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Undiagnosed metabolic disorders v1.615 G6PC Arina Puzriakova Phenotypes for gene: G6PC were changed from Glycogen storage disease type 1a, von Gierke (Glycogen storage disorders); fasting intolerance with enlarged liver, renal tubular disease; Glycogen storage disease Ia, 232200; Glycogen Storage Disease Type I; Glycogen Storage Disorders- Liver; Glycogen Storage Disease; Glycogen Storage Disease Ia to Glycogen storage disease Ia, OMIM:232200
Undiagnosed metabolic disorders v1.614 ALAS2 Arina Puzriakova Phenotypes for gene: ALAS2 were changed from X-linked dominant protoporphyria (Porphyrias with acute painful photosensitivity); X-linked sideroblastic anaemia (XLSA) (Porphyrias with acute painful photosensitivity); Erythropoietic protoporphyria, mild variant to Anemia, sideroblastic, 1, OMIM:300751; Protoporphyria, erythropoietic, X-linked, OMIM:300752
Undiagnosed metabolic disorders v1.613 SLC6A19 Tracy Lester reviewed gene: SLC6A19: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Undiagnosed metabolic disorders v1.608 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Undiagnosed metabolic disorders v1.607 ATP5E Sarah Leigh edited their review of gene: ATP5E: Added comment: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; Changed rating: GREEN; Changed publications to: 27604308, 34954817, 20566710
Undiagnosed metabolic disorders v1.607 PIGM Sarah Leigh Tag non-coding-known-pathogenic tag was added to gene: PIGM.
Undiagnosed metabolic disorders v1.607 PIGM Sarah Leigh changed review comment from: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; to: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).
Undiagnosed metabolic disorders v1.606 PIGM Sarah Leigh edited their review of gene: PIGM: Added comment: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; Changed rating: GREEN
Undiagnosed metabolic disorders v1.604 SEC23B Arina Puzriakova Phenotypes for gene: SEC23B were changed from COPII component SEC23B (Disorders of multiple glycosylation and other glycosylation pathways, V-ATPase deficiencies); Dyserythropoietic anemia, congenital, type II 224100 to Dyserythropoietic anemia, congenital, type II, OMIM:224100; COPII component SEC23B (Disorders of multiple glycosylation and other glycosylation pathways, V-ATPase deficiencies)
Undiagnosed metabolic disorders v1.603 SEC23B Arina Puzriakova Added comment: Comment on mode of inheritance: There is limited evidence linking this gene with Cowden syndrome (monoallelic variants). Only one family has been reported to date (PMID:26522472). This gene:disease association is provisional in OMIM, 'limited' disease confidence category in G2P and is not listed in ClinGen (whereas CDAII is). Biallelic phenotype remains relevant to this panel (PMID: 35163229).

On this basis, updating the MOI from 'Both mono- and biallelic' to 'Biallelic' only.
Undiagnosed metabolic disorders v1.603 SEC23B Arina Puzriakova Mode of inheritance for gene: SEC23B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.600 SLC6A20 Sarah Leigh edited their review of gene: SLC6A20: Added comment: The gene disease associations of SLC6A20 with Hyperglycinuria (OMIM:138500) and Iminoglycinuria, digenic (OMIM:242600) have been refuted in OMIM. The single SLC6A20 variant rs17279437 has been reclassified as a polymorphism, because it is present in 19,986 of 278,932 alleles and in 856 homozygotes in the gnomAD database (v2.1.1), for an allele frequency of 0.07165 (Personal Communication to OMIM from Hamosh, A. Baltimore, Md. 3rd April 2023).; Changed rating: RED; Changed phenotypes to: Hyperglycinuria 138500, Iminoglycinuria, digenic 242600
Undiagnosed metabolic disorders v1.599 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Disorders of CoQ10 biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Coenzyme Q10 deficiency, primary, 7; Disorders of ubiquinone metabolism and biosynthesis to Coenzyme Q10 deficiency, primary, 7, OMIM:616276
Undiagnosed metabolic disorders v1.596 SLC12A3 Sarah Leigh commented on gene: SLC12A3: Heterozygous digenic SLC12A3 and CLCNKB variants have been associated with a variant of Gitelman syndrome (PMID: 26770037;30999883). However, the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Undiagnosed metabolic disorders v1.596 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.595 SLC22A5 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).; to: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BIALLELIC, autosomal or pseudoautosomal. Although, heterozygous SLC22A5 variants have been seen in a few cases, these are detectable biochemically and are not associated with clear clinical presentation (PMID: 10545605; 11261427).
Undiagnosed metabolic disorders v1.594 SLC22A5 Sarah Leigh Phenotypes for gene: SLC22A5 were changed from Carnitine transporter deficiency (Disorders of carnitine transport and the carnitine cycle); Propionicacidemia to Carnitine deficiency, systemic primary, OMIM:212140; systemic primary carnitine deficiency disease, MONDO:0008919
Undiagnosed metabolic disorders v1.592 SLC22A5 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for SLC22A5 variants should be BOTH Monoallelic and Biallelic. Although, most of the evidence for symptoms associated SLC22A5 are seen in a patients with biallelic variants (HGNC:10969, OMIM:603377, Gen2Phen, Orphanet:118781, ClinGen), a few individuals heterozygous for SLC22A5 variants have been seen with a milder phenotype (PMID: 10545605; 11261427).
Undiagnosed metabolic disorders v1.592 SLC22A5 Sarah Leigh Mode of inheritance for gene: SLC22A5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.586 OGDH Sarah Leigh reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.585 OGDH Sarah Leigh Phenotypes for gene: OGDH were changed from 2-Oxoglutarate dehydrogenase deficiency (Disorders of the citric acid cycle); Alpha-ketoglutarate dehydrogenase deficiency, 203740; (OXOGLUTARIC ACIDURIA) to Alpha-ketoglutarate dehydrogenase deficiency, OMIM:203740; oxoglutaricaciduria, MONDO:0008759
Undiagnosed metabolic disorders v1.581 PC Arina Puzriakova Phenotypes for gene: PC were changed from Pyruvate carboxylase deficiency (Disorders of gluconeogenesis); lactic acidosis, hypotonia, encephalopathy; Pyruvate carboxylase deficiency 266150; Pyruvate carboxylase deficiency to Pyruvate carboxylase deficiency, OMIM:266150
Undiagnosed metabolic disorders v1.579 SUCLA2 Arina Puzriakova Phenotypes for gene: SUCLA2 were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonicaciduria), 612073; Mitochondrial DNA Depletion Syndrome to Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), OMIM:612073; Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity
Undiagnosed metabolic disorders v1.574 SPG7 Sarah Leigh Mode of inheritance for gene: SPG7 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.573 SPG7 Sarah Leigh edited their review of gene: SPG7: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. Numerous biallelic SPG7 variants have been reported (PMIDs: 9635427; 16534102; 17646629; 18200586, 20186691; 22571692) and at least five monoallelic SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (PMIDs: 18200586; 22571692). For this reason, the mode of inheritance for this gene should be BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form) autosomal or pseudoautosomal.; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.571 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Isolated complex IV deficiency; Leigh syndrome due to cytochrome c oxidase deficiency, 256000Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2, 615119; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Undiagnosed metabolic disorders v1.570 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Isolated complex IV deficiency; Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due to cytochrome coxidase deficiency; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046; Encephalopathy, progressive mitochondrial, with proximal renal tubulopathy due to cytochrome coxidase deficiency
Undiagnosed metabolic disorders v1.567 GPHN Arina Puzriakova Phenotypes for gene: GPHN were changed from Mo cofactor deficiency, complementation group C (Disorders of molybdenum cofactor metabolism); epileptic encephalopathy; Molybdenum cofactor deficiency C 615501 to Molybdenum cofactor deficiency C, OMIM:615501; Mo cofactor deficiency, complementation group C (Disorders of molybdenum cofactor metabolism)
Undiagnosed metabolic disorders v1.563 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from ST3GAL3-CDG (Disorders of protein N-glycosylation); Intellectual disability to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Undiagnosed metabolic disorders v1.561 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia, autosomal dominant, 3, 609286; Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions (monoallelic); Mitochondrial Membrane Protein-Associated Neurodegeneration (biallelic); Mitochondrial DNA Depletion Syndrome (biallelic) to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Undiagnosed metabolic disorders v1.559 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Complex II (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Isolated complex II deficiency; Leigh syndrome, 256000; Mitochondrial respiratory chain complex II deficiency, 252011; Cardiomyopathy, dilated, 1GG, 613642; Paragangliomas 5, 614165; Mitochondrial Respiratory Chain Complex II Deficiency to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Undiagnosed metabolic disorders v1.558 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4,610131; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Undiagnosed metabolic disorders v1.557 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Undiagnosed metabolic disorders v1.552 LYRM4 Arina Puzriakova reviewed gene: LYRM4: Rating: GREEN; Mode of pathogenicity: ; Publications: 31497476, 23814038; Phenotypes: Combined oxidative phosphorylation deficiency 19, OMIM: 615595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.551 SDHA Arina Puzriakova Added comment: Comment on mode of inheritance: This gene was recently included on a gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) on behalf of GMS Mitochondrial providers, indicating that the MOI should be updated from 'biallelic' only to 'both mono- and biallelic' on Mitochondrial GMS panels (R354 and R63). As there was sufficient supporting evidence for the change, the MOI has also been updated to 'both' on this panel to ensure all panels reflect correct knowledge. Heterozygous variants can be associated with abnormal mitochondrial accumulation and therefore also within the scope of the panel.
Undiagnosed metabolic disorders v1.551 SDHA Arina Puzriakova Mode of inheritance for gene: SDHA was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.547 NDUFA12 Arina Puzriakova Added comment: Comment on list classification: Gene was recently upgraded from Amber to Green on GMS panels and therefore also updating the rating here to ensure all panels display correct knowledge.
Undiagnosed metabolic disorders v1.546 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21617257, 33715266, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.546 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from Complex V (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); ?Combined oxidative phosphorylation deficiency 22 616045; ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4 615228 to Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228
Undiagnosed metabolic disorders v1.545 ATP5A1 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to support this gene-disease association and therefore ATP5A1 has been promoted to Green.
Undiagnosed metabolic disorders v1.543 ATP5A1 Arina Puzriakova Added comment: Comment on mode of inheritance: Two families (with two affected sibs each) reported with recessive variants and supported by functional studies (PMIDs: 23599390; 23596069). Six unrelated patients have been reported with heterozygous variants; including one recurrent variant c.620G>A in four cases, c.545G>A and c.1037C>T in the remaining two, respectively (PMIDs: 34483339; 34954817).
Undiagnosed metabolic disorders v1.543 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.542 APOB Arina Puzriakova Mode of inheritance for gene: APOB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.541 APOA5 Arina Puzriakova Mode of inheritance for gene: APOA5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.540 ALDH18A1 Arina Puzriakova Mode of inheritance for gene: ALDH18A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.539 DHTKD1 Arina Puzriakova Mode of inheritance for gene: DHTKD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.538 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Undiagnosed metabolic disorders v1.538 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Undiagnosed metabolic disorders v1.538 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Undiagnosed metabolic disorders v1.538 TTC37 Sarah Leigh commented on gene: TTC37: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.
Undiagnosed metabolic disorders v1.538 SKIV2L Sarah Leigh commented on gene: SKIV2L: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.
Undiagnosed metabolic disorders v1.538 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
Undiagnosed metabolic disorders v1.537 SLC37A4 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'biallelic' to 'both mono- and biallelic' to the next GMS panel update.

Biallelic LOF variants in this gene cause glycogen storage disorder while monoallelic variants in SLC37A4 are linked to a congenital disorder of glycosylation in OMIM (MIM# 619525) and G2P (definitive disease confidence). Therefore both inheritance patterns are relevant to this panel.
Undiagnosed metabolic disorders v1.537 SLC37A4 Arina Puzriakova Mode of inheritance for gene: SLC37A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.535 ACO2 Sarah Leigh Added comment: Comment on mode of inheritance: PMID: 34056600 reports 61 cases of genetically unsolved inherited optic neuropathies who were harbouring variants in ACO2, of which 50 carried dominant variants (the remaining 11 cases were biallelic). The authors state that this is the first report of monoallelic pathogenic ACO2 variants resulting in dominant optic atrophy.
