v0.3758 CARD14 Zornitza Stark Gene: card14 has been classified as Green List (High Evidence).
Mendeliome v0.3758 CARD14 Zornitza Stark Phenotypes for gene: CARD14 were changed from to Pityriasis rubra pilaris (MIM#173200)
Mendeliome v0.3755 CARD14 Zornitza Stark reviewed gene: CARD14: Rating: GREEN; Mode of pathogenicity: None; Publications: 22703878, 27760266; Phenotypes: Pityriasis rubra pilaris (MIM#173200); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.3755 TRPV3 Zornitza Stark Gene: trpv3 has been classified as Green List (High Evidence).
Mendeliome v0.3752 EPHB2 Zornitza Stark Gene: ephb2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3749 EPHB2 Zornitza Stark Classified gene: EPHB2 as Amber List (moderate evidence)
Mendeliome v0.3749 EPHB2 Zornitza Stark Gene: ephb2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3748 ACTN1 Zornitza Stark Gene: actn1 has been classified as Green List (High Evidence).
Mendeliome v0.3745 DSG3 Zornitza Stark Gene: dsg3 has been classified as Red List (Low Evidence).
Mendeliome v0.3745 DSG3 Zornitza Stark gene: DSG3 was added
gene: DSG3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: DSG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DSG3 were set to 30528827
Phenotypes for gene: DSG3 were set to Mucosal blistering
Review for gene: DSG3 was set to RED
Added comment: One individual with recurrent blisters and erosions in the oral mucosa since birth homozygous for p(.R287*).
Sources: Expert list
Mendeliome v0.3744 ITGA9 Zornitza Stark Gene: itga9 has been classified as Red List (Low Evidence).
Mendeliome v0.3744 ITGA9 Zornitza Stark Classified gene: ITGA9 as Red List (low evidence)
Mendeliome v0.3744 ITGA9 Zornitza Stark Gene: itga9 has been classified as Red List (Low Evidence).
Mendeliome v0.3743 MADD Zornitza Stark Gene: madd has been classified as Green List (High Evidence).
Mendeliome v0.3740 UNC45A Zornitza Stark Gene: unc45a has been classified as Green List (High Evidence).
Mendeliome v0.3740 UNC45A Zornitza Stark Phenotypes for gene: UNC45A were changed from to Cholestasis; Diarrhoea; Bone fragility; Impaired hearing
Mendeliome v0.3737 UNC45A Zornitza Stark reviewed gene: UNC45A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29429573; Phenotypes: Cholestasis, Diarrhoea, Bone fragility, Impaired hearing; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3737 SLC5A6 Zornitza Stark Phenotypes for gene: SLC5A6 were changed from Developmental delay; epilepsy; neurodegeneration to Developmental delay; epilepsy; neurodegeneration; Neurodegeneration, infantile-onset, biotin-responsive, MIM# 618973
Mendeliome v0.3736 SLC5A6 Zornitza Stark edited their review of gene: SLC5A6: Changed phenotypes: Developmental delay, epilepsy, neurodegeneration, Neurodegeneration, infantile-onset, biotin-responsive, MIM# 618973
Mendeliome v0.3736 SMO Zornitza Stark Phenotypes for gene: SMO were changed from Microcephaly, congenital heart disease, polydactyly, aganglionosis; Curry-Jones syndrome, somatic mosaic 601707 to Microcephaly, congenital heart disease, polydactyly, aganglionosis, Pallister-Hall-like syndrome, MIM# 241800; Curry-Jones syndrome, somatic mosaic 601707
Mendeliome v0.3735 SMO Zornitza Stark edited their review of gene: SMO: Changed phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis, Pallister-Hall-like syndrome, MIM# 241800, Curry-Jones syndrome, somatic mosaic 601707
Mendeliome v0.3735 HFE2 Zornitza Stark Gene: hfe2 has been classified as Green List (High Evidence).
