PanelApp (stage)

Activity

Filter

Cancel
Date Panel Item Activity
80 actions
Miscellaneous Metabolic Disorders v1.28 ALDOB Zornitza Stark gene: ALDOB was added
gene: ALDOB was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: ALDOB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ALDOB were set to Fructose intolerance, hereditary, MIM# 229600
Review for gene: ALDOB was set to GREEN
Added comment: Well established gene-disease association.

Clinical symptoms of HFI include gastrointestinal distress (nausea, vomiting, diarrhea, abdominal pain, anorexia), jaundice, bleeding tendency, renal tubular dysfunction and metabolic disturbances following dietary exposure to fructose, sucrose, or sorbitol. If large quantities of fructose are ingested, lethargy, seizures, and/or progressive coma may ensue. Persistent fructose exposure can result in chronic growth restriction, failure to thrive, renal and hepatic failure, and risk of death.

Symptoms appear in infancy at the time of weaning.

Treatment: Lifelong dietary restriction of fructose, sucrose, and sorbitol.

Assessed as 'strong actionability' by ClinGen.

Of particular note, a 24% sucrose solution (routinely administered to hospitalized neonates for minor procedures) should not be given to neonates known to have HFI. This recommendation is supported by case reports of reported accidental and iatrogenic fructose infusion-related serious organ failure events and/or deaths.

Alerts should be placed in the patient's chart or medical record to notify practitioners to the HFI diagnosis and to the medical risks associated with exposures to fructose and related metabolites. The patient is advised to wear at all times a medically approved alert bracelet/necklace that provides information about the diagnosis of HFI.

Evidence from 50 patients presenting with confirmed and symptomatic HFI shows that upon dietary restriction of fructose, the improvement observed is dramatic: vomiting and gastrointestinal symptoms resolved nearly immediately, bleeding tendency resolves in ~24 hours, renal tubular dysfunction can resolve in as little as 3 days, and clinical and biological findings, with the exception of hepatomegaly, resolved within a few weeks. Normal growth occurred in 2-3 years. In the 50 symptomatic patients and 5 patients who received treatment from birth, liver enlargement persisted in spite of treatment and resolution of fibrosis.
Sources: Expert Review
Miscellaneous Metabolic Disorders v1.26 THAP11 Zornitza Stark gene: THAP11 was added
gene: THAP11 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to 28449119
Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Review for gene: THAP11 was set to RED
Added comment: Single individual reported with homozygous missense variant, supportive functional data.
Sources: Expert Review
Miscellaneous Metabolic Disorders v1.25 ZNF143 Zornitza Stark gene: ZNF143 was added
gene: ZNF143 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF143 were set to 27349184
Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1, MONDO:0002012, ZNF143-related
Review for gene: ZNF143 was set to RED
Added comment: Single individual reported with compound heterozygous variants.
Sources: Expert Review
Miscellaneous Metabolic Disorders v1.19 SLC1A1 Zornitza Stark gene: SLC1A1 was added
gene: SLC1A1 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: SLC1A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC1A1 were set to 21123949
Phenotypes for gene: SLC1A1 were set to Dicarboxylic aminoaciduria, MIM#222730
Review for gene: SLC1A1 was set to AMBER
Added comment: Only two families reported and mouse KO. Rated as LIMITED by ClinGen.
Sources: Expert Review
Miscellaneous Metabolic Disorders v1.17 SLC16A1 Zornitza Stark gene: SLC16A1 was added
gene: SLC16A1 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: SLC16A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SLC16A1 were set to 25390740
Phenotypes for gene: SLC16A1 were set to Monocarboxylate transporter 1 deficiency, MIM# 616095
Review for gene: SLC16A1 was set to GREEN
Added comment: 3 individuals with bi-allelic and 5 with mono-allelic variants reported. Individuals with bi-allelic variants had more severe presentation, including mild ID but unclear if this is primary or secondary to episodes of ketoacidosis.