Undiagnosed metabolic disorders v1.535 ACO2 Sarah Leigh Mode of inheritance for gene: ACO2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.534 PRODH Sarah Leigh Added comment: Comment on list classification: Evidence for the association of PRODH variants with Hyperprolinemia, type I, OMIM; 239500 has been classified as Definitive by ClinGen Aminoacidopathy Gene Curation Expert Panel on 04/27/2021
(https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f28c677-a9b4-4bb3-9aed-14af97ad9896-2021-04-27T160000.000Z).
Undiagnosed metabolic disorders v1.533 PRODH Sarah Leigh Phenotypes for gene: PRODH were changed from Hyperprolinaemia type I (Disorders of ornithine or proline metabolism); Hyperprolinemia, type I 239500 to Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400
Undiagnosed metabolic disorders v1.532 MT-TH Arina Puzriakova Tag gene-checked tag was added to gene: MT-TH.
Undiagnosed metabolic disorders v1.532 FH Arina Puzriakova Phenotypes for gene: FH were changed from Fumarase deficiency (Disorders of the citric acid cycle); Fumarase deficiency, 606812 to Fumarase deficiency, OMIM:606812; Disorders of the citric acid cycle
Undiagnosed metabolic disorders v1.531 SLC16A1 Sarah Leigh changed review comment from: Comment on phenotypes: mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7; to: Comment on phenotypes: Previous phenotype entry: mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7
Undiagnosed metabolic disorders v1.531 SLC16A1 Sarah Leigh edited their review of gene: SLC16A1: Changed phenotypes to: Erythrocyte lactate transporter defect, OMIM:245340, Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021, Monocarboxylate transporter 1 deficiency, OMIM:616095; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.531 SLC16A1 Sarah Leigh Added comment: Comment on phenotypes: mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7
Undiagnosed metabolic disorders v1.531 SLC16A1 Sarah Leigh Phenotypes for gene: SLC16A1 were changed from mainly ketosis with borderline reduction in glucose; Hyperinsulinemic hypoglycemia, familial, 7 to Erythrocyte lactate transporter defect, OMIM:245340; Hyperinsulinemic hypoglycemia, familial, 7, OMIM:610021; Monocarboxylate transporter 1 deficiency, OMIM:616095
Undiagnosed metabolic disorders v1.530 SETX Sarah Leigh Phenotypes for gene: SETX were changed from Secondary CoQ10 deficiency (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Amyotrophic lateral sclerosis/motor neuron disease; Charcot-Marie-Tooth disease; Hereditary ataxia to Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002; Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433
Undiagnosed metabolic disorders v1.529 SETX Sarah Leigh edited their review of gene: SETX: Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 1, OMIM:606002, Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433
Undiagnosed metabolic disorders v1.527 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Optic atrophy 1, 165500; {Glaucoma, normal tension, susceptibility to}, 606657; Optic atrophy plus syndrome, 125250; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Undiagnosed metabolic disorders v1.526 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Charcot-Marie-Tooth disease, type 2A2, 609260; Hereditary motor and sensory neuropathy VI, 601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Undiagnosed metabolic disorders v1.525 C19orf12 Sarah Leigh Added comment: Comment on mode of inheritance: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Undiagnosed metabolic disorders v1.525 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.524 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Neurodegeneration with brain iron accumulation (NBIA) (Disorder of iron metabolism); Neurodegeneration with brain iron accumulation 4, 614298; Mitochondrial Membrane Protein-Associated Neurodegeneration to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Undiagnosed metabolic disorders v1.522 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease (CMT4A); Charcot-Marie-Tooth disease, axonal, type 2K; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis; Charcot-Marie-Tooth disease, recessive intermediate, A; Charcot-Marie-Tooth disease, type 4A to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Undiagnosed metabolic disorders v1.518 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.
Undiagnosed metabolic disorders v1.518 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.517 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.517 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; respiratory chain disorder; hearing loss to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Undiagnosed metabolic disorders v1.516 SPTLC1 Sarah Leigh Mode of inheritance for gene: SPTLC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Undiagnosed metabolic disorders v1.514 SPTLC1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.514 SPTLC1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.514 SPTLC1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.511 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Source NHS GMS was added to STR: ATXN7_CAG.
Undiagnosed metabolic disorders v1.509 DNM2 Arina Puzriakova Mode of inheritance for gene: DNM2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.508 CPT2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI was updated from 'Biallelic' to 'Both mono- and biallelic'. Although most cases are associated with biallelic variants, symptomatic heterozygous patients have also been described (PMID: 15622536; 21913903; 23184072; 24843804). Severity of symptoms tends to correlate with residual CPT enzyme activity but it is plausible that heterozygotes may still be tested under this panel. Both MOIs are listed in OMIM for this phenotype (MIM# 255110)
Undiagnosed metabolic disorders v1.508 CPT2 Arina Puzriakova Mode of inheritance for gene: CPT2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.506 CPT2 Arina Puzriakova Phenotypes for gene: CPT2 were changed from Carnitine palmitoyltransferase II (CPTII) deficiency (Disorders of carnitine transport and the carnitine cycle); CPT deficiency, hepatic, type II 600649; CPT II deficiency, lethal neonatal 608836 to CPT II deficiency, infantile, OMIM:600649; CPT II deficiency, lethal neonatal, OMIM:608836; CPT II deficiency, myopathic, stress-induced, OMIM:255110; Carnitine palmitoyltransferase II (CPTII) deficiency (Disorders of carnitine transport and the carnitine cycle)
Undiagnosed metabolic disorders v1.505 RBCK1 Arina Puzriakova Phenotypes for gene: RBCK1 were changed from Polyglucosan body myopathy 1 with or without immunodeficiency 615895 to Polyglucosan body myopathy 1 with or without immunodeficiency, OMIM:615895
Undiagnosed metabolic disorders v1.502 SLC30A10 Arina Puzriakova Phenotypes for gene: SLC30A10 were changed from Hypermanganesemia with dystonia, polycythemia, and cirrhosis (Disorder of magnesium metabolism); Early onset dystonia; Parkinson Disease and Complex Parkinsonism; Hypermanganesemia with dystonia 1 613280 to Hypermanganesemia with dystonia 1, OMIM:613280
Undiagnosed metabolic disorders v1.501 HIBADH Zornitza Stark gene: HIBADH was added
gene: HIBADH was added to Undiagnosed 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
Undiagnosed metabolic disorders v1.500 APOB Sarah Leigh edited their review of gene: APOB: Added comment: The mode of inheritance for APOB should be both monoallelic and biallelic, as Hypercholesterolemia, familial, 2 OMIM:144010 is monoallelic and Hypobetalipoproteinemia OMIM:615558 is biallelic.; Changed rating: GREEN; Changed mode of pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.497 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI from 'Biallelic' to 'Both mono- and biallelic'.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, six unrelated individuals with de novo monoallelic missense variants in CLPB were identified (PMID: 34140661). The phenotype strongly overlapped with that observed in the recessive disease, including 3-MGA-uria in all cases.
Undiagnosed metabolic disorders v1.497 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.495 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria with the following: cataract, renal cysts and nephrocalcinosis; progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder; cataract, neutropenia, epilepsy; congenital microcephaly and severe encephalopathy to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Undiagnosed metabolic disorders v1.494 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300; Friedreich ataxia with retained reflexes, 229300; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Undiagnosed metabolic disorders v1.493 GLS Arina Puzriakova commented on gene: GLS: Added 'watchlist_MOI' tag to highlight monoallelic phenotype (MIM# 618339) which is also relevant to this panel, but as there is only a single case reported to date this is not yet sufficient to update the MOI.
Undiagnosed metabolic disorders v1.493 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Undiagnosed metabolic disorders v1.492 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Myoclonic epilepsy of Unverricht and Lundborg (Other metabolic disorders); Intellectual disability to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Undiagnosed metabolic disorders v1.489 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Undiagnosed metabolic disorders v1.487 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Retinitis pigmentosa (other congenital disorders of glycosylation); Posterior segment abnormalities to Retinitis pigmentosa 59, OMIM:613861; ?Congenital disorder of glycosylation, type 1bb, OMIM:613861; Posterior segment abnormalities
Undiagnosed metabolic disorders v1.486 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 OMIM:615350; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 MONDO:0014140; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 OMIM:615351; muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 MONDO:0014141; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Undiagnosed metabolic disorders v1.485 SLC25A15 Arina Puzriakova Phenotypes for gene: SLC25A15 were changed from HHH syndrome (Urea cycle disorders and inherited hyperammonaemias); Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, 238970 to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970; HHH syndrome (Urea cycle disorders and inherited hyperammonaemias)
Undiagnosed metabolic disorders v1.484 GBE1 Arina Puzriakova Phenotypes for gene: GBE1 were changed from Glycogen storage disease type IV, Andersen (Glycogen storage disorders); failure to thrive in addition to hepatomegaly van have neuromuscular adult form ( polyglucosan body ideas which presents with neurogenic bladder, gait difficulties; Glycogen storage disease IV, 232500; Polyglucosan body disease, adult form, 263570; Glycogen Storage Disease Type IV; Glycogen Storage Disorders- Liver; Glycogen Storage Disorders- Muscle; Glycogen Storage Disease to Glycogen storage disease IV, OMIM:232500; Polyglucosan body disease, adult form, OMIM:263570
Undiagnosed metabolic disorders v1.482 ALDH3A2 Arina Puzriakova Phenotypes for gene: ALDH3A2 were changed from Sj gren - Larsson syndrome (Other disorders of lipid and lipoprotein metabolism); Inherited white matter disorders; Intellectual disability to Sjogren-Larsson syndrome, OMIM:270200
Undiagnosed metabolic disorders v1.481 C12orf65 Arina Puzriakova Phenotypes for gene: C12orf65 were changed from Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 7, 613559; Spastic paraplegia 55, autosomal recessive, 615035 to Combined oxidative phosphorylation deficiency 7, OMIM:613559; Spastic paraplegia 55, autosomal recessive, OMIM:615035; Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Undiagnosed metabolic disorders v1.480 SERAC1 Arina Puzriakova Phenotypes for gene: SERAC1 were changed from Methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome (MEGDEL) (Organic acidurias); Disorders of mitochondrial membrane lipids (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis); 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 614739 to 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, OMIM:614739; Disorders of mitochondrial membrane lipids (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Undiagnosed metabolic disorders v1.479 FDX2 Sarah Leigh Phenotypes for gene: FDX2 were changed from Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy 251900 to Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy OMIM:251900; mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy MONDO:0020714
Undiagnosed metabolic disorders v1.477 APOA5 Sarah Leigh commented on gene: APOA5: The Q3_21_MOI tag has been added to this gene as the MOI should be changed to - BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Undiagnosed metabolic disorders v1.477 APOA5 Sarah Leigh edited their review of gene: APOA5: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for familial hypertriglycidaemia. Both risk polymorphisms (PMID 12417525; 12915450) and rarer APOA5 variants have been identified in hyperchylomicronemia, late-onset (OMIM:144650) and susceptibility to hypertriglyceridemia (OMIM:145750)(PMID: 23307945; 27678447; 16200213). In general, cases carrying biallelic variants (both polymorphisms and rarer variants) have a severer phenotype than monoallelic carriers (PMID: 12417525; 23307945; 27678447; 16200213).; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.473 APOA1 Sarah Leigh commented on gene: APOA1: Both biallelic and monoallelic APOA1 variants are associated with OMIM:618463, however, heterozygous cases have either a milder phenotype or are unaffected. Certain heterozygous APOA1 variants are regarded as Amyloidogenic and are associated with OMIM:105200 (PMID 32022753, 24 variants listed in table 1).