Mendeliome v0.3735 HFE2 Zornitza Stark Phenotypes for gene: HFE2 were changed from to Hemochromatosis, type 2A, MIM# 602390
Mendeliome v0.3733 HFE2 Zornitza Stark reviewed gene: HFE2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hemochromatosis, type 2A, MIM# 602390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3733 FAM50A Zornitza Stark Gene: fam50a has been classified as Green List (High Evidence).
Mendeliome v0.3733 FAM50A Zornitza Stark Classified gene: FAM50A as Green List (high evidence)
Mendeliome v0.3733 FAM50A Zornitza Stark Gene: fam50a has been classified as Green List (High Evidence).
Mendeliome v0.3732 FAM50A Zornitza Stark gene: FAM50A was added
gene: FAM50A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943
Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261)
Review for gene: FAM50A was set to GREEN
Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference. The authors provide clinical details on 6 affected individuals from 5 families. Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6). In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam). In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40). Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3). Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones). Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt. Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish. Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins. Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism. Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.).
Sources: Literature
Mendeliome v0.3731 ADK Zornitza Stark Gene: adk has been classified as Green List (High Evidence).
Mendeliome v0.3731 ADK Zornitza Stark Phenotypes for gene: ADK were changed from to Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300
Mendeliome v0.3728 ADK Zornitza Stark reviewed gene: ADK: Rating: GREEN; Mode of pathogenicity: None; Publications: 21963049, 17120046; Phenotypes: Hypermethioninemia due to adenosine kinase deficiency, MIM# 614300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3728 SGK3 Zornitza Stark gene: SGK3 was added
gene: SGK3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SGK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SGK3 were set to 31821448
Phenotypes for gene: SGK3 were set to Hypophosphatemic rickets
Review for gene: SGK3 was set to RED
Added comment: 5 individuals from one family where a splice site variant segregated with disease.
Sources: Literature
Mendeliome v0.3727 SEC24D Zornitza Stark Gene: sec24d has been classified as Green List (High Evidence).
Mendeliome v0.3724 P4HB Zornitza Stark Gene: p4hb has been classified as Green List (High Evidence).
Mendeliome v0.3721 MPDZ Zornitza Stark Gene: mpdz has been classified as Green List (High Evidence).
Mendeliome v0.3715 B3GNT2 Zornitza Stark Classified gene: B3GNT2 as Amber List (moderate evidence)
Mendeliome v0.3715 B3GNT2 Zornitza Stark Gene: b3gnt2 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3714 SOX6 Zornitza Stark Phenotypes for gene: SOX6 were changed from ADHD; Craniosynostosis; Osteochondromas to ADHD; Craniosynostosis; Osteochondromas; Tolchin-Le Caignec syndrome, MIM#618971
Mendeliome v0.3713 HYLS1 Melanie Marty changed review comment from: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human and patient cells have shown mislocalisation of the protein to the nucleus (PMID: 15843405, PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774).