All patients presented with bouts of ketoacidosis provoked by fasting or infections in the first years of life. Ketoacidotic episodes were preceded by poor feeding and vomiting and were associated with dehydration, which was a consequence of osmotic diuresis and vomiting. In all patients, treatment with intravenous glucose or dextrose, combined with bicarbonate, led to rapid clearance of metabolic acidosis. Early initiation of treatment appeared to prevent ketoacidosis, and ensuring adequate caloric intake reduced the number of episodes. The frequency of ketoacidotic episodes appeared to decrease over time, and none of the patients had documented ketoacidosis after 7 years of age, although some patients had marked ketonuria associated with mild infections.
Sources: Expert Review
Miscellaneous Metabolic Disorders v1.14 FDFT1 Zornitza Stark gene: FDFT1 was added
gene: FDFT1 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: FDFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDFT1 were set to 29909962
Phenotypes for gene: FDFT1 were set to squalene synthase deficiency MONDO:0032566
Review for gene: FDFT1 was set to GREEN
Added comment: Rare disorder of cholesterol biosynthesis, similar to Smith-Lemli-Opitz syndrome. Only 3 individuals with squalene synthase deficiency from 2 families with homozygous/compound heterozygous variants reported. Metabolite profiles from affected individuals suggested a defect at the level of squalene synthase. Reduced protein expression in patient cells.
Sources: Expert Review
Miscellaneous Metabolic Disorders v1.9 NAT8L Krithika Murali gene: NAT8L was added
gene: NAT8L was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: NAT8L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAT8L were set to 11310630; 19807691; 32275776
Phenotypes for gene: NAT8L were set to ?N-acetylaspartate deficiency - MIM#614063
Review for gene: NAT8L was set to AMBER
Added comment: Absence of brain N-acetylaspartate, has been described in only one patient, with truncal ataxia, marked developmental delay, seizures and secondary microcephaly (first described by - PMID: 11310630 Martin et al 2001). PMID: 19807691 - Wiame et al 2009 identified in this patient a homozygous 19 bp NAT8L gene deletion, resulting in a change in reading frame and the absence of production of a functional protein. The affected individual is adopted and testing of the biological parents was not possible. The authors provide supportive functional studies.
Sources: Literature
Miscellaneous Metabolic Disorders v1.9 HIBADH Alison Yeung gene: HIBADH was added
gene: HIBADH was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: HIBADH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIBADH were set to 34176136
Phenotypes for gene: HIBADH were set to organic aciduria
Review for gene: HIBADH was set to RED
Added comment: Single family reported with two siblings presenting with 3-Hydroxyisobutyric aciduria. Male sib with neurodevelopmental symptoms, female sibling asymptomatic. No functional studies
Sources: Literature
Miscellaneous Metabolic Disorders v1.7 GDPAG Bryony Thompson STR: GDPAG was added
STR: GDPAG was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for STR: GDPAG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: GDPAG were set to 30970188
Phenotypes for STR: GDPAG were set to Global developmental delay, progressive ataxia, and elevated glutamine MIM#618412
Review for STR: GDPAG was set to GREEN
STR: GDPAG was marked as clinically relevant
Added comment: NM_014905.5(GLS):c.-212_-210GCA[X]
3 unrelated cases with glutaminase deficiency were compound heterozygous (2) or homozygous for expansion of the repeat, 680-900 repeats in blood samples and 400-110 repeats in fibroblasts. In an analysis of 8295 genomes the median size of the repeat was 14 repeats (8-16 repeats range). There was 1 heterozygous allele with 90 repeats. Functional assays suggest the predominant effect of the repeats is at the level of histone modifications. Epigenetic gene silencing is the mechanism of disease of the repeat. Other variant types are also reported with disease.
Sources: Literature
Miscellaneous Metabolic Disorders v1.4 SLC10A1 Zornitza Stark gene: SLC10A1 was added
gene: SLC10A1 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: SLC10A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC10A1 were set to 24867799; 27882152; 28835676; 29290974; 31201272
Phenotypes for gene: SLC10A1 were set to Familial hypercholanemia-2, MIM#619256
Review for gene: SLC10A1 was set to GREEN
Added comment: IEM characterised by persistently increased plasma levels of conjugated bile salts apparent from infancy. Most patients are asymptomatic and have no liver dysfunction, although some neonates may have transient jaundice or transiently elevated liver enzymes. These abnormalities improve with age. The bile acid defect can result in impaired absorption of fat-soluble vitamins, including D and K, causing decreased bone mineral density or prolonged prothrobin time (PT).