Undiagnosed metabolic disorders v1.473 APOA1 Sarah Leigh Phenotypes for gene: APOA1 were changed from Apolipoprotein A-I deficiency (Disorders of high density lipoprotein metabolism); Amyloidosis, 3 or more types 105200; ApoA-I and apoC-III deficiency, combined; Corneal clouding, autosomal recessive; Hypoalphalipoproteinemia 604091 to Amyloidosis, 3 or more types OMIM:105200; familial visceral amyloidosis MONDO:0007099; ApoA-I and apoC-III deficiency, combined OMIM:618463; Hypoalphalipoproteinemia, primary, 2, with or without corneal clouding OMIM:618463; hypoalphalipoproteinemia, primary, 2 MONDO:0032766
Undiagnosed metabolic disorders v1.471 COQ2 Ivone Leong Added comment: Comment on phenotypes: Previously:
Disorders of CoQ10 biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only));Disorders of ubiquinone metabolism and biosynthesis;Coenzyme Q10 deficiency, primary, 1, 607426;Coenzyme Q10 deficiency;{Multiple system atrophy, susceptibility to}, 146500
Undiagnosed metabolic disorders v1.471 COQ2 Ivone Leong Phenotypes for gene: COQ2 were changed from Disorders of CoQ10 biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of ubiquinone metabolism and biosynthesis; Coenzyme Q10 deficiency, primary, 1, 607426; Coenzyme Q10 deficiency; {Multiple system atrophy, susceptibility to}, 146500 to Coenzyme Q10 deficiency, primary, 1, OMIM:607426
Undiagnosed metabolic disorders v1.470 VKORC1 Ivone Leong Phenotypes for gene: VKORC1 were changed from Vitamin K epoxide reductase deficiency (Other disorders of vitamins and cofactors); Inherited bleeding disorders to Vitamin K-dependent clotting factors, combined deficiency of, 2, OMIM:607473
Undiagnosed metabolic disorders v1.469 ABCB7 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)" to "X-LINKED: hemizygous mutation in males, biallelic mutations in females" as there is no evidence that carrier females have ataxia.
Undiagnosed metabolic disorders v1.469 ABCB7 Ivone Leong Mode of inheritance for gene: ABCB7 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Undiagnosed metabolic disorders v1.468 ALDH18A1 Sarah Leigh Added comment: Comment on phenotypes: Hypoprolinaemia, Cutis laxa, autosomal recessive, type IIIa (Disorders of ornithine or proline metabolism);Cutis laxa, autosomal recessive, type IIIA (Delta-1-pyrroline 5 carboxylic acid synthetase deficiency) 219150
Undiagnosed metabolic disorders v1.468 ALDH18A1 Sarah Leigh Phenotypes for gene: ALDH18A1 were changed from Hypoprolinaemia, Cutis laxa, autosomal recessive, type IIIa (Disorders of ornithine or proline metabolism); Cutis laxa, autosomal recessive, type IIIA (Delta-1-pyrroline 5 carboxylic acid synthetase deficiency) 219150 to Cutis laxa, autosomal dominant 3 OMIM:616603; cutis laxa, autosomal dominant 3 MONDO:0014706; Cutis laxa, autosomal recessive, type IIIA OMIM:219150; ALDH18A1-related de Barsy syndrome MONDO:0009053; Spastic paraplegia 9A, autosomal dominant OMIM:601162; hereditary spastic paraplegia 9A MONDO:0011006; Spastic paraplegia 9B, autosomal recessive OMIM:616586; autosomal recessive complex spastic paraplegia type 9B MONDO:0014702
Undiagnosed metabolic disorders v1.466 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Lactic acidosis; Methylglutaconic aciduria; Neurological abnormalities; Cerebellar hypoplasia; Optic atrophy; Hypertrophic cardiomyopathy; Scoliosis; Spinal muscular atrophy to Harel-Yoon syndrome, OMIM:617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; Lactic acidosis; Methylglutaconic aciduria
Undiagnosed metabolic disorders v1.465 ATAD3A Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'Biallelic' to 'Both mono- and biallelic'.

At least 6 families with heterozygous variants (PMID: 27640307; 28158749) and 7 unrelated families with biallelic SNVs in this gene (PMID: 27640307; 29053797; 31727539; 32607449; 33845882). Metabolic evaluation often show elevated 3-methylglutaconate and lactate in patients with variants in this gene.
Undiagnosed metabolic disorders v1.465 ATAD3A Arina Puzriakova Mode of inheritance for gene: ATAD3A was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.462 ALDH18A1 Sarah Leigh reviewed gene: ALDH18A1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.462 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from GDP-Man:Dol-P mannosyltransferase deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Congenital disorder of glycosylation, type Ie 608799; GDP-Man:Dol-P mannosyltransferase deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type Ie, OMIM:608799; GDP-Man:Dol-P mannosyltransferase deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Undiagnosed metabolic disorders v1.458 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple mitochondrial dysfunctions syndrome 1 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Undiagnosed metabolic disorders v1.457 WFS1 Eleanor Williams Added comment: Comment on phenotypes: Original phenotypes were: Wolfram syndrome 1 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Congenital hearing impairment (profound/severe); Diabetes with additional phenotypes suggestive of a monogenic aetiology; Familial diabetes; Hereditary ataxia; Inherited optic neuropathies.
Undiagnosed metabolic disorders v1.457 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome 1 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Congenital hearing impairment (profound/severe); Diabetes with additional phenotypes suggestive of a monogenic aetiology; Familial diabetes; Hereditary ataxia; Inherited optic neuropathies to Wolfram syndrome 1, OMIM:222300
Undiagnosed metabolic disorders v1.456 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.454 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.453 B4GALT1 Arina Puzriakova Phenotypes for gene: B4GALT1 were changed from Beta-1,4-galactosyltransferase 1 deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Congenital disorder of glycosylation, type IId 607091; Beta-1,4-galactosyltransferase 1 deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type IId, OMIM:607091
Undiagnosed metabolic disorders v1.451 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Perrault syndrome 4, 615300; Perrault syndrome to Perrault syndrome 4, OMIM:615300; Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only); Multiple respiratory chain complex deficiencies (disorders of protein synthesis
Undiagnosed metabolic disorders v1.449 GNE Sarah Leigh Phenotypes for gene: GNE were changed from UDP-GlcNAc epimerase/kinase deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Sialuria (Other lysosomal disorders); Nonaka myopathy 605820; ADUDP-GlcNAc epimerase/kinase deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Sialuria OMIM:269921; sialuria MONDO:0010028; Nonaka myopathy OMIM:605820; GNE myopathy MONDO:0011603
Undiagnosed metabolic disorders v1.448 GNE Sarah Leigh Mode of inheritance for gene: GNE was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.445 NDUFC2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Undiagnosed metabolic disorders v1.444 NDUFC2 Sarah Leigh commented on gene: NDUFC2: Associated with relevant phenotype in OMIM, but not Gen2Phen. At least 2 variants have been reported in two unrelated cases, together with supportive functional evidence (PMID 32969598). There are also 2 families with complex I deficiency with reported by Carl Fratter (10 May 2019, Oxford University Hospitals NHS Trust).
Undiagnosed metabolic disorders v1.442 MAGT1 Sarah Leigh Phenotypes for gene: MAGT1 were changed from Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia 300853 to Congenital disorder of glycosylation, type Icc OMIM:301031; congenital disorder of glycosylation, type ICC MONDO:0026729; Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia OMIM:300853; X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia MONDO:0010455
Undiagnosed metabolic disorders v1.441 MAGT1 Sarah Leigh commented on gene: MAGT1: PMID 31036665 and PMID 31714901 demonstrate that variants in MAGT1 can result in disruption of glycosylation. This effect could be rescued in vitro by transfection of MAGT1 mRNA (PMID 31714901).
This gene is subject to skewed X-inactivation.
Undiagnosed metabolic disorders v1.441 MSMO1 Arina Puzriakova Phenotypes for gene: MSMO1 were changed from Sterol-C4-methyl oxidase deficiency (Disorders of sterol biosynthesis); Microcephaly, congenital cataract, and psoriasiform dermatitis, 616834; (SC4MOL DEFICIENCY) to Sterol-C4-methyl oxidase deficiency (Disorders of sterol biosynthesis); Microcephaly, congenital cataract, and psoriasiform dermatitis, OMIM:616834; Microcephaly-congenital cataract-psoriasiform dermatitis syndrome, MONDO:0014793
Undiagnosed metabolic disorders v1.440 GLS Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber. There are sufficient cases, supported by functional data, to rate this gene Green - however, detection of the 5' UTR triplet expansion (PMID:30970188) must first be validated within the Genomics England pipeline.

When excluding cases with the STR, the remaining evidence is not sufficient for inclusion as diagnostic-grade and therefore keeping Amber until the STR is validated or additional cases arise.
Undiagnosed metabolic disorders v1.439 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Glucosidase 1 deficiency (Disorders of protein N-glycosylation) to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Undiagnosed metabolic disorders v1.437 GLS Arina Puzriakova Added comment: Comment on mode of inheritance: As evidence for pathogenicity of monoallelic variants is limited (currently only 1 case), MOI will remain as 'Biallelic' until further cases emerge that support an association between monoallelic variants and disease.
Undiagnosed metabolic disorders v1.436 GLS Arina Puzriakova reviewed gene: GLS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30970188, 30575854, 30239721; Phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412, Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733, Developmental and epileptic encephalopathy 71, OMIM:618328, Developmental and epileptic encephalopathy, 71, MONDO:0032678, ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339, Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.433 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to GREEN
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism.

There is enough evidence to support a gene-disease association, so this gene has been rated Green.
Sources: Literature
Undiagnosed metabolic disorders v1.431 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.424 AHCY Arina Puzriakova Added comment: Comment on list classification: Promoted from Red to Green - multiple unrelated families with this neurometabolic disorder caused by biallelic variants in AHCY.
Undiagnosed metabolic disorders v1.423 AHCY Arina Puzriakova Deleted their comment
Undiagnosed metabolic disorders v1.422 AHCY Arina Puzriakova Phenotypes for gene: AHCY were changed from S-adenosylhomocysteine hydrolase deficiency (Disorders of the metabolism of sulphur amino acids) to Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Disorders of the metabolism of sulphur amino acids
Undiagnosed metabolic disorders v1.420 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.
Undiagnosed metabolic disorders v1.419 AHCY Arina Puzriakova commented on gene: AHCY: Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)
Undiagnosed metabolic disorders v1.419 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 15024124, 16435181, 16736098, 20852937, 22959829, 26095522, 26527160, 28779239, 30121674, 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.418 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.418 ALG14 Sarah Leigh edited their review of gene: ALG14: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Undiagnosed metabolic disorders v1.417 ALG14 Sarah Leigh Added comment: Comment on list classification: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous (p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Undiagnosed metabolic disorders v1.416 SLC25A4 Sarah Leigh Added comment: Comment on mode of inheritance: Because Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR 615418 is also relevant to this panel.
Undiagnosed metabolic disorders v1.416 SLC25A4 Sarah Leigh Mode of inheritance for gene: SLC25A4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.415 ISCU Sarah Leigh changed review comment from: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant in ISCU associated with mitochondrial myopathy, which justifies the mode of inheritance recorded.; to: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant missense p.G97V variant has been reported and therefore this may represent a specific mechanism of action. Further evidence is needed to determine which (if any) other monoallelic variants will cause disease beyond mitochondrial myopathy, which justifies the mode of inheritance recorded.
Undiagnosed metabolic disorders v1.415 ISCU Sarah Leigh Added comment: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant in ISCU associated with mitochondrial myopathy, which justifies the mode of inheritance recorded.