2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932).

No other variants have been reported as pathogenic in this gene.; to: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human cells have shown mislocalisation of the protein to the nucleus (PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774).

2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932).

No other variants have been reported as pathogenic in this gene.
Mendeliome v0.3713 CNTN2 Zornitza Stark Gene: cntn2 has been classified as Red List (Low Evidence).
Mendeliome v0.3713 CNTN2 Zornitza Stark gene: CNTN2 was added
gene: CNTN2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNTN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTN2 were set to 23518707
Phenotypes for gene: CNTN2 were set to Epilepsy
Review for gene: CNTN2 was set to RED
Added comment: Single family reported in 2013, supportive mouse model.
Sources: Literature
Mendeliome v0.3712 DNAH8 Zornitza Stark Classified gene: DNAH8 as Green List (high evidence)
Mendeliome v0.3712 DNAH8 Zornitza Stark Gene: dnah8 has been classified as Green List (High Evidence).
Mendeliome v0.3711 DTNA Zornitza Stark Gene: dtna has been classified as Red List (Low Evidence).
Mendeliome v0.3708 DTNA Zornitza Stark Classified gene: DTNA as Red List (low evidence)
Mendeliome v0.3708 DTNA Zornitza Stark Gene: dtna has been classified as Red List (Low Evidence).
Mendeliome v0.3707 HYLS1 Zornitza Stark Gene: hyls1 has been classified as Green List (High Evidence).
Mendeliome v0.3702 RAC1 Zornitza Stark Gene: rac1 has been classified as Green List (High Evidence).
Mendeliome v0.3698 FANCD2 Zornitza Stark Gene: fancd2 has been classified as Green List (High Evidence).
Mendeliome v0.3696 BCOR Zornitza Stark Gene: bcor has been classified as Green List (High Evidence).
Mendeliome v0.3691 ARSE Zornitza Stark Gene: arse has been classified as Green List (High Evidence).
Mendeliome v0.3691 ARSE Zornitza Stark Phenotypes for gene: ARSE were changed from to Chondrodysplasia punctata, X-linked recessive, MIM# 302950
Mendeliome v0.3690 ARSE Zornitza Stark reviewed gene: ARSE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Chondrodysplasia punctata, X-linked recessive, MIM# 302950; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.3690 TPP1 Zornitza Stark Gene: tpp1 has been classified as Green List (High Evidence).
Mendeliome v0.3690 TPP1 Zornitza Stark Phenotypes for gene: TPP1 were changed from to Ceroid lipofuscinosis, neuronal, 2, MIM# 204500; Spinocerebellar ataxia, autosomal recessive 7, MIM# 609270
Mendeliome v0.3687 PSAT1 Zornitza Stark Gene: psat1 has been classified as Green List (High Evidence).
Mendeliome v0.3684 TPP1 Michelle Torres reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31283065; Phenotypes: Ceroid lipofuscinosis, neuronal, 2 204500, Spinocerebellar ataxia, autosomal recessive 7 609270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.3684 FBXO11 Zornitza Stark Gene: fbxo11 has been classified as Green List (High Evidence).
Mendeliome v0.3681 FRMD7 Zornitza Stark Gene: frmd7 has been classified as Green List (High Evidence).
Mendeliome v0.3678 AIFM1 Zornitza Stark Gene: aifm1 has been classified as Green List (High Evidence).
Mendeliome v0.3678 AIFM1 Zornitza Stark Phenotypes for gene: AIFM1 were changed from to Combined oxidative phosphorylation deficiency 6, 300816; Cowchock syndrome, 310490; Deafness, X-linked 5, 300614; Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, 300232
Mendeliome v0.3675 AIFM1 Elena Savva reviewed gene: AIFM1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28842795; Phenotypes: Combined oxidative phosphorylation deficiency 6, 300816, Cowchock syndrome, 310490, Deafness, X-linked 5, 300614, Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, 300232; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v0.3675 PIGQ Zornitza Stark edited their review of gene: PIGQ: Added comment: Homozygous or compound heterozygous mutations in PIGQ cause Epileptic encephalopathy, early infantile, 77 (MIM #618548).

Johnstone et al (2020 - PMID: 32588908) describe the phenotype of 7 children (from 6 families) with biallelic PIGQ pathogenic variants. The authors also review the phenotype of 3 subjects previously reported in the literature (by Martin et al, Alazami et al, Starr et al - respective PMIDs: 24463883, 25558065, 31148362).

Affected individuals displayed severe to profound global DD/ID and seizures with onset in the first year of life. There were variable other features incl. - among others - genitourinary, cardiac, skeletal, ophthalmological anomalies, gastrointestinal issues. Within the cohort there was significant morbidity/mortality.

PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q protein, playing a role (early) in the biosynthesis of the GPI-anchor. Several genes in the GPI biosynthesis pathway cause multi-system disease with DD/ID and seizures. Flow cytometry has been used in individuals with PIGQ-related disorder. Serum ALP was elevated in some (4) although - as the authors comment - elevations are more typical in disorders affecting later steps of GPI biosynthesis.