Some variants are recurrent (founder effect likely) but at least 3 different variants reported, mouse model.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.340 SHPK Bryony Thompson gene: SHPK was added
gene: SHPK was added to Miscellaneous Metabolic Disorders. 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
Miscellaneous Metabolic Disorders v0.337 PDXK Bryony Thompson gene: PDXK was added
gene: PDXK was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: PDXK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDXK were set to 32522499; 31187503; 27604308
Phenotypes for gene: PDXK were set to Neuropathy, hereditary motor and sensory, type VIC, with optic atrophy MIM#618511; Disorders of pyridoxine metabolism
Review for gene: PDXK was set to GREEN
Added comment: 6 individuals from 3 unrelated families with biallelic variants, and supporting cellular and biochemical assays.
Sources: Literature
Miscellaneous Metabolic Disorders v0.335 DMGDH Bryony Thompson gene: DMGDH was added
gene: DMGDH was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: DMGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMGDH were set to 11231903; 18937046; 28881522; 27604308
Phenotypes for gene: DMGDH were set to Dimethylglycine dehydrogenase deficiency MIM#605850; Disorders and variants of other enzymes that oxidise xenobiotics
Review for gene: DMGDH was set to AMBER
Added comment: Apparently only 2 cases with biallelic variants reported, and in vitro functional analyses the originally reported variant (H109R)
Sources: Literature
Miscellaneous Metabolic Disorders v0.332 CD320 Bryony Thompson gene: CD320 was added
gene: CD320 was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: CD320 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD320 were set to 29663633; 27604308; 30303736
Phenotypes for gene: CD320 were set to Methylmalonic aciduria, transient, due to transcobalamin receptor defect MIM#613646; Disorders of cobalamin absorption, transport and metabolism
Review for gene: CD320 was set to GREEN
Added comment: At least 9 cases reported with biallelic variants, all but 1 case are homozygous for p.Glu88del. The AF of this variant is ~1% in gnomAD v2.1.1, with 12 homozygotes. However, this is not unexpected given the apparent asymptomatic nature of the metabolic condition. Null mouse model has vitamin B12 deficiency.
Sources: Literature
Miscellaneous Metabolic Disorders v0.327 KHK Bryony Thompson gene: KHK was added
gene: KHK was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: KHK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KHK were set to 7833921; 27604308; 29870677
Phenotypes for gene: KHK were set to Fructosuria MIM#229800; Disorders of fructose metabolism
Review for gene: KHK was set to AMBER
Added comment: Single family with a non-pathogenic phenotype and a supporting mouse model
Sources: Literature
Miscellaneous Metabolic Disorders v0.326 GGT1 Bryony Thompson Added comment: Comment on list classification: Dominant form appears to be a benign metabolic condition. Currently only one recessive family reported, therefore insufficient evidence to determine clinical phenotype.
Miscellaneous Metabolic Disorders v0.323 PREPL Bryony Thompson gene: PREPL was added
gene: PREPL was added to Miscellaneous Metabolic Disorders. Sources: Literature
SV/CNV tags were added to gene: PREPL.
Mode of inheritance for gene: PREPL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PREPL were set to 28726805; 27604308
Phenotypes for gene: PREPL were set to Myasthenic syndrome, congenital, 22 MIM#616224; hypotonia-cystinuria syndrome; Disorders of amino acid transport
Review for gene: PREPL was set to GREEN
Added comment: 5 cases with isolated PREPL deficiency, 3 with hypotonia-cystinuria syndrome, and 2 with atypical hypotonia-cystinuria syndrome
Sources: Literature
Miscellaneous Metabolic Disorders v0.322 SLC36A2 Bryony Thompson changed review comment from: 5 families with iminoglycinuria or hyperglycinuria with classic semidominant inheritance pattern in which 2 nonfunctional alleles conferred the IG phenotype whereas 1 nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype only when combined with haploinsufficiency of the imino acid transporter SLC6A20 or deficiency of the neutral amino acid transporter SLC6A19.
Sources: Literature; to: 5 families with iminoglycinuria or hyperglycinuria with classic semidominant inheritance pattern in which 2 nonfunctional alleles conferred the IG phenotype whereas 1 nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype only when combined with haploinsufficiency of the imino acid transporter SLC6A20 or deficiency of the neutral amino acid transporter SLC6A19. Additional homozygote reported in 2015.
Sources: Literature
Miscellaneous Metabolic Disorders v0.321 SLC36A2 Bryony Thompson gene: SLC36A2 was added
gene: SLC36A2 was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: SLC36A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SLC36A2 were set to 19033659; 26141664; 27604308
Phenotypes for gene: SLC36A2 were set to Hyperglycinuria MIM#138500; Iminoglycinuria, digenic MIM#242600; Disorders of amino acid transport
Review for gene: SLC36A2 was set to GREEN
Added comment: 5 families with iminoglycinuria or hyperglycinuria with classic semidominant inheritance pattern in which 2 nonfunctional alleles conferred the IG phenotype whereas 1 nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype only when combined with haploinsufficiency of the imino acid transporter SLC6A20 or deficiency of the neutral amino acid transporter SLC6A19.
Sources: Literature
Miscellaneous Metabolic Disorders v0.318 GCSH Bryony Thompson gene: GCSH was added
gene: GCSH was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: GCSH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GCSH were set to 1671321; 27604308
Phenotypes for gene: GCSH were set to Glycine encephalopathy MIM#605899; Disorders of serine, glycine or glycerate metabolism
Review for gene: GCSH was set to RED
Added comment: Single case reported
Sources: Literature
Miscellaneous Metabolic Disorders v0.314 PSPH Bryony Thompson gene: PSPH was added
gene: PSPH was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: PSPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSPH were set to 14673469; 25080166; 27604308; 26888760; 25152457
Phenotypes for gene: PSPH were set to Phosphoserine phosphatase deficiency MIM#614023; Disorders of serine, glycine or glycerate metabolism
Review for gene: PSPH was set to GREEN
Added comment: 9 cases in 4 families reported with biallelic variants
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.310 DHTKD1 Bryony Thompson gene: DHTKD1 was added
gene: DHTKD1 was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: DHTKD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHTKD1 were set to 27604308; 23141293; 29661920; 25860818
Phenotypes for gene: DHTKD1 were set to 2-aminoadipic 2-oxoadipic aciduria MIM#204750; Disorders of histidine, tryptophan or lysine metabolism
Review for gene: DHTKD1 was set to GREEN
Added comment: >10 cases with biallelic variants reported and null mouse model has severe metabolic abnormalities
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.309 TDO2 Bryony Thompson gene: TDO2 was added
gene: TDO2 was added to Miscellaneous Metabolic Disorders. Sources: Literature
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: Literature
Miscellaneous Metabolic Disorders v0.299 SUGCT Bryony Thompson gene: SUGCT was added
gene: SUGCT was added to Miscellaneous Metabolic Disorders. Sources: Literature
Mode of inheritance for gene: SUGCT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUGCT were set to 28766179; 18926513; 33483254; 32779420; 27604308
Phenotypes for gene: SUGCT were set to Glutaric aciduria III MIM#231690; Organic acidurias
Review for gene: SUGCT was set to GREEN
Added comment: At least 10 cases reported with glutaric aciduria 3. There is insufficient evidence to define any specific clinical phenotype as attributable to GA3. GA3 is a naturally occurring biochemical trait in mouse models.
Sources: Literature
Miscellaneous Metabolic Disorders v0.292 PCK1 Bryony Thompson gene: PCK1 was added
gene: PCK1 was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: PCK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCK1 were set to 24863970; 28216384; 26971250; 27604308
Phenotypes for gene: PCK1 were set to Phosphoenolpyruvate carboxykinase deficiency, cytosolic MIM#261680; Disorders of gluconeogenesis
Review for gene: PCK1 was set to GREEN
Added comment: 6 cases from 4 families with biallelic variants and supporting biochemical results and in vitro assays
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.284 PINK1 Zornitza Stark gene: PINK1 was added
gene: PINK1 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: PINK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PINK1 were set to 27604308; 15087508; 16207731; 18003639; 18524835
Phenotypes for gene: PINK1 were set to Parkinson disease 6, early onset, MIM# 605909
Review for gene: PINK1 was set to GREEN
Added comment: The PINK1 gene encodes a mitochondrially located serine/threonine kinase. Multiple families reported.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.282 PNP Zornitza Stark gene: PNP was added
gene: PNP was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: PNP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNP were set to 3029074; 1384322; 11453975; 32695102; 32514656
Phenotypes for gene: PNP were set to Immunodeficiency due to purine nucleoside phosphorylase deficiency, MIM# 613179
Review for gene: PNP was set to GREEN
Added comment: Purine nucleoside phosphorylase deficiency is a rare autosomal recessive immunodeficiency disorder characterized mainly by decreased T-cell function. Some patients also have neurologic impairment.