Undiagnosed metabolic disorders v1.415 ISCU Sarah Leigh Mode of inheritance for gene: ISCU was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.413 DDC Lothar Schlueter reviewed gene: DDC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28100251, 30952622; Phenotypes: Aromatic L-amino acid decarboxylase deficiency 608643, floppy child, dystonia, hypotonia, developmental delay, oculogyric crisis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.413 FMO3 Rebecca Foulger Phenotypes for gene: FMO3 were changed from Trimethylaminuria (Disorders and variants of enzymes that oxidise xenobiotics other than cytochrome P450) to Trimethylaminuria, 602079
Undiagnosed metabolic disorders v1.410 SETX Catherine Snow reviewed gene: SETX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Amyotrophic lateral sclerosis 4, juvenile, 602433, Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, 606002; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.409 SKIV2L Catherine Snow reviewed gene: SKIV2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 22444670, 30397475; Phenotypes: Trichohepatoenteric syndrome 2, 614602; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.408 SLC12A3 Catherine Snow reviewed gene: SLC12A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22009145; Phenotypes: Gitelman syndrome, 263800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.407 SLC18A2 Catherine Snow reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31240161, 23363473, 26497564, 28716265; Phenotypes: ?Parkinsonism-dystonia, infantile, 2, 618049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.406 SLC35A2 Catherine Snow reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30746764; Phenotypes: Congenital disorder of glycosylation, type IIm, 300896; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Undiagnosed metabolic disorders v1.405 SLC3A1 Catherine Snow reviewed gene: SLC3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12239244; Phenotypes: Cystinuria, 220100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.405 SLC6A3 Catherine Snow Phenotypes for gene: SLC6A3 were changed from Dopamine transporter deficiency syndrome (Other disorders of neurotransmitter metabolism) ; Early onset dystonia; Intellectual disability; Parkinson Disease and Complex Parkinsonism to Parkinsonism-dystonia, infantile, 1, 613135; Dopamine transporter deficiency syndrome (Other disorders of neurotransmitter metabolism); Early onset dystonia; Intellectual disability; Parkinson Disease and Complex Parkinsonism
Undiagnosed metabolic disorders v1.403 SLC6A3 Catherine Snow Added comment: Comment on list classification: ted from Amber to Green. SLC6A3 is associated with an appropriate phenotype on OMIM. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.402 RBP4 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. RBP4 is associated with retinoid metabolism on OMIM, but not on Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.400 SLC6A8 Catherine Snow reviewed gene: SLC6A8: Rating: GREEN; Mode of pathogenicity: None; Publications: 21660517; Phenotypes: Cerebral creatine deficiency syndrome 1, 300352; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Undiagnosed metabolic disorders v1.399 SLC7A9 Catherine Snow reviewed gene: SLC7A9: Rating: GREEN; Mode of pathogenicity: None; Publications: 12239244; Phenotypes: Cystinuria, 220100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.398 NNT Catherine Snow gene: NNT was added
gene: NNT was added to Undiagnosed metabolic disorders. Sources: Expert Review
Mode of inheritance for gene: NNT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NNT were set to 27129361; 28546232
Phenotypes for gene: NNT were set to Glucocorticoid deficiency 4, with or without mineralocorticoid deficiency, 614736
Review for gene: NNT was set to GREEN
Added comment: Relevant phenotype in OMIM but not in Gene2Phenotype. Sufficient cases in OMIM to classify NNT as Green
Sources: Expert Review
Undiagnosed metabolic disorders v1.396 TRAP1 Catherine Snow gene: TRAP1 was added
gene: TRAP1 was added to Undiagnosed metabolic disorders. Sources: Expert list
Mode of inheritance for gene: TRAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAP1 were set to 24152966
Phenotypes for gene: TRAP1 were set to VACTERL; CAKUT
Review for gene: TRAP1 was set to GREEN
Added comment: Not in OMIM or Gene2Phenotype. Recessive mutations reported in 2 families with CAKUT, and 3 families with VACTERL. Metabolism phenotype as the encoded protein has ATPase activity and interacts with tumor necrosis factor type I.
Sources: Expert list
Undiagnosed metabolic disorders v1.395 MRPL12 Catherine Snow gene: MRPL12 was added
gene: MRPL12 was added to Undiagnosed metabolic disorders. Sources: Expert list
Mode of inheritance for gene: MRPL12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL12 were set to 23603806
Phenotypes for gene: MRPL12 were set to Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Review for gene: MRPL12 was set to RED
Added comment: A single reported family in the literature therefore classified as Red.
Sources: Expert list
Undiagnosed metabolic disorders v1.392 LARS Catherine Snow changed review comment from: LARS1 has a relevant phenotype and is in OMIM, but not in Gene2Phenotype. PMID: 30349989 describes a premature girl who was identified to have compound hetrozygous variants in LARS1, this has caused infantile liver failure syndrome, type 1 (ILFS1). The paper also summarised the clinical features of reported patients with infantile liver failure syndrome type 1 caused by cytosolic leucine-tRNA synthetase deficiency, in total 6 compound hetrozygous variants identified in 14 patients in 7 families. Sufficient variants and relevant phenotype to upgrade LARS1 from Red to Green.
Sources: Expert Review; to: LARS1 has a relevant phenotype and is in OMIM, but not in Gene2Phenotype. PMID: 30349989 describes a premature girl who was identified to have compound hetrozygous variants in LARS1, this has caused infantile liver failure syndrome, type 1 (ILFS1). The paper also summarised the clinical features of reported patients with infantile liver failure syndrome type 1 caused by cytosolic leucine-tRNA synthetase deficiency, in total 6 compound hetrozygous variants identified in 14 patients in 7 families. Sufficient variants and relevant phenotype to classify LARS1 as Green.
Sources: Expert Review
Undiagnosed metabolic disorders v1.392 LARS Catherine Snow gene: LARS was added
gene: LARS was added to Undiagnosed metabolic disorders. Sources: Expert Review
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 28774368; 30349989; 22607940
Phenotypes for gene: LARS were set to ?Infantile liver failure syndrome 1, 615438
Review for gene: LARS was set to GREEN
Added comment: LARS1 has a relevant phenotype and is in OMIM, but not in Gene2Phenotype. PMID: 30349989 describes a premature girl who was identified to have compound hetrozygous variants in LARS1, this has caused infantile liver failure syndrome, type 1 (ILFS1). The paper also summarised the clinical features of reported patients with infantile liver failure syndrome type 1 caused by cytosolic leucine-tRNA synthetase deficiency, in total 6 compound hetrozygous variants identified in 14 patients in 7 families. Sufficient variants and relevant phenotype to upgrade LARS1 from Red to Green.
Sources: Expert Review
Undiagnosed metabolic disorders v1.389 TTC37 Catherine Snow reviewed gene: TTC37: Rating: GREEN; Mode of pathogenicity: None; Publications: 25976726, 28292286, 31132033; Phenotypes: Trichohepatoenteric syndrome 1, 222470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.387 ST3GAL3 Catherine Snow reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21907012, 23252400, 31584066; Phenotypes: Epileptic encephalopathy, early infantile, 15, 615006: Mental retardation, autosomal recessive 12, 611090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.387 TH Catherine Snow reviewed gene: TH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753243; Phenotypes: Segawa syndrome, recessive, 605407; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.386 WFS1 Catherine Snow Added comment: Comment on list classification: Promoted from Amber to Green. WFS1 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.385 VKORC1 Catherine Snow changed review comment from: Comment on list classification: Promoted from Amber to Green. PTS is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: Comment on list classification: Promoted from Amber to Green. VKORC1 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.384 VKORC1 Catherine Snow reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2, 607473, Warfarin resistance, 122700; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.383 VIPAS39 Catherine Snow reviewed gene: VIPAS39: Rating: GREEN; Mode of pathogenicity: None; Publications: 22753090, 26808426; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.381 VPS33B Catherine Snow reviewed gene: VPS33B: Rating: GREEN; Mode of pathogenicity: None; Publications: 18853461; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 1, 208085; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.380 UQCRB Catherine Snow reviewed gene: UQCRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25446085 28604960 12709789 23454382; Phenotypes: Mitochondrial complex III deficiency, nuclear type 3, 615158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.379 UMOD Catherine Snow edited their review of gene: UMOD: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Undiagnosed metabolic disorders v1.379 UMOD Catherine Snow changed review comment from: Promoted from Amber to Green. UMOD is associated with an appropriate phenotype on OMIM but not in Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: Promoted from Amber to Green. UMOD is associated with an appropriate phenotype on OMIM but not in Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.378 UMOD Catherine Snow reviewed gene: UMOD: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422399, 29180396; Phenotypes: Hyperuricemic nephropathy, familial juvenile 1, 162000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Undiagnosed metabolic disorders v1.377 TUFM Catherine Snow edited their review of gene: TUFM: Changed phenotypes: Combined oxidative phosphorylation deficiency 4, 610678
Undiagnosed metabolic disorders v1.377 TUFM Catherine Snow edited their review of gene: TUFM: Changed publications: 28132884, 25735936, 17160893, 26741492
Undiagnosed metabolic disorders v1.377 TUFM Catherine Snow reviewed gene: TUFM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 28132884, 25735936, 17160893, 26741492; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.375 TTPA Catherine Snow reviewed gene: TTPA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ataxia with isolated vitamin E deficiency, 277460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.373 TREX1 Catherine Snow reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 12624136, 25604658; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.373 TCN2 Catherine Snow Added comment: Comment on publications: There are >3 unrelated cases reported in the literature.
Undiagnosed metabolic disorders v1.371 TCN2 Catherine Snow reviewed gene: TCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 19373259; Phenotypes: Transcobalamin II deficiency, 275350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.369 TAT Catherine Snow reviewed gene: TAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 28255985; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.369 STS Catherine Snow Added comment: Comment on publications: There are >3 unrelated cases.
Undiagnosed metabolic disorders v1.368 STS Catherine Snow changed review comment from: Comment on list classification: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.

This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.; to: Comment on list classification: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.
Undiagnosed metabolic disorders v1.366 STS Catherine Snow reviewed gene: STS: Rating: GREEN; Mode of pathogenicity: None; Publications: 1539590, 29672931; Phenotypes: Ichthyosis, X-linked, 308100; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Undiagnosed metabolic disorders v1.365 ISCA2 Sarah Leigh gene: ISCA2 was added
gene: ISCA2 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: ISCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA2 were set to 25539947; 29359243
Phenotypes for gene: ISCA2 were set to Multiple mitochondrial dysfunctions syndrome 4 616370
Review for gene: ISCA2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two different ethinicities. Rated green based on review of Anna de Burca (Clinical Fellow, Genomic England).
Sources: Literature
Undiagnosed metabolic disorders v1.364 DNM2 Sarah Leigh Added comment: Comment on list classification: This gene was added as Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter (May 2019) on behalf of GMS mitochondrial specialist test group: 1 case with multiple deletions and COX negative fibres; 5 cases presented in a poster with dominant DMN2 variants (had COX deficient muscle fibres, one case with the p.Arg369Trp revealed disruption of the dynamic mitochondrial network, https://doi.org/10.1016/j.nmd.2012.06.124). From panels: Possible mitochondrial disorder - nuclear genes (Version 0.187) and Mitochondrial DNA maintenance disorder (Version 0.8).
Undiagnosed metabolic disorders v1.362 DNM2 Sarah Leigh Phenotypes for gene: DNM2 were changed from Centronuclear myopathy 1 160150; -Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482 to Centronuclear myopathy 1 160150; Charcot-Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Undiagnosed metabolic disorders v1.361 SLC2A1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. SLC2A1 is associated with GLUT1 deficiency syndrome 1 and GLUT1 deficiency syndrome 2 on OMIM and Gene2Phenotype. There are >3 unrelated cases reported on OMIM. Therefore, there is enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.358 HSPA9 Sarah Leigh gene: HSPA9 was added
gene: HSPA9 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: HSPA9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSPA9 were set to 26598328
Phenotypes for gene: HSPA9 were set to Even-plus syndrome 616854
Review for gene: HSPA9 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two unrelated cases.
Sources: Literature
Undiagnosed metabolic disorders v1.357 FDX2 Sarah Leigh Added comment: Comment on list classification: Based on reviews from Carl Fratter and Zornitza Stark (below).
This gene was added as Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter (May 2019) on behalf of GMS mitochondrial specialist test group: 3 unrelated familties; iron sulfur pathway. From panel: Possible mitochondrial disorder - nuclear genes (Version 0.187).
Promoted from red to amber, based on the expert review by Zornitza Stark (Australian Genomics) and the literature. FDX2 is associated with a phenotype in OMIM and not Gene2Phenotype. PMID: 24281368 describes a patient born of consanguineous Jewish Moroccan patents with episodic mitochondrial myopathy without optic atrophy or reversible leukoencephalopathy. The authors identified a homozygous missense variant in this gene (M1L). PMID: 30010796 describes 6 patients from 2 apparently unrelated Brazilian familes from the same geographical region with episodic mitochondrial myopathy. All affected individuals had the same homozygous variant (P144L). No haplotype analysis was performed. As there are only 2 different variants reported in this gene and no haplotype analysis was performed in PMID: 30010796 it was decided that there is currently not enough evidence to promote this gene to green status.