More than 10 variants have been reported to date (missense / pLoF).; Changed phenotypes: Epileptic encephalopathy, early infantile, 77, MIM# 618548
Mendeliome v0.3674 SEC61B Zornitza Stark Gene: sec61b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3674 SEC61B Zornitza Stark Classified gene: SEC61B as Amber List (moderate evidence)
Mendeliome v0.3674 SEC61B Zornitza Stark Gene: sec61b has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3672 CHI3L1 Zornitza Stark Gene: chi3l1 has been classified as Red List (Low Evidence).
Mendeliome v0.3671 CHI3L1 Zornitza Stark Classified gene: CHI3L1 as Red List (low evidence)
Mendeliome v0.3671 CHI3L1 Zornitza Stark Gene: chi3l1 has been classified as Red List (Low Evidence).
Mendeliome v0.3670 C3orf52 Zornitza Stark Gene: c3orf52 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3670 C3orf52 Zornitza Stark Classified gene: C3orf52 as Amber List (moderate evidence)
Mendeliome v0.3670 C3orf52 Zornitza Stark Gene: c3orf52 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3669 C3orf52 Zornitza Stark gene: C3orf52 was added
gene: C3orf52 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C3orf52 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C3orf52 were set to 32336749
Phenotypes for gene: C3orf52 were set to Localized hypotrichosis
Review for gene: C3orf52 was set to AMBER
Added comment: 2 families with 4 individuals with localised hypotrichosis and homozygous variants in C3ORF52. C3ORF52 was found to be coexpressed with lipase H in the inner root sheath of the hair follicle and the two proteins were found to directly interact. The LAH-causing variants were associated with decreased C3ORF52 expression and resulted in markedly reduced lipase H–mediated 2-acyl-lysophosphatidic acid (LPA) biosynthesis. Same pathway as two other genes for localised hypotrichosis (LIPH and LPAR6)
Sources: Literature
Mendeliome v0.3668 NDUFA8 Zornitza Stark Gene: ndufa8 has been classified as Red List (Low Evidence).
Mendeliome v0.3668 NDUFA8 Zornitza Stark gene: NDUFA8 was added
gene: NDUFA8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NDUFA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA8 were set to 32385911
Phenotypes for gene: NDUFA8 were set to NDUFA8-related mitochondrial disease; Developmental delay; microcehaly; seizures
Review for gene: NDUFA8 was set to RED
Added comment: Single individual reported with homozygous variant, fibroblasts showed apparent biochemical defects in mitochondrial complex I.
Sources: Literature
Mendeliome v0.3667 DLG5 Zornitza Stark Gene: dlg5 has been classified as Green List (High Evidence).
Mendeliome v0.3667 DLG5 Zornitza Stark Classified gene: DLG5 as Green List (high evidence)
Mendeliome v0.3667 DLG5 Zornitza Stark Gene: dlg5 has been classified as Green List (High Evidence).
Mendeliome v0.3665 AHR Zornitza Stark Gene: ahr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3665 AHR Zornitza Stark Classified gene: AHR as Amber List (moderate evidence)
Mendeliome v0.3665 AHR Zornitza Stark Gene: ahr has been classified as Amber List (Moderate Evidence).
Mendeliome v0.3664 M1AP Zornitza Stark Gene: m1ap has been classified as Green List (High Evidence).
Mendeliome v0.3664 M1AP Zornitza Stark Classified gene: M1AP as Green List (high evidence)
Mendeliome v0.3664 M1AP Zornitza Stark Gene: m1ap has been classified as Green List (High Evidence).
Mendeliome v0.3662 RELN Zornitza Stark Gene: reln has been classified as Green List (High Evidence).
Mendeliome v0.3662 RELN Zornitza Stark Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), MIM# 257320; ankylosing spondylitis to Lissencephaly 2 (Norman-Roberts type), MIM# 257320; {Epilepsy, familial temporal lobe, 7}, MIM# 616436; ankylosing spondylitis
Mendeliome v0.3661 RELN Zornitza Stark Phenotypes for gene: RELN were changed from to Lissencephaly 2 (Norman-Roberts type), MIM# 257320; ankylosing spondylitis
Mendeliome v0.3658 CALCRL Zornitza Stark Gene: calcrl has been classified as Red List (Low Evidence).
Mendeliome v0.3658 CALCRL Zornitza Stark Classified gene: CALCRL as Red List (low evidence)
Mendeliome v0.3658 CALCRL Zornitza Stark Gene: calcrl has been classified as Red List (Low Evidence).
Mendeliome v0.3657 CALCRL Hazel Phillimore gene: CALCRL was added
gene: CALCRL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CALCRL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CALCRL were set to PMID: 30115739
Phenotypes for gene: CALCRL were set to ?Lymphatic malformation 8 (MIM# 618773); hydrops fetalis
Review for gene: CALCRL was set to RED
Added comment: Homozygous in-frame deletion (Val205del) in the CALCRL gene (Val205del) in a 22 week-old fetus with hydrops details due to lymphatic malformation. Consanguineous parents.
Heterozygosity of the variant was also suggested to be associated with spontaneous miscarriage and subfertility. Consanguineous family with 8 total miscarriages from 3 carrier women, and 2 of these were confirmed to be due to hydrops fetalis.
Note: possible association of a variant in ASAH1 gene that is associated with Farber lipogranulomatosis which can sometimes present with antenatal hydrops fetalis. (Homozygosity in one of the fetuses, fetus and heterozygosity in some of the family members).
In vitro biochemical assays indicated that the variant causes misfolding of the protein and reduced association with its chaperone, RAMP2, and reduced translocation to the plasma membrane. (PMID: 30115739; Mackie, DI. et al., 2018).
Sources: Literature
Mendeliome v0.3657 RELN Chern Lim reviewed gene: RELN: Rating: AMBER; Mode of pathogenicity: None; Publications: 32001840; Phenotypes: ankylosing spondylitis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.3657 AHR Chern Lim gene: AHR was added
gene: AHR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AHR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AHR were set to 29726989; 31896775
Phenotypes for gene: AHR were set to ?Retinitis pigmentosa 85 MIM#618345; foveal hypoplasia and infantile nystagmus
Review for gene: AHR was set to AMBER
Added comment: - One reported homozygous splice variant in a consanguineous family & a mouse model (PMID: 29726989)