Severity and age of onset dependent on amount of residual activity. Multiple families reported.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.281 POR Zornitza Stark Marked gene: POR as ready
Miscellaneous Metabolic Disorders v0.281 POR Zornitza Stark Gene: por has been classified as Green List (High Evidence).
Miscellaneous Metabolic Disorders v0.281 POR Zornitza Stark Classified gene: POR as Green List (high evidence)
Miscellaneous Metabolic Disorders v0.281 POR Zornitza Stark Gene: por has been classified as Green List (High Evidence).
Miscellaneous Metabolic Disorders v0.280 POR Zornitza Stark gene: POR was added
gene: POR was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: POR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POR were set to 27604308; 14758361; 15793702; 15220035; 15483095; 16470797
Phenotypes for gene: POR were set to Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis 201750; Disordered steroidogenesis due to cytochrome P450 oxidoreductase 613571
Review for gene: POR was set to GREEN
Added comment: Well established gene-disease association.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.278 PRODH Zornitza Stark gene: PRODH was added
gene: PRODH was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: PRODH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRODH were set to 17412540; 12217952
Phenotypes for gene: PRODH were set to Hyperprolinemia, type I 239500; Proline oxidase deficiency
Review for gene: PRODH was set to GREEN
Added comment: At least 5 unrelated families reported.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.274 PSAT1 Zornitza Stark gene: PSAT1 was added
gene: PSAT1 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: PSAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSAT1 were set to 32077105
Phenotypes for gene: PSAT1 were set to Phosphoserine aminotransferase deficiency MIM#610992; Neu-Laxova syndrome 2 MIM#616038
Review for gene: PSAT1 was set to GREEN
Added comment: Severity of disease correlates with residual enzyme activity. Multiple families reported.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.272 RBP4 Zornitza Stark gene: RBP4 was added
gene: RBP4 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: RBP4 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: RBP4 were set to 9888420; 23189188; 25910211; 32323592; 29847795; 29178648; 27892788
Phenotypes for gene: RBP4 were set to Microphthalmia, isolated, with coloboma 10, MIM# 616428; Retinal dystrophy, iris coloboma, and comedogenic acne syndrome, MIM# 615147
Review for gene: RBP4 was set to GREEN
Added comment: Retinol-binding protein (RBP) is a monomeric-binding protein that specifically transports retinol, the alcoholic form of vitamin A, in plasma from its main store site, the liver, to target cells.

At least 4 families with bi-allelic variants and at least 2 families with mono allelic variants. Functional data including animal models.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.269 RPIA Zornitza Stark gene: RPIA was added
gene: RPIA was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: RPIA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPIA were set to 14988808; 31056085; 31247379
Phenotypes for gene: RPIA were set to Ribose 5-phosphate isomerase deficiency, MIM# 608611; Leukoencephalopathy
Review for gene: RPIA was set to GREEN
Added comment: Three unrelated families reported.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.261 GPHN Bryony Thompson gene: GPHN was added
gene: GPHN was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: GPHN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPHN were set to 27604308; 11095995; 22040219; 9812897
Phenotypes for gene: GPHN were set to Molybdenum cofactor deficiency C MIM#615501; Disorders of molybdenum cofactor metabolism
Review for gene: GPHN was set to GREEN
Added comment: 4 cases in 2 unrelated families and a supporting null mouse model.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.253 MTHFR Bryony Thompson gene: MTHFR was added
gene: MTHFR was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: MTHFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFR were set to 27604308; 7920641
Phenotypes for gene: MTHFR were set to Homocystinuria due to MTHFR deficiency MIM#236250; Disorders of folate metabolism and transport
Review for gene: MTHFR was set to GREEN
gene: MTHFR was marked as current diagnostic
Added comment: Well-established gene-disease association(see OMIM entry). Homocystinuria due to MTHFR deficiency is classified as a metabolic disorder by NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of folate metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.251 MSMO1 Bryony Thompson gene: MSMO1 was added
gene: MSMO1 was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: MSMO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MSMO1 were set to 27604308; 21285510; 24144731; 33161406; 28673550
Phenotypes for gene: MSMO1 were set to Microcephaly, congenital cataract, and psoriasiform dermatitis MIM#616834; Disorders of the metabolism of sterols
Review for gene: MSMO1 was set to GREEN
gene: MSMO1 was marked as current diagnostic
Added comment: 5 cases in 4 unrelated families reported, with supporting biochemical assays demonstrating an inborn error of sterol metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.245 MMADHC Bryony Thompson gene: MMADHC was added
gene: MMADHC was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: MMADHC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMADHC were set to 27604308; 18385497
Phenotypes for gene: MMADHC were set to Homocystinuria, cblD type, variant 1 MIM#277410; Methylmalonic aciduria and homocystinuria, cblD type MIM#277410; Methylmalonic aciduria, cblD type, variant 2 MIM#277410; Disorders of cobalamin absorption, transport and metabolism
Review for gene: MMADHC was set to GREEN
gene: MMADHC was marked as current diagnostic
Added comment: Well-established gene-disease association(see OMIM entry). Methylmalonic acidemia with homocystinuria is classified as a metabolic disorder by NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of vitamin metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.243 MMACHC Bryony Thompson gene: MMACHC was added
gene: MMACHC was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: MMACHC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMACHC were set to 27604308; 16311595
Phenotypes for gene: MMACHC were set to Methylmalonic aciduria and homocystinuria, cblC type MIM#277400; Disorders of cobalamin absorption, transport and metabolism
Review for gene: MMACHC was set to GREEN
gene: MMACHC was marked as current diagnostic
Added comment: Well-established gene-disease association(see OMIM entry). Methylmalonic acidemia with homocystinuria is classified as a metabolic disorder by NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of vitamin metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.239 SC5D Zornitza Stark gene: SC5D was added
gene: SC5D was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: SC5D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SC5D were set to 17853487; 12189593; 12812989; 24142275
Phenotypes for gene: SC5D were set to Lathosterolosis, MIM# 607330
Review for gene: SC5D was set to GREEN
Added comment: Lathosterolosis (LATHOS) is an autosomal recessive disorder characterized by a recognizable pattern of multiple congenital anomalies involving axial and appendicular skeleton, liver, central nervous and urogenital systems, and lysosomal storage. It is caused by a defect of cholesterol biosynthesis due to sterol C5-desaturase deficiency.