Undiagnosed metabolic disorders v1.356 FDX2 Sarah Leigh gene: FDX2 was added
gene: FDX2 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: FDX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDX2 were set to 24281368; 28803783; 30010796
Phenotypes for gene: FDX2 were set to Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy 251900
Review for gene: FDX2 was set to GREEN
Added comment: Sources: Literature
Undiagnosed metabolic disorders v1.351 DNM2 Sarah Leigh gene: DNM2 was added
gene: DNM2 was added to Undiagnosed metabolic disorders. Sources: Other
Mode of inheritance for gene: DNM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: DNM2 were set to Centronuclear myopathy 1 160150; -Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Undiagnosed metabolic disorders v1.351 DNM2 Sarah Leigh gene: DNM2 was added
gene: DNM2 was added to Undiagnosed metabolic disorders. Sources: Other
Mode of inheritance for gene: DNM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: DNM2 were set to Centronuclear myopathy 1 160150; -Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Undiagnosed metabolic disorders v1.350 COX8A Sarah Leigh gene: COX8A was added
gene: COX8A was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: COX8A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX8A were set to 26685157
Phenotypes for gene: COX8A were set to ?Mitochondrial complex IV deficiency 220110
Review for gene: COX8A was set to RED
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 1 variant reported in a 12.5-year old girl, born of Turkish parents who were likely distantly related, with mitochondrial complex I deficiency. The proband died from cardiorespiratory failure associated with infection and metabolic crisis at 12.5 years. No further variants reported to date (30/09/2019).
Sources: Literature
Undiagnosed metabolic disorders v1.349 COQ7 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in unrelated cases, together with supportive functional studies.
Undiagnosed metabolic disorders v1.348 COQ7 Sarah Leigh gene: COQ7 was added
gene: COQ7 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: COQ7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ7 were set to 26084283; 28409910
Phenotypes for gene: COQ7 were set to ?Coenzyme Q10 deficiency, primary, 8 616733
Review for gene: COQ7 was set to GREEN
Added comment: This gene was added as Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter (May 2019) on behalf of GMS mitochondrial specialist test group: 3 unrelated individuals and functional studies. From panel: Possible mitochondrial disorder - nuclear genes (Version 0.187).
Sources: Literature
Undiagnosed metabolic disorders v1.347 TMEM126A Sarah Leigh Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Associated with the phenotype Optic atrophy 7 612989 in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in unrelated cases.
The red rating is based on Helen Britain's opinion that, the phenotype of Optic atrophy 7 612989 will not present via a metabolic team. TMEM126A is green on the Optic neuropathy panel.
Undiagnosed metabolic disorders v1.344 PDK3 Sarah Leigh Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least three unrelated cases, together with functional studies.
Undiagnosed metabolic disorders v1.343 PDK3 Sarah Leigh Added comment: Comment on mode of pathogenicity: A gain of function mechanism has been reported for the p.R158H variant, resulting in a more activity than the wild-type kinase (PMID: 23297365).
Undiagnosed metabolic disorders v1.343 PDK3 Sarah Leigh Mode of pathogenicity for gene: PDK3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Undiagnosed metabolic disorders v1.342 PDK1 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. PDK1 is mentioned in the supplimentary material in PMID 27604308, however, no details of variants nor phenotypes are mentioned.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Not associated with phenotype in OMIM or in Gen2Phen. PDK1 is mentioned in the supplimentary material in PMID 27604308, however, no details of variants nor phenotypes are mentioned.
Undiagnosed metabolic disorders v1.342 NDUFA12 Sarah Leigh changed review comment from: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: One case with a single homozygous terminating variant, together with functional studies.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: One case with a single homozygous terminating variant, together with functional studies.
Undiagnosed metabolic disorders v1.342 MRPS16 Sarah Leigh changed review comment from: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: single homozygous terminating variant in two 'unrelated' cases, together with functional studies.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: single homozygous terminating variant in two 'unrelated' cases, together with functional studies.
Undiagnosed metabolic disorders v1.342 COX4I2 Sarah Leigh changed review comment from: Comment on list classification: This gene should remain Amber due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter.
One homozygous variant (c.412G>A, p.E138K) reported in 5 Arab Muslim patients with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (612714) (PMID 19268275) and heterozygous variant (c.253C>T, p.R85W) found together with a heterozygous COX10 variant (c.1096G>T, p.V366L)(PMID 22592081).; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
This gene should remain Amber due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter.
One homozygous variant (c.412G>A, p.E138K) reported in 5 Arab Muslim patients with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (612714) (PMID 19268275) and heterozygous variant (c.253C>T, p.R85W) found together with a heterozygous COX10 variant (c.1096G>T, p.V366L)(PMID 22592081).
Undiagnosed metabolic disorders v1.342 COA5 Sarah Leigh changed review comment from: Associated with phenotype in OMIM and as a possible G2P. At least 1 variant reported.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. Associated with phenotype in OMIM and as a possible G2P. At least 1 variant reported.
Undiagnosed metabolic disorders v1.342 ATP5E Sarah Leigh changed review comment from: Comment on list classification: Updated information and Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: 1 reported case with functional studies.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. Updated information and Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: 1 reported case with functional studies.
Undiagnosed metabolic disorders v1.342 ATP5A1 Sarah Leigh changed review comment from: Comment on list classification: Two variants together with functional studies. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys in this publication have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys in this publication have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.
Undiagnosed metabolic disorders v1.339 PDK3 Sarah Leigh Phenotypes for gene: PDK3 were changed from Pyruvate dehydrogenase kinase deficiency (Disorders of pyruvate metabolism); ?Charcot-Marie-Tooth disease, X-linked dominant, 6 300905 to ?Charcot-Marie-Tooth disease, X-linked dominant, 6 300905
Undiagnosed metabolic disorders v1.338 PDK1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. PDK1 is mentioned in the supplimentary material in PMID 27604308, however, no details of variants nor phenotypes are mentioned.
Undiagnosed metabolic disorders v1.335 NDUFA12 Sarah Leigh Added comment: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: One case with a single homozygous terminating variant, together with functional studies.
Undiagnosed metabolic disorders v1.333 MRPS16 Sarah Leigh Added comment: Comment on list classification: Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: single homozygous terminating variant in two 'unrelated' cases, together with functional studies.
Undiagnosed metabolic disorders v1.332 MRPS16 Sarah Leigh Added comment: Comment on phenotypes: Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); CORPUS CALLOSUM, AGENESIS OF, WITH DYSMORPHISM AND FATAL LACTIC ACIDOSIS
Undiagnosed metabolic disorders v1.332 MRPS16 Sarah Leigh Phenotypes for gene: MRPS16 were changed from Required for mitochondrial gene expression (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Combined oxidative phosphorylation deficiency 2, 610498; CORPUS CALLOSUM, AGENESIS OF, WITH DYSMORPHISM AND FATAL LACTIC ACIDOSIS to Combined oxidative phosphorylation deficiency 2 610498
Undiagnosed metabolic disorders v1.330 COX4I2 Sarah Leigh Phenotypes for gene: COX4I2 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis 612714 to Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis 612714
Undiagnosed metabolic disorders v1.328 COX4I2 Sarah Leigh Added comment: Comment on list classification: This gene should remain Amber due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter.
One homozygous variant (c.412G>A, p.E138K) reported in 5 Arab Muslim patients with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (612714) (PMID 19268275) and heterozygous variant (c.253C>T, p.R85W) found together with a heterozygous COX10 variant (c.1096G>T, p.V366L)(PMID 22592081).
Undiagnosed metabolic disorders v1.326 COA5 Sarah Leigh Phenotypes for gene: COA5 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 to ?Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 616500
Undiagnosed metabolic disorders v1.322 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from Complex V (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits) to ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 614053
Undiagnosed metabolic disorders v1.321 ATP5E Sarah Leigh Added comment: Comment on publications: pmid 27626380: knockout of the mouse homolog of human ATP5E is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Undiagnosed metabolic disorders v1.320 ATP5E Sarah Leigh Added comment: Comment on list classification: Updated information and Amber review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: 1 reported case with functional studies.
Undiagnosed metabolic disorders v1.316 ATP5A1 Sarah Leigh changed review comment from: Comment on list classification: Two variants together with functional studies. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.; to: Comment on list classification: Two variants together with functional studies. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys in this publication have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.
Undiagnosed metabolic disorders v1.314 SPTLC1 Catherine Snow reviewed gene: SPTLC1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20097765, 21618344, 20097765, 30420926; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IA, 162400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Undiagnosed metabolic disorders v1.312 SPTLC2 Catherine Snow reviewed gene: SPTLC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 20920666; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IC, 613640; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Undiagnosed metabolic disorders v1.312 SPR Catherine Snow changed review comment from: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association. Sepiapterin reductase (SR) deficiency leads to altered tetrahydrobiopterin (BH4) biosynthesis and abnormal biogenic amine metabolism. Most individuals improve with L-dopa administration, therefore treatable tag has been added.; to: Promoted from Amber to Green. This gene is associated with a relevant disease in OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association. Sepiapterin reductase (SR) deficiency leads to altered tetrahydrobiopterin (BH4) biosynthesis and abnormal biogenic amine metabolism. Most individuals improve with L-dopa administration, therefore treatable tag has been added.
Undiagnosed metabolic disorders v1.310 SPR Catherine Snow reviewed gene: SPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 22018912, 22522443, 22018912, 24588500, 28189489, 21431957, 16650784; Phenotypes: Dystonia, dopa-responsive, due to sepiapterin reductase deficiency 612716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.310 SLC25A12 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 biallelic variants reported in unrelated cases.
Undiagnosed metabolic disorders v1.309 SLC25A12 Ivone Leong Phenotypes for gene: SLC25A12 were changed from Disorders of mitochondrial solute import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Inherited white matter disorders to Disorders of mitochondrial solute import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Inherited white matter disorders; Epileptic encephalopathy, early infantile, 39 612949; Hypomyelination, global cerebral, 612949
Undiagnosed metabolic disorders v1.307 SDHC Ivone Leong reviewed gene: SDHC: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.307 SDHAF2 Ivone Leong reviewed gene: SDHAF2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.307 SC5D Ivone Leong Added comment: Comment on publications: There are >3 unrelated cases and an animal model.
Undiagnosed metabolic disorders v1.306 SC5D Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.
Undiagnosed metabolic disorders v1.305 RNASEH2B Ivone Leong changed review comment from: Comment on list classification: Demoted from Amber to Red. RNASEH2B is associated with Aicardi-Goutieres syndrome 2 on OMIM and Gene2Phenotype. There are 2 unrelated cases on OMIM supporting the gene-disease link between RNASEH2B with Aicardi-Goutieres syndrome; however, RNASEH2B does not appear to be associated with a metabolic phenotype. Therefore this gene has been demoted to red.; to: Comment on list classification: Demoted from Amber to Red. RNASEH2B is associated with Aicardi-Goutieres syndrome 2 on OMIM and Gene2Phenotype. There are 2 unrelated cases on OMIM about RNASEH2B causing Aicardi-Goutieres syndrome; however, RNASEH2B does not appear to be associated with a metabolic phenotype. Therefore this gene has been demoted to red.
Undiagnosed metabolic disorders v1.305 RNASEH2C Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red. RNASEH2C is associated with Aicardi-Goutieres syndrome 3 on OMIM and Gene2Phenotype. There are 2 unrelated cases from the same geographical region on OMIM about RNASEH2C causing Aicardi-Goutieres syndrome; however, RNASEH2C does not appear to be associated with a metabolic phenotype. Therefore this gene has been demoted to red.
Undiagnosed metabolic disorders v1.304 RNASEH2B Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red. RNASEH2B is associated with Aicardi-Goutieres syndrome 2 on OMIM and Gene2Phenotype. There are 2 unrelated cases on OMIM supporting the gene-disease link between RNASEH2B with Aicardi-Goutieres syndrome; however, RNASEH2B does not appear to be associated with a metabolic phenotype. Therefore this gene has been demoted to red.
Undiagnosed metabolic disorders v1.302 RNASEH2A Ivone Leong changed review comment from: RNASEH2A is associated with Aicardi-Goutieres syndrome 4 on OMIM and Gene2Phenotype. RNASEH2A does not appear to be associated with a metabolic phenotype. Therefore this gene will remain Amber.; to: RNASEH2A is associated with Aicardi-Goutieres syndrome 4 on OMIM and Gene2Phenotype. There are >3 unrelated cases on OMIM supporting the gene-disease link between RNASEH2A with Aicardi-Goutieres syndrome; however, RNASEH2A does not appear to be associated with a metabolic phenotype. Therefore this gene has been demoted to red.