- A homozygous nonsense variant in 1 consanguineous family with foveal hypoplasia and infantile nystagmus (PMID:31896775).
Sources: Literature
Mendeliome v0.3657 CRY1 Zornitza Stark Gene: cry1 has been classified as Green List (High Evidence).
Mendeliome v0.3657 CRY1 Zornitza Stark Classified gene: CRY1 as Green List (high evidence)
Mendeliome v0.3657 CRY1 Zornitza Stark Gene: cry1 has been classified as Green List (High Evidence).
Mendeliome v0.3656 FBXL7 Zornitza Stark Gene: fbxl7 has been classified as Red List (Low Evidence).
Mendeliome v0.3656 FBXL7 Zornitza Stark Phenotypes for gene: FBXL7 were changed from Hennekam lymphangiectasia-lymphedema syndrome; lymphedema; protein‐losing enteropathy; dental anomalies; camptodactyly; microtia; small auditory canals; ductive hearing loss; middle ear anomalies, bifid scrotum, and facial dysmorphic features including hypertelorism, telecanthus, epicanthal folds, downslanting palpebral fissures, broad and depressed nasal bridge, and thickened nasal alae. to Hennekam lymphangiectasia-lymphedema syndrome
Mendeliome v0.3655 FBXL7 Zornitza Stark Classified gene: FBXL7 as Red List (low evidence)
Mendeliome v0.3655 FBXL7 Zornitza Stark Gene: fbxl7 has been classified as Red List (Low Evidence).
Mendeliome v0.3654 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Progressive neurological disorder to Progressive neurological disorder; Leigh-like syndrome
Mendeliome v0.3653 HPDL Zornitza Stark Gene: hpdl has been classified as Green List (High Evidence).
Mendeliome v0.3653 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Neurological disorder to Progressive neurological disorder
Mendeliome v0.3652 HPDL Zornitza Stark Classified gene: HPDL as Green List (high evidence)
Mendeliome v0.3652 HPDL Zornitza Stark Gene: hpdl has been classified as Green List (High Evidence).
Mendeliome v0.3651 NCKAP1L Zornitza Stark Gene: nckap1l has been classified as Green List (High Evidence).
Mendeliome v0.3651 NCKAP1L Zornitza Stark Classified gene: NCKAP1L as Green List (high evidence)
Mendeliome v0.3651 NCKAP1L Zornitza Stark Gene: nckap1l has been classified as Green List (High Evidence).