More than 5 unrelated families reported.
Sources: Expert Review
Miscellaneous Metabolic Disorders v0.234 SLC2A1 Zornitza Stark gene: SLC2A1 was added
gene: SLC2A1 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: SLC2A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SLC2A1 were set to GLUT1 deficiency syndrome 1, infantile onset, severe, 606777; GLUT1 deficiency syndrome 2, childhood onset, 612126; Disorders of glucose transport
Review for gene: SLC2A1 was set to GREEN
Added comment: Well established gene disease association.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.231 SLC30A10 Zornitza Stark gene: SLC30A10 was added
gene: SLC30A10 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: SLC30A10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A10 were set to 22341972
Phenotypes for gene: SLC30A10 were set to Hypermanganesemia with dystonia 1, MIM# 613280
Review for gene: SLC30A10 was set to GREEN
Added comment: Hypermanganesemia with dystonia-1 (HMNDYT1) is an autosomal recessive metabolic disorder characterized by increased serum manganese, motor neurodegeneration with extrapyramidal features, polycythemia, and hepatic dysfunction, which leads to cirrhosis in some cases. Intellectual function is preserved.

More than 5 unrelated families reported.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.229 SLC39A14 Zornitza Stark gene: SLC39A14 was added
gene: SLC39A14 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: SLC39A14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A14 were set to 27231142; 29685658
Phenotypes for gene: SLC39A14 were set to Hypermanganesemia with dystonia 2, MIM# 617013
Review for gene: SLC39A14 was set to GREEN
Added comment: Hypermanganesemia with dystonia-2 (HMNDYT2) is an autosomal recessive neurodegenerative disorder characterized predominantly by loss of motor milestones in the first years of life. Affected individuals then develop rapidly progressive abnormal movements, including dystonia, spasticity, bulbar dysfunction, and variable features of parkinsonism, causing loss of ambulation. Cognition may be impaired, but is better preserved than motor function. The disorder results from abnormal accumulation of manganese (Mn), which is toxic to neurons. Chelation therapy, if started early, may provide clinical benefit.

More than 5 unrelated families reported.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.227 SLC39A4 Zornitza Stark gene: SLC39A4 was added
gene: SLC39A4 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: SLC39A4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A4 were set to 27604308; 12068297
Phenotypes for gene: SLC39A4 were set to Acrodermatitis enteropathica MIM#201100; (Disorder of zinc metabolism)
Review for gene: SLC39A4 was set to GREEN
Added comment: More than 3 unrelated families reported.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.224 SLC46A1 Zornitza Stark gene: SLC46A1 was added
gene: SLC46A1 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: SLC46A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC46A1 were set to 17446347; 17129779; 21333572
Phenotypes for gene: SLC46A1 were set to Folate malabsorption, hereditary, MIM# 229050
Review for gene: SLC46A1 was set to GREEN
Added comment: 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.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.222 SLC5A1 Zornitza Stark gene: SLC5A1 was added
gene: SLC5A1 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: SLC5A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC5A1 were set to 27604308; 2008213; 8195156; 20486940
Phenotypes for gene: SLC5A1 were set to Glucose/galactose malabsorption MIM# 606824; (Disorders of glucose transport)
Review for gene: SLC5A1 was set to GREEN
Added comment: At least 3 unrelated families reported, presentation is with osmotic diarrhoea.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.217 SLC5A6 Zornitza Stark gene: SLC5A6 was added
gene: SLC5A6 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: SLC5A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC5A6 were set to 29669219; 23104561; 31754459; 27904971; 31392107
Phenotypes for gene: SLC5A6 were set to SLC5A6-related Neurodevelopmental Disorder
Review for gene: SLC5A6 was set to GREEN
Added comment: At least 5 variants published in three unrelated famililies (4 cases total) with SLC5A6-related Neurodevelopmental Disorder, together with supportive functional studies (PMID 29669219; 23104561). One of the cases had mixed semiology seizures including focal dyscognitive, absence, tonic spasms and generalised convulsive seizures with electrographic features of encephalopathy with generalised and independent multifocal spike-wave discharges (PMID 31754459), another case had brain, immune, bone and intestinal dysfunction (PMID 27904971) and the third had metabolic dysfunction mimicking biotinidase deficiency (PMID 31392107). This condition could be treated with biotin supplementation and introduction of pantothenic acid supplementation (PMID 31392107).
Sources: Expert list
Miscellaneous Metabolic Disorders v0.215 SLC6A19 Zornitza Stark gene: SLC6A19 was added
gene: SLC6A19 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: SLC6A19 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SLC6A19 were set to Hartnup disorder, MIM# 234500; Hyperglycinuria, MIM# 138500; Iminoglycinuria, MIM# 242600
Review for gene: SLC6A19 was set to GREEN
Added comment: Bi-allelic variants associated with Hartnup disorder, which is characterised by impaired transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa. Symptoms include transient manifestations of pellagra, cerebellar ataxia, and psychosis.