Undiagnosed metabolic disorders v1.301 HARS2 Sarah Leigh Added comment: Comment on publications: PMID: 21464306: One family reported, with five affected siblings who were compound heterozygous for variants L200V and V368L. Functional evidence in c.elegans was provided. PMID: 27650058: patients with sporadic Perrault syndrome IV-1 and VI-I were homozygous for the c.1010A>G (p.Tyr337Cys) variant. The patients were claimed not to be related, but originated from the same region in Morocco and the variant was characterised as being in the same haplotype, suggesting a founder effect. Found at a frequency of 1/121332 in Exac.
Undiagnosed metabolic disorders v1.300 HARS2 Sarah Leigh Added comment: Comment on list classification: This gene was discussed on the NHSE GMS Mitochondrial Specialist Group Meeting call on 25th February 2019. It was confirmed that Perrault syndrome was relevant for this panel, and that there was enough evidence for the gene to be Green.
Undiagnosed metabolic disorders v1.299 FECH Sarah Leigh Added comment: Comment on phenotypes: Erythropoietic protoporphyria (Porphyrias with acute painful photosensitivity);Erythropoietic protoporphyria, mild variant
Undiagnosed metabolic disorders v1.299 FECH Sarah Leigh Phenotypes for gene: FECH were changed from Erythropoietic protoporphyria (Porphyrias with acute painful photosensitivity); Erythropoietic protoporphyria, mild variant to Protoporphyria, erythropoietic, 1 177000
Undiagnosed metabolic disorders v1.298 FECH Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 16 variants identified in unrelated cases.
Undiagnosed metabolic disorders v1.297 FECH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.295 DHODH Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 11 variants reported in 6 families (PMID 19915526), together with a knockout mouse model (PMID 27626380).
Undiagnosed metabolic disorders v1.294 DHODH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.294 DHODH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.294 DHODH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.294 DHODH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.294 DHODH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.294 DHCR24 Sarah Leigh Added comment: Comment on phenotypes: Desmosterolosis (Disorders of sterol biosynthesis);Intellectual disability;Unexplained skeletal dysplasia
Undiagnosed metabolic disorders v1.294 DHCR24 Sarah Leigh Phenotypes for gene: DHCR24 were changed from Desmosterolosis (Disorders of sterol biosynthesis); Intellectual disability; Unexplained skeletal dysplasia to Desmosterolosis 602398
Undiagnosed metabolic disorders v1.292 DHCR24 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in at least cases, two of the variants were in cis in a case which was compound heterozygous with another variant (PMID 11519011). Supportive functional studies were also presented.
Undiagnosed metabolic disorders v1.291 DHCR24 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.291 DHCR24 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.291 DHCR24 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.291 DCXR Sarah Leigh Added comment: Comment on phenotypes: Essential pentosuria (Disorders of pentose metabolism) is a benign inborn error of metabolism, in which 1 to 4 gm of the pentose L-xylulose is excreted in the urine each day, as a result some patients maybe treated inappropriately for diabetes mellitus with insulin (PMID 22042873).
Undiagnosed metabolic disorders v1.289 DCXR Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 2 variants identified within Ashkenazi Jewish population, that functional studies have shown to be loss of function variants that result in lack of the normal DCXR protein.
Undiagnosed metabolic disorders v1.287 CYP7B1 Sarah Leigh commented on gene: CYP7B1: Treatable tag: the only surviving patient with oxysterol 7α-hydroxylase deficiency recovered from liver failure after chenodeoxycholic acid (CDCA) treatment beginning at 3 months of age PMID: 31337596
Undiagnosed metabolic disorders v1.286 CYP7B1 Sarah Leigh Added comment: Comment on list classification: At least 10 variants identified in unrelated cases of Spastic paraplegia 5A, autosomal recessive 270800 and one of these variants was also found in 3 unrelated cases of Bile acid synthesis defect, congenital, 3 613812, which is a more relevant phenotype for metabolic panels.
Undiagnosed metabolic disorders v1.285 PTS Ivone Leong Phenotypes for gene: PTS were changed from 6-Pyruvoyl-tetrahydropterin synthase deficiency (Disorders of pterin metabolism); Intellectual disability to 6-Pyruvoyl-tetrahydropterin synthase deficiency (Disorders of pterin metabolism); Intellectual disability; Hyperphenylalaninemia, BH4-deficient, A 261640
Undiagnosed metabolic disorders v1.284 PTS Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. PTS is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.283 CYP7B1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.283 CYP7B1 Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 10 variants identified in unrelated cases of Spastic paraplegia 5A, autosomal recessive 270800 and one of these variants was also found in a case of Bile acid synthesis defect, congenital, 3 613812.
Undiagnosed metabolic disorders v1.280 CTSC Sarah Leigh Added comment: Comment on phenotypes: Other lysosomal disorders, Cathepsin-related disorders;Unexplained skeletal dysplasia
Undiagnosed metabolic disorders v1.280 CTSC Sarah Leigh Phenotypes for gene: CTSC were changed from Papillon-Lef vre syndrome (Other lysosomal disorders, Cathepsin-related disorders); Unexplained skeletal dysplasia to Haim-Munk syndrome 245010; Papillon-Lefevre syndrome 245000; Periodontitis 1, juvenile 170650
Undiagnosed metabolic disorders v1.279 CTSC Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 13 variants identified in unrelated cases of Papillon-Lefevre syndrome 245000.
Undiagnosed metabolic disorders v1.278 CTSC Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.278 CLDN19 Sarah Leigh Added comment: Comment on phenotypes: Disorder of magnesium metabolism; Renal tract calcification (or Nephrolithiasis/nephrocalcinosis)
Undiagnosed metabolic disorders v1.278 CLDN19 Sarah Leigh Phenotypes for gene: CLDN19 were changed from Hypomagnesaemia type 5, renal with ocular involvement (Disorder of magnesium metabolism); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis) to Hypomagnesemia 5, renal, with ocular involvement 248190
Undiagnosed metabolic disorders v1.276 CLDN19 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in at least 6 unrelated cases.
Undiagnosed metabolic disorders v1.275 CLDN19 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.275 CLDN16 Sarah Leigh Added comment: Comment on phenotypes: Disorder of magnesium metabolism; Renal tract calcification (or Nephrolithiasis/nephrocalcinosis)
Undiagnosed metabolic disorders v1.275 CLDN16 Sarah Leigh Phenotypes for gene: CLDN16 were changed from Hypomagnesaemia type 3, renal (Disorder of magnesium metabolism); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis) to Hypomagnesemia 3, renal 248250
Undiagnosed metabolic disorders v1.274 CLDN16 Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 19 variants identified in unrelated cases.
Undiagnosed metabolic disorders v1.273 CLDN16 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.273 CISD2 Sarah Leigh Added comment: Comment on phenotypes: Mitochondrial respiratory chain disorders (caused by nuclear variants only) ;Diabetes with additional phenotypes suggestive of a monogenic aetiology
Undiagnosed metabolic disorders v1.273 CISD2 Sarah Leigh Phenotypes for gene: CISD2 were changed from Wolfram syndrome 2 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Diabetes with additional phenotypes suggestive of a monogenic aetiology; Intellectual disability to Wolfram syndrome 2 604928
Undiagnosed metabolic disorders v1.271 CISD2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as both RD and IF Gen2Phen gene. At least 3 variants reported in unrelated cases, together with segration and functional studies.
Undiagnosed metabolic disorders v1.270 CISD2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.270 CISD2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.270 CISD2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.269 APOB Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 5 variants associated with Hypobetalipoproteinemia 615558 without other variants in other genes and 2 variants associated with Hypercholesterolemia, familial, 2 144010 in numberous cases.
Undiagnosed metabolic disorders v1.268 APOB Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.268 ALPL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.268 ALPL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.268 ALPL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.268 ALPL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.268 ALPL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.268 ALPL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.266 ALPL Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 16 variants reported in hypophosphatasia, infantile 241500, some of these variants and others were found in childhood and adult Hypophosphatasia and two addtional variants were reported in a case of perinatal lethal hypophosphatasia (PMID 11745997).
Undiagnosed metabolic disorders v1.264 IER3IP1 Helen Brittain reviewed gene: IER3IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly, epilepsy, and diabetes syndrome, 614231; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.263 ALDH3A2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.263 ALDH3A2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.263 ALDH3A2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.262 ALAS2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.261 ADSL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.261 ADSL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.261 ADSL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.260 ADA Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.260 ADA Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.260 ADA Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.260 ADA Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.260 ADA Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.259 ACY1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.259 ACY1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.258 ABHD12 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.258 ABHD12 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.258 ABHD12 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.258 ABHD12 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.258 ABHD12 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.258 ABHD12 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.257 ABCG8 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.257 ABCG8 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.256 ABCG5 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.256 ALDH3A2 Sarah Leigh edited their review of gene: ALDH3A2: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported.; Changed rating: GREEN; Changed publications: 27604308, 10792573, 10577908; Changed phenotypes: Sjogren-Larsson syndrome 270200
Undiagnosed metabolic disorders v1.256 ALAS2 Sarah Leigh edited their review of gene: ALAS2: Added comment: Associated with phenotype in OMIM and not in Gen2Phen. At least 18 variants identified in Anemia, sideroblastic, 1 300751 and two variants in Protoporphyria, erythropoietic, X-linked 300752 in six unrelated families, together with functional studies.; Changed rating: GREEN; Changed publications: 27604308, 1570328, 7560104, 12663458, 18760763; Changed phenotypes: Anemia, sideroblastic, 1 300751, Protoporphyria, erythropoietic, X-linked 300752
Undiagnosed metabolic disorders v1.256 ADSL Sarah Leigh edited their review of gene: ADSL: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 8 variants reported associated with adenylosuccinase deficiency in at least 10 unrelated cases.; Changed rating: GREEN; Changed publications: 27604308, 18830228, 12016589, 10090474; Changed phenotypes: Adenylosuccinase deficiency 103050, Intellectual disability, Epileptic encephalopathy
Undiagnosed metabolic disorders v1.256 ADA Sarah Leigh edited their review of gene: ADA: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 30 variants reported associated with Adenosine deaminase deficiency.; Changed rating: GREEN; Changed publications: 27604308, 3684597, 2783588, 1680289; Changed phenotypes: Adenosine deaminase deficiency, partial 102700, Severe combined immunodeficiency due to ADA deficiency 102700, Combined B and T cell defect, SCID, Infantile enterocolitis & monogenic inflammatory bowel disease
Undiagnosed metabolic disorders v1.256 ACY1 Sarah Leigh edited their review of gene: ACY1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in at least 9 unrelated cases.; Changed rating: GREEN; Changed publications: 27604308, 24117009, 17562838, 16465618; Changed phenotypes: Aminoacylase 1 deficiency 609924, Intellectual disability
Undiagnosed metabolic disorders v1.256 ABHD12 Sarah Leigh edited their review of gene: ABHD12: Added comment: Associated with phenotype in OMIM and not in Gen2Phen. At least 7 variants identified in at least 6 unrelated cases; Changed rating: GREEN; Changed publications: 27604308, 20797687, 24697911 ; Changed phenotypes: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract 612674, Hereditary ataxia, Posterior segment abnormalities, Congenital hearing impairment (profound/severe), PHARC syndrome (Disorders of complex lipid synthesis)
Undiagnosed metabolic disorders v1.256 ABCG8 Sarah Leigh edited their review of gene: ABCG8: Added comment: Associated with phenotype in OMIM and not in Gen2Phen. At least 9 variants identified in numberous unrelated cases; Changed rating: GREEN; Changed publications: 27604308, 11452359, 15996216, 11099417, 22981120; Changed phenotypes: Sitosterolemia 210250, Familial hypercholesterolaemia
Undiagnosed metabolic disorders v1.256 ABCG5 Sarah Leigh edited their review of gene: ABCG5: Added comment: Associated with phenotype in OMIM and not in Gen2Phen. At least 8 variants identified in unrelated cases; Changed rating: GREEN; Changed publications: 27604308, 11099417, 11138003, 20719861, 17976197; Changed phenotypes: Sitosterolemia 210250, Familial hypercholesterolaemia
Undiagnosed metabolic disorders v1.254 PSPH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.254 PSPH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.254 PSPH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.254 PSAT1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for ?Phosphoserine aminotransferase deficiency 610992; Neu-Laxova syndrome 2 616038. At least 5 variants reported in 6 cases of Neu-Laxova syndrome 2 616038 and 2 variants in a case of ?Phosphoserine aminotransferase deficiency 610992.
Undiagnosed metabolic disorders v1.251 PSAT1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.251 PRPS1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for Arts syndrome 301835, Charcot-Marie-Tooth disease, X-linked recessive, 5 311070, Deafness, X-linked 1 304500 and Phosphoribosylpyrophosphate synthetase superactivity 300661. At least 22 variants have been reported across the phenotypes.
Undiagnosed metabolic disorders v1.250 PRPS1 Sarah Leigh Added comment: Comment on phenotypes: Phosphoribosyl pyrophosphate synthetase 1 defects (Disorders of purine metabolism)
Undiagnosed metabolic disorders v1.250 PRPS1 Sarah Leigh Phenotypes for gene: PRPS1 were changed from Phosphoribosyl pyrophosphate synthetase 1 defects (Disorders of purine metabolism); Charcot-Marie-Tooth disease; Congenital hearing impairment (profound/severe); Intellectual disability; Intellectual_disability to Arts syndrome 301835; Charcot-Marie-Tooth disease, X-linked recessive, 5 311070; Deafness, X-linked 1 304500; Gout, PRPS-related 300661; Phosphoribosylpyrophosphate synthetase superactivity 300661
Undiagnosed metabolic disorders v1.249 PRPS1 Sarah Leigh Mode of inheritance for gene: PRPS1 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Undiagnosed metabolic disorders v1.247 ATP5A1 Sarah Leigh Added comment: Comment on list classification: Two variants together with functional studies. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.
Undiagnosed metabolic disorders v1.246 PRPS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.246 PRPS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.246 PRPS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.246 PRPS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.246 PRPS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.246 PRPS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.246 PRPS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.245 POR Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 10 variants associated with Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis 201750 and 6 variants associated with Disordered steroidogenesis due to cytochrome P450 oxidoreductase 613571.
Undiagnosed metabolic disorders v1.244 POR Sarah Leigh Phenotypes for gene: POR were changed from Antley-Bixler syndrome with disordered steroidogenesis; Craniosynostosis syndromes phenotypes; Disorders of sex development; Unexplained skeletal dysplasia to Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis 201750; Disordered steroidogenesis due to cytochrome P450 oxidoreductase 613571
Undiagnosed metabolic disorders v1.243 POR Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.243 POR Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.243 POR Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.243 POR Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.243 POR Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.242 PNP Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 10 variants reported.
Undiagnosed metabolic disorders v1.240 PNP Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.240 PINK1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.240 PINK1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.240 PINK1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 12 variants were reported.
Undiagnosed metabolic disorders v1.237 PINK1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.237 PINK1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.237 PIGM Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 1 variant was reported in 2 unrelated families (PMID 16767100), together with supportive functional studies (PMID 17442906 & 25293775).
Undiagnosed metabolic disorders v1.233 PHGDH Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for both phenotypes. At least 6 variants reported in 6 unrelated cases of Phosphoglycerate dehydrogenase deficiency 601815 and 4 variants reported in 4 unrelated cases of Neu-Laxova syndrome 1 256520.
Undiagnosed metabolic disorders v1.231 PHGDH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.231 PHGDH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.231 PHGDH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.230 PEPD Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 11 variants reported.
Undiagnosed metabolic disorders v1.229 PEPD Sarah Leigh Added comment: Comment on phenotypes: Prolidase deficiency (Other disorders of peptide metabolism)
Undiagnosed metabolic disorders v1.229 PEPD Sarah Leigh Phenotypes for gene: PEPD were changed from Prolidase deficiency (Other disorders of peptide metabolism); Intellectual disability to Prolidase deficiency 170100
Undiagnosed metabolic disorders v1.228 PEPD Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.228 PDPR Sarah Leigh Added comment: Comment on list classification: Not associated with a phenotype in OMIM or in Gen2Phen. At least 1 variant reported in a case of global developmental delay, typical Joubert syndrome, according to PMID 25558065.
Undiagnosed metabolic disorders v1.227 PCSK9 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gain of function variants are responsible for Hypercholesterolemia, familial, 3 603776, while loss of function variants are responsible for {Low density lipoprotein cholesterol level QTL 1} 603776.
Undiagnosed metabolic disorders v1.227 PCSK9 Sarah Leigh Mode of pathogenicity for gene: PCSK9 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Undiagnosed metabolic disorders v1.226 PCSK9 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 gain of function variants reported in unrelated cases of Hypercholesterolemia, familial, 3 603776 and at least 5 loss of function variants have been reported in unrelated cases of {Low density lipoprotein cholesterol level QTL 1} 603776.
Undiagnosed metabolic disorders v1.223 PCSK9 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.223 PCK1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in unrelated cases.
Undiagnosed metabolic disorders v1.219 PANK2 Sarah Leigh Phenotypes for gene: PANK2 were changed from HARP syndrome 607236; Neurodegeneration with brain iron accumulation 234200Pantothenate kinases deficiency (Other disorders of vitamins and cofactors); Neurodegeneration with brain iron accumulation (NBIA) (Disorder of iron metabolism); Early onset dystonia; Parkinson Disease and Complex Parkinsonism; Posterior segment abnormalities to HARP syndrome 607236; Neurodegeneration with brain iron accumulation 234200
Undiagnosed metabolic disorders v1.218 PANK2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 13 variants reported for Neurodegeneration with brain iron accumulation 234200 and 3 variants in 2 unrelated cases of HARP syndrome 607236.
Undiagnosed metabolic disorders v1.217 PANK2 Sarah Leigh Phenotypes for gene: PANK2 were changed from Pantothenate kinases deficiency (Other disorders of vitamins and cofactors); Neurodegeneration with brain iron accumulation (NBIA) (Disorder of iron metabolism); Early onset dystonia; Parkinson Disease and Complex Parkinsonism; Posterior segment abnormalities to HARP syndrome 607236; Neurodegeneration with brain iron accumulation 234200Pantothenate kinases deficiency (Other disorders of vitamins and cofactors); Neurodegeneration with brain iron accumulation (NBIA) (Disorder of iron metabolism); Early onset dystonia; Parkinson Disease and Complex Parkinsonism; Posterior segment abnormalities
Undiagnosed metabolic disorders v1.216 PANK2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.216 PANK2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.216 PANK2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.216 PANK2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.216 PANK2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.216 OPLAH Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants have been reported. It is not clear whether the mode of inheritance is biallelic or monoallelic as homozygous and heterozygote cases have been seen. The PMID 21651516 reports two sibs who are homozygous for a terminating variant, the younger brother is 5-oxoprolinase deficiency, however, his clinically unaffected sister just has increased 5-oxoproline excretion.
Undiagnosed metabolic disorders v1.214 OPLAH Sarah Leigh Added comment: Comment on phenotypes: Oxoprolinuria (Disorders of the gamma-glutamyl cycle)
Undiagnosed metabolic disorders v1.214 OPLAH Sarah Leigh Phenotypes for gene: OPLAH were changed from Oxoprolinuria (Disorders of the gamma-glutamyl cycle); 5-oxoprolinase deficiency, 260005 to 5-oxoprolinase deficiency 260005
Undiagnosed metabolic disorders v1.213 OCRL Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for both Dent disease 2 300555 and Lowe syndrome 309000. At least 5variants reported in Dent disease 2 300555 and 4 variants in Lowe syndrome 309000.
Undiagnosed metabolic disorders v1.212 OCRL Sarah Leigh Added comment: Comment on phenotypes: Lowe syndrome (Disorders of amino acid transport);Cataracts;Intellectual disability;Intellectual_disability;Renal tract calcification (or Nephrolithiasis/nephrocalcinosis)
Undiagnosed metabolic disorders v1.212 OCRL Sarah Leigh Phenotypes for gene: OCRL were changed from Lowe syndrome (Disorders of amino acid transport); Cataracts; Intellectual disability; Intellectual_disability; Renal tract calcification (or Nephrolithiasis/nephrocalcinosis) to Dent disease 2 300555; Lowe syndrome 309000
Undiagnosed metabolic disorders v1.210 OCRL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.210 OCRL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.210 OCRL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.210 OCRL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.210 OCRL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.210 OCRL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.210 OCRL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.210 NDUFB9 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 1 variant reported, together with supportive functional studies.
Undiagnosed metabolic disorders v1.209 NDUFB9 Sarah Leigh Added comment: Comment on publications: PMID: 22200994 Reports one probound heterozygous for a variant (c.140G>T, p.Arg47Leu) within NDUFB9 with parents not available for genetic testing, and in vitro complement studies in patient fibroblasts showed wildtype NDUFB9 did not rescue complex I activity, therefore was deemed not pathogenic. Reports two brothers homozygous for a variant in the gene, with parents who are heterozygous carriers (c.191T>C, p.Leu64Pro). In vitro, fibroblasts from the proband showed low complex I activity, and wildtype NDUFB9 rescued complex I activity.
Undiagnosed metabolic disorders v1.207 MVK Sarah Leigh Mode of inheritance for gene: MVK was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.206 MVK Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 8 variants reported in Hyper-IgD syndrome 260920, 9 variants reported in Mevalonic aciduria 610377 and 8 variants reported in Porokeratosis 3, multiple types 175900.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants reported for each phenotype.
Undiagnosed metabolic disorders v1.205 MVK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 8 variants reported in Hyper-IgD syndrome 260920, 9 variants reported in Mevalonic aciduria 610377 and 8 variants reported in Porokeratosis 3, multiple types 175900.
Undiagnosed metabolic disorders v1.204 MVK Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.204 MVK Sarah Leigh Added comment: Comment on phenotypes: Mevalonate kinase deficiency (Disorders of sterol biosynthesis);Infantile enterocolitis & monogenic inflammatory bowel disease
Undiagnosed metabolic disorders v1.204 MVK Sarah Leigh Phenotypes for gene: MVK were changed from Mevalonate kinase deficiency (Disorders of sterol biosynthesis); Infantile enterocolitis & monogenic inflammatory bowel disease to Hyper-IgD syndrome 260920; Mevalonic aciduria 610377; Porokeratosis 3, multiple types 175900
Undiagnosed metabolic disorders v1.201 MTPAP Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 2 variants identified in unrelated cases, and supportive functional studies.
Undiagnosed metabolic disorders v1.200 MTFMT Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 8 variants reported.
Undiagnosed metabolic disorders v1.197 MTFMT Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.197 MRPL3 Sarah Leigh Added comment: Comment on list classification: This gene was rated as Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter (May 2019) on behalf of GMS mitochondrial specialist test group: 2 unrelated families (4 sibs + 1 unrelated case) and functional studies. From panel: Possible mitochondrial disorder - nuclear genes (Version 0.187).
Undiagnosed metabolic disorders v1.194 MOCS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in at least 8 unrelated cases, together with supportive functional studies.
Undiagnosed metabolic disorders v1.191 MOCS2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.191 MOCS1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported unrelated cases.
Undiagnosed metabolic disorders v1.188 MOCS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.187 MAOA Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 4 variants reported in unrelated cases.
Undiagnosed metabolic disorders v1.185 MAGT1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 3 variants reported in unrelated cases, together with mouse knock-out model (PMID 29581357).
Undiagnosed metabolic disorders v1.184 MAGT1 Sarah Leigh Phenotypes for gene: MAGT1 were changed from IAP-CDG (Disorders of protein N-glycosylation); Combined B and T cell defect to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia 300853
Undiagnosed metabolic disorders v1.183 MAGT1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.183 LIPC Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.183 LIPC Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two unrelated families with Hepatic lipase deficiency, 614025.
Undiagnosed metabolic disorders v1.182 LIPC Sarah Leigh Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two unrelated families with Hepatic lipase deficiency, 614025.
Undiagnosed metabolic disorders v1.177 LDLRAP1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 11 variants reported.
Undiagnosed metabolic disorders v1.173 LDLR Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Over 2000 variants reported.