Hyperglycinuria/iminoglycinuria: The imino acids, proline and hydroxyproline, share a renal tubular reabsorptive mechanism with glycine. Iminoglycinuria is a benign inborn error of amino acid transport, and is also a normal finding in neonates and infants under 6 months of age (Chesney, 2001). Early studies of families with iminoglycinuria suggested genetic complexity, with homozygotes developing IG and heterozygotes manifesting only hyperglycinuria (HG)
Sources: Expert list
Miscellaneous Metabolic Disorders v0.210 MCEE Bryony Thompson gene: MCEE was added
gene: MCEE was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: MCEE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCEE were set to 27604308; 16752391; 32521958; 31146325; 32719376; 30682498
Phenotypes for gene: MCEE were set to Methylmalonyl-CoA epimerase deficiency MIM#251120; Organic acidurias
Review for gene: MCEE was set to GREEN
gene: MCEE was marked as current diagnostic
Added comment: Over 10 cases with biallelic variants reported. Methylmalonic acidemia is classified as a metabolic disorder by NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of amino acid and peptide metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.202 LMBRD1 Bryony Thompson gene: LMBRD1 was added
gene: LMBRD1 was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: LMBRD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMBRD1 were set to 19136951; 27604308
Phenotypes for gene: LMBRD1 were set to Methylmalonic aciduria and homocystinuria, cblF type MIM#277380; Disorders of cobalamin absorption, transport and metabolism
Review for gene: LMBRD1 was set to GREEN
gene: LMBRD1 was marked as current diagnostic
Added comment: Well-established gene-disease association (see OMIM entry). Methylmalonic aciduria and homocystinuria is a disorder of cobalamin metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.196 LARS Bryony Thompson gene: LARS was added
gene: LARS was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 22607940; 30349989; 28774368
Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1 MIM#615438; disorder of leucine metabolism
Review for gene: LARS was set to GREEN
Added comment: 7 families reported
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.194 KYNU Bryony Thompson gene: KYNU was added
gene: KYNU was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: KYNU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KYNU were set to 17334708; 28792876; 31923704
Phenotypes for gene: KYNU were set to Hydroxykynureninuria MIM#236800; Vertebral, cardiac, renal, and limb defects syndrome 2 MIM#617661; Disorders of histidine, tryptophan or lysine metabolism
Review for gene: KYNU was set to GREEN
Added comment: At least 6 unrelated cases reported with biallelic variants, and a supporting null mouse model
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.180 HAAO Bryony Thompson gene: HAAO was added
gene: HAAO was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: HAAO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HAAO were set to 28792876
Phenotypes for gene: HAAO were set to Vertebral, cardiac, renal, and limb defects syndrome 1 MIM#617660; NAD deficiency
Review for gene: HAAO was set to GREEN
Added comment: 2 unrelated cases reported with homozygous variants from consanguineous families, and a supporting mouse model.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.176 GPD1 Bryony Thompson gene: GPD1 was added
gene: GPD1 was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: GPD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPD1 were set to 32591995; 22226083; 33447932
Phenotypes for gene: GPD1 were set to Hypertriglyceridemia, transient infantile MIM#614480; glycerol-3-phosphate dehydrogenase deficiency
Review for gene: GPD1 was set to GREEN
gene: GPD1 was marked as current diagnostic
Added comment: At least 17 cases reported
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.174 GNMT Bryony Thompson gene: GNMT was added
gene: GNMT was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: GNMT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNMT were set to 11810299; 14739680; 17937387; 27207470
Phenotypes for gene: GNMT were set to Glycine N-methyltransferase deficiency MIM#606664; Disorders of the metabolism of sulphur amino acids
Review for gene: GNMT was set to GREEN
Added comment: Only 5 cases in 4 families reported thus far, and a supporting null mouse model. The clinical presentation of the reported cases (mild hepatomegaly and chronic elevation of the transaminase levels in the blood without liver disease) suggests a benign disorder, however hypermethioninemia is a reported risk factor for various neurological complications regardless of the cause.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.173 GLYCTK Bryony Thompson changed review comment from: At least 4 unrelated cases reported
Sources: NHS GMS; to: At least 4 unrelated cases reported. D-glyceric aciduria is classified as a metabolic disorder by the NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of amino acid metabolism
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.172 GLYCTK Bryony Thompson gene: GLYCTK was added
gene: GLYCTK was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: GLYCTK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLYCTK were set to 20949620; 31837836
Phenotypes for gene: GLYCTK were set to D-glyceric aciduria MIM#220120; Disorders of serine, glycine or glycerate metabolism
Review for gene: GLYCTK was set to GREEN
gene: GLYCTK was marked as current diagnostic
Added comment: At least 4 unrelated cases reported
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.170 GLUL Bryony Thompson gene: GLUL was added
gene: GLUL was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: GLUL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLUL were set to 16267323; 21353613; 33150193
Phenotypes for gene: GLUL were set to Glutamine deficiency, congenital MIM#610015; disorder of amino acid metabolism
Review for gene: GLUL was set to GREEN
gene: GLUL was marked as current diagnostic
Added comment: At least 5 cases in 4 families have been reported with glutamine deficiency.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.158 GIF Bryony Thompson gene: GIF was added
gene: GIF was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: GIF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GIF were set to 27604308; 14695536; 14576042
Phenotypes for gene: GIF were set to Intrinsic factor deficiency MIM#261000; Disorders of cobalamin absorption, transport and metabolism
Review for gene: GIF was set to GREEN
gene: GIF was marked as current diagnostic
Added comment: Well-established gene-disease association (see OMIM entry). Intrinsic factor deficiency is classified as a metabolic disorder by the NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of vitamin metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.156 GCLC Bryony Thompson gene: GCLC was added
gene: GCLC was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: GCLC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GCLC were set to 27604308; 10515893; 18024385; 11118286; 10733484; 12663448
Phenotypes for gene: GCLC were set to Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency MIM#230450; Disorders of the gamma-glutamyl cycle
Review for gene: GCLC was set to GREEN
gene: GCLC was marked as current diagnostic
Added comment: At least 9 cases reported and a mouse model. GCLC deficiency is an inborn error of amino acid and peptide metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.148 GALM Bryony Thompson gene: GALM was added
gene: GALM was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: GALM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALM were set to 30451973; 30910422
Phenotypes for gene: GALM were set to Galactosemia IV MIM#618881; Disorders of galactose metabolism
Review for gene: GALM was set to GREEN
gene: GALM was marked as current diagnostic
Added comment: 8 unrelated cases with galactosaemia and supporting in vitro assays. GALM deficiency is an inborn error of galactose metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.137 AMN Bryony Thompson gene: AMN was added
gene: AMN was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: AMN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMN were set to 12590260
Phenotypes for gene: AMN were set to Imerslund-Grasbeck syndrome 2 MIM#618882; Disorders of cobalamin absorption, transport and metabolism
Review for gene: AMN was set to GREEN
gene: AMN was marked as current diagnostic
Added comment: Well-established gene-disease association (see OMIM entry). AMN-related intrinsic factor receptor deficiency (Imerslund-Grasbeck syndrome) is classified as a metabolic disorder by the NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of vitamin metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.127 DHODH Bryony Thompson gene: DHODH was added
gene: DHODH was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: DHODH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHODH were set to 19915526
Phenotypes for gene: DHODH were set to Miller syndrome MIM#263750; Disorders of pyrimidine metabolism
Review for gene: DHODH was set to GREEN
gene: DHODH was marked as current diagnostic
Added comment: >3 cases reported. Biallelic variants cause an inborn error of pyrimidine metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.123 DHCR24 Bryony Thompson gene: DHCR24 was added
gene: DHCR24 was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: DHCR24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHCR24 were set to 11519011; 21559050; 21671375
Phenotypes for gene: DHCR24 were set to Desmosterolosis MIM#602398; Disorders of the metabolism of sterols
Review for gene: DHCR24 was set to GREEN
gene: DHCR24 was marked as current diagnostic
Added comment: At least 4 families reported. Desmosterolosis is classified as a metabolic disorder by the NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of sterol metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.121 DCXR Bryony Thompson gene: DCXR was added
gene: DCXR was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: DCXR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCXR were set to 22042873
Phenotypes for gene: DCXR were set to Pentosuria MIM#260800; Disorders of pentose metabolism
Review for gene: DCXR was set to GREEN
Added comment: At least 9 Ashkenazi Jewish probands reported. The condition is clinically benign
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.115 CUBN Bryony Thompson gene: CUBN was added
gene: CUBN was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: CUBN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CUBN were set to 10080186; 31613795
Phenotypes for gene: CUBN were set to Proteinuria, chronic benign MIM#618884; Imerslund-Grasbeck syndrome 1 MIM#261100; Intrinsic factor receptor deficiency due to CUBN mutations (Disorders of cobalamin absorption, transport and metabolism)
Review for gene: CUBN was set to GREEN
gene: CUBN was marked as current diagnostic
Added comment: Well-established gene-disease associations (see OMIM entry). CUBN deficiency causes an inborn error of cobalamin metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.111 CTH Bryony Thompson gene: CTH was added
gene: CTH was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: CTH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTH were set to 12574942; 20584029; 24761004; 15151507
Phenotypes for gene: CTH were set to Cystathioninuria MIM#219500
Review for gene: CTH was set to RED
Added comment: >3 cases reported with cystathioninuria with no striking pathologic features. Due to inconsistency and wide variety of disease associations, it is considered to be a benign biochemical anomaly. Null mouse model demonstrates homocysteinemia/cystathioninemia but develop with no apparent abnormality.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.97 BCKDK Bryony Thompson gene: BCKDK was added
gene: BCKDK was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: BCKDK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCKDK were set to 22956686; 24449431
Phenotypes for gene: BCKDK were set to Branched-chain ketoacid dehydrogenase kinase deficiency MIM#614923; disorder of branched-chain amino acid metabolism
Review for gene: BCKDK was set to GREEN
Added comment: 5 unrelated families with homozygous variants and supporting functional assays on patient-derived cells.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.95 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
Miscellaneous Metabolic Disorders v0.94 BCAT2 Bryony Thompson gene: BCAT2 was added
gene: BCAT2 was added to Miscellaneous Metabolic Disorders. 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
Miscellaneous Metabolic Disorders v0.77 SUOX Zornitza Stark gene: SUOX was added
gene: SUOX was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: SUOX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUOX were set to 9428520; 15952210; 31127934]
Phenotypes for gene: SUOX were set to Sulfite oxidase deficiency, MIM# 272300
Review for gene: SUOX was set to GREEN
Added comment: More than 5 unrelated families reported.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.69 UGT1A1 Zornitza Stark gene: UGT1A1 was added
gene: UGT1A1 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: UGT1A1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: UGT1A1 were set to Bilirubin UDP-glucuronosyltransferase 1 deficiency (Disorders of bile acid metabolism and transport); Crigler-Najjar syndrome, type I 218800; Crigler-Najjar syndrome, type II 606785
Review for gene: UGT1A1 was set to GREEN
Added comment: Well established gene-disease association.
Sources: Expert Review
Miscellaneous Metabolic Disorders v0.59 WDR45 Zornitza Stark gene: WDR45 was added
gene: WDR45 was added to Miscellaneous Metabolic Disorders. Sources: Expert list
Mode of inheritance for gene: WDR45 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: WDR45 were set to 23176820
Phenotypes for gene: WDR45 were set to Neurodegeneration with brain iron accumulation 5, MIM# 300894
Review for gene: WDR45 was set to GREEN
Added comment: The WDR45 gene has an important role in the autophagy pathway, which is the major intracellular degradation system by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation.

More than 20 unrelated individuals reported. XLD.
Sources: Expert list
Miscellaneous Metabolic Disorders v0.43 ALDH6A1 Bryony Thompson gene: ALDH6A1 was added
gene: ALDH6A1 was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: ALDH6A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH6A1 were set to 32151545; 10947204; 21863277; 23835272
Phenotypes for gene: ALDH6A1 were set to Methylmalonate semialdehyde dehydrogenase deficiency MIM#614105; disorder of valine and pyrimidine metabolism
Review for gene: ALDH6A1 was set to GREEN
gene: ALDH6A1 was marked as current diagnostic
Added comment: At least 5 unrelated cases reported. Inborn error of valine and pyrimidine catabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.39 ALDH4A1 Bryony Thompson gene: ALDH4A1 was added
gene: ALDH4A1 was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: ALDH4A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH4A1 were set to 9700195; 31884946
Phenotypes for gene: ALDH4A1 were set to Hyperprolinemia, type II MIM#239510; disorders of ornithine or proline metabolism
Review for gene: ALDH4A1 was set to GREEN
gene: ALDH4A1 was marked as current diagnostic
Added comment: At least 4 unrelated cases reported. Biallelic variants cause an inborn error or ornithine/proline metabolism.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.24 AKR1D1 Bryony Thompson gene: AKR1D1 was added
gene: AKR1D1 was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: AKR1D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AKR1D1 were set to 12970144; 20522910; 15030995
Phenotypes for gene: AKR1D1 were set to Bile acid synthesis defect, congenital, 2 MIM#235555
Review for gene: AKR1D1 was set to GREEN
gene: AKR1D1 was marked as current diagnostic
Added comment: Inborn error of bile acid metabolism. At least 6 cases (with 5 variants) in 5 families reported.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.22 AHCY Bryony Thompson gene: AHCY was added
gene: AHCY was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: AHCY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AHCY were set to 28779239; 26095522; 20852937; 15024124; 27626380
Phenotypes for gene: AHCY were set to Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase MIM#613752
Review for gene: AHCY was set to GREEN
gene: AHCY was marked as current diagnostic
Added comment: S-adenosylhomocysteine hydrolase deficiency causes an inborn error in methionine metabolism. >3 cases reported with biallelic variants. Mouse model is homozygous-lethal.
Sources: NHS GMS
Miscellaneous Metabolic Disorders v0.4 ABCD4 Bryony Thompson gene: ABCD4 was added
gene: ABCD4 was added to Miscellaneous Metabolic Disorders. Sources: NHS GMS
Mode of inheritance for gene: ABCD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCD4 were set to 22922874; 31113616; 30651581; 28572511
Phenotypes for gene: ABCD4 were set to Methylmalonic aciduria and homocystinuria, cblJ type MIM#614857
Review for gene: ABCD4 was set to GREEN
Added comment: Inborn error of vitamin B12 metabolism - >3 unrelated cases and a supporting mouse model
PMID: 22922874 - 2 unrelated cases with biallelic variants. Expression of wildtype ABCD4 in patient fibroblasts led to rescue of the biochemical phenotype.
PMID: 30651581 - a Chinese case with a homozygous variant c.423C>G (p.Asn141Lys)
PMID: 28572511 - 1 compound het case with supporting functional assays
PMID: 31113616 - abcd4 null zebrafish model leads to vitamin B 12-deficiency anemia
Sources: NHS GMS