Undiagnosed metabolic disorders v1.171 LDLR Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.169 LBR Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for Greenberg skeletal dysplasia 215140. At least 15 variants have been reported, in 5 unrelated cases of Pelger-Huet anomaly 169400, 3 unrelated cases of Pelger-Huet anomaly with mild skeletal anomalies 618019, 5 unrelated cases of Greenberg skeletal dysplasia 215140 and in a single case of ?Reynolds syndrome 613471.
Undiagnosed metabolic disorders v1.168 LBR Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.168 LBR Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.168 LBR Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.168 LBR Sarah Leigh Added comment: Comment on phenotypes: Greenberg skeletal dysplasia (Disorders of sterol biosynthesis);Fetal hydrops;Unexplained skeletal dysplasia
Undiagnosed metabolic disorders v1.168 LBR Sarah Leigh Phenotypes for gene: LBR were changed from Greenberg skeletal dysplasia (Disorders of sterol biosynthesis); Fetal hydrops; Unexplained skeletal dysplasia to ?Reynolds syndrome 613471; Greenberg skeletal dysplasia 215140; Pelger-Huet anomaly 169400; Pelger-Huet anomaly with mild skeletal anomalies 618019
Undiagnosed metabolic disorders v1.167 ISCU Sarah Leigh Added comment: Comment on list classification: Sufficient published reported biallelic cases, with supportive functional studies. The most frequent reported variant c.343+382G>C g.108567650G>C is deep in intron five of the gene and strengthens a weak splicing acceptor site, with consequent retention of a 100-bp intronic sequence upstream of the known terminal exon, introduction of a stop codon and decreased levels of ISCU mRNA and protein (PMID 18304497). This may be missed by standard sequencing.
Undiagnosed metabolic disorders v1.166 ISCU Sarah Leigh Tag non-coding-known-pathogenic tag was added to gene: ISCU.
Undiagnosed metabolic disorders v1.165 ISCU Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.165 HSD17B10 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for 2-methyl-3-hydroxybutyrylL-coA dehydrogenase deficiency and for mental retardation syndromic X-linked type 10 . At least 8 variants reported.
Undiagnosed metabolic disorders v1.163 HSD17B10 Sarah Leigh Added comment: Comment on phenotypes: 2-Methyl-3-hydroxybutyric aciduria, HSD10 disease (Organic acidurias);Intellectual disability;Intellectual_disability
Undiagnosed metabolic disorders v1.163 HSD17B10 Sarah Leigh Phenotypes for gene: HSD17B10 were changed from 2-Methyl-3-hydroxybutyric aciduria, HSD10 disease (Organic acidurias); Intellectual disability; Intellectual_disability to HSD10 mitochondrial disease 300438
Undiagnosed metabolic disorders v1.162 HSD17B10 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.162 HSD17B10 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.162 HSD17B10 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.161 HPS1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in at least 5 unrelated cases.
Undiagnosed metabolic disorders v1.160 HPS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.160 HPS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.160 HPS1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.160 HPS1 Sarah Leigh Added comment: Comment on phenotypes: Hermansky-Pudlak Syndrome (Other lysosomal disorders);Infantile enterocolitis & monogenic inflammatory bowel disease;Inherited bleeding disorders
Undiagnosed metabolic disorders v1.160 HPS1 Sarah Leigh Phenotypes for gene: HPS1 were changed from Hermansky-Pudlak Syndrome (Other lysosomal disorders); Infantile enterocolitis & monogenic inflammatory bowel disease; Inherited bleeding disorders to Hermansky-Pudlak syndrome 1 203300
Undiagnosed metabolic disorders v1.158 HPD Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for both phenotypes. At least 4 variants reported in unrelated cases of Tyrosinemia, type III 276710 and 4 variants in 6 unrelated cases of Hawkinsinuria 140350 (at least 2 of these cases were compound heterozygotes).
Undiagnosed metabolic disorders v1.155 HPD Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.155 HADH Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. Numerous variants reported in unrelated cases of Hyperinsulinemic hypoglycemia, familial, 4 609975.
Undiagnosed metabolic disorders v1.152 HADH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.152 HADH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.152 HADH Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.152 GNMT Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in 2 unrelated cases, with supportive functional data.
Undiagnosed metabolic disorders v1.150 GLUL Sarah Leigh Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 3 variants reported in unrelated cases.
Undiagnosed metabolic disorders v1.148 GLUL Sarah Leigh Added comment: Comment on phenotypes: Glutamine deficiency, congenital (Other disorder of amino acid metabolism);Intellectual disability
Undiagnosed metabolic disorders v1.148 GLUL Sarah Leigh Phenotypes for gene: GLUL were changed from Glutamine deficiency, congenital (Other disorder of amino acid metabolism); Intellectual disability to Glutamine deficiency, congenital 610015
Undiagnosed metabolic disorders v1.147 GLUL Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.147 GK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 8 variants reported.
Undiagnosed metabolic disorders v1.146 GK Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.146 GK Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.145 GK Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 8 variants reported.
Undiagnosed metabolic disorders v1.144 GK Sarah Leigh Added comment: Comment on mode of inheritance: This moi has been changed to be in with OMIM and Gen2Phen.
Undiagnosed metabolic disorders v1.143 GK Sarah Leigh Mode of inheritance for gene: GK was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Undiagnosed metabolic disorders v1.141 GK Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.141 GK Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.141 GK Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.140 GAMT Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in 4 unrelated cases.
Undiagnosed metabolic disorders v1.138 FTCD Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 15 variants reported.
Undiagnosed metabolic disorders v1.137 FGFR2 Sarah Leigh Mode of inheritance for gene: FGFR2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Undiagnosed metabolic disorders v1.136 FGFR2 Sarah Leigh Added comment: Comment on list classification: Associated with 14 phenotypes in OMIM and as confirmed Gen2Phen gene for acrocephalosyndactyly type V, Antley-Bixler syndrome, Apert syndrome, Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome, familial scaphocephaly syndrome, Jackson-Weiss syndrome, lacrimo-auriculo-dento-digital syndrome. At least 44 variants reported.
Undiagnosed metabolic disorders v1.135 FGFR2 Sarah Leigh Phenotypes for gene: FGFR2 were changed from Antley-Bixler syndrome type without disordered steroidogenesis; Arthrogryposis; Bilateral microtia; Choanal atresia; Craniosynostosis syndromes phenotypes; Deafness and congenital structural abnormalities; Unexplained skeletal dysplasia to Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis 207410; Apert syndrome 101200; Beare-Stevenson cutis gyrata syndrome 123790; Bent bone dysplasia syndrome 614592; Craniofacial-skeletal-dermatologic dysplasia 101600; Craniosynostosis, nonspecific; Crouzon syndrome 123500; Gastric cancer, somatic 613659; Jackson-Weiss syndrome 123150; LADD syndrome 149730; Pfeiffer syndrome 101600; Saethre-Chotzen syndrome 101400; Scaphocephaly and Axenfeld-Rieger anomaly; Scaphocephaly, maxillary retrusion, and mental retardation 609579
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 FGFR2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.134 DPM3 Sarah Leigh Phenotypes for gene: DPM3 were changed from DMP3-CDG (other congenital disorders of glycosylation); Congenital disorder of glycosylation, type Io 612937 to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 612937
Undiagnosed metabolic disorders v1.132 DPM3 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported as homozygotes in two unrelated cases, together with segregation and supportive functional studies.
Undiagnosed metabolic disorders v1.131 DHDDS Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.131 DHDDS Sarah Leigh changed review comment from: Amber review assigned as this gene is Green on the V1 panel(s) named as a phenotype(s); to: Amber review assigned as this gene is Green on the V1 panel(s) named as a phenotype(s)
Undiagnosed metabolic disorders v1.131 TANGO2 Sarah Leigh Added comment: Comment on list classification: Based on recommendations of Helen Britain (Clinical Fellow, Genomics England) as cases will have of periods of decompensation that are associated with hypoglycaemia and hyperammonaemia.
Undiagnosed metabolic disorders v1.130 TANGO2 Sarah Leigh gene: TANGO2 was added
gene: TANGO2 was added to Undiagnosed metabolic disorders. Sources: Other
Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TANGO2 were set to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration 616878
Review for gene: TANGO2 was set to GREEN
Added comment: Sources: Other
Undiagnosed metabolic disorders v1.129 STAT2 Sarah Leigh Added comment: Comment on list classification: Based on recommendation of Helen Britain (Clinical Fellow, Genomics England), that the majority of cases will be presenting in the context of overwhelming infection. The raised lactate and encephalomyopathy are potentially relevant phenotypes for this panel, however more evidence is needed on how common this presentation is, and whether it is always clearly associated with a proven infection.
Undiagnosed metabolic disorders v1.128 STAT2 Sarah Leigh gene: STAT2 was added
gene: STAT2 was added to Undiagnosed metabolic disorders. Sources: Other
Mode of inheritance for gene: STAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STAT2 were set to Immunodeficiency 44 616636
Review for gene: STAT2 was set to AMBER
Added comment: Sources: Other
Undiagnosed metabolic disorders v1.127 IER3IP1 Sarah Leigh Added comment: Comment on list classification: Based on recommendation of Helen Britain (Clinical Fellow, Genomics England), that patients will present with features of microcephaly / neonatal diabetes / developmental delay, rather than metabolic disorder.
Undiagnosed metabolic disorders v1.126 IER3IP1 Sarah Leigh gene: IER3IP1 was added
gene: IER3IP1 was added to Undiagnosed metabolic disorders. Sources: Other
Mode of inheritance for gene: IER3IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IER3IP1 were set to 21835305; 22991235; 24138066
Phenotypes for gene: IER3IP1 were set to Microcephaly, epilepsy, and diabetes syndrome 614231
Review for gene: IER3IP1 was set to AMBER
Added comment: Sources: Other
Undiagnosed metabolic disorders v1.124 POLG2 Sarah Leigh Added comment: Comment on mode of inheritance: Reporting and characterization of a homozygous POLG2 variant in mitochondrial DNA depletion syndrome and in an autosomal recessive epilepsy family without ophthalmoplegia (PMID 27592148; 30157269; 31286721).
Undiagnosed metabolic disorders v1.124 POLG2 Sarah Leigh Mode of inheritance for gene: POLG2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.123 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Hereditary ataxia to Friedreich ataxia, 229300; Friedreich ataxia with retained reflexes, 229300; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Undiagnosed metabolic disorders v1.122 FXN Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 9 variants identified in unrelated cases.
FXN is rated Red on the mitochondrial panels on the recommendation of the GMS mitochondrial specialist test group, including by Carl Fratter (Oxford University Hospitals NHS Trust). As it is associated with Friedreich’s ataxia, which is technically a mitochondrial disorder, but the phenotype is different to other mitochondrial conditions.
Undiagnosed metabolic disorders v1.121 FXN Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.121 RANBP2 Sarah Leigh Added comment: Comment on list classification: Demoted RANBP2 from Green to Amber following review by Zornitza Stark and agreement from Helen Brittain (Genomics England clinical team). Recent papers report patients with symptoms (including seizures) after a viral illness (PMID:30796099, PMID:28336122, PMID:25128471). However, listed as a susceptibility locus in OMIM, and papers report incomplete penetrance: variant present in asymptomatic maternal grandmother in PMID:30796099 and in the father in PMID:28336122. Therefore further information (e.g. on penetrance) is required for a clear gene:disease association.
Undiagnosed metabolic disorders v1.120 PGAM2 Sarah Leigh changed review comment from: Comment on list classification: Additional case with biallelic variant and rhabdomyolysis; to: Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 4 variants identified in 3 unrelated cases.
Undiagnosed metabolic disorders v1.120 MANBA Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.120 DHCR7 Sarah Leigh Added comment: Comment on list classification: Associated with phenotype in OMIM and as confirmed Gen2Phen gene. At least 21 variants reported.
Undiagnosed metabolic disorders v1.119 DHCR7 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.119 DHCR7 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.119 DHCR7 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.119 DHCR7 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.119 DHCR7 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.119 DHCR7 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.119 DHCR7 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.119 SDHB Sarah Leigh Added comment: Comment on phenotypes: Cowden syndrome 2, 612359 has been removed from SDHB as this gene is not associated with this phenotype.
Undiagnosed metabolic disorders v1.117 FUT8 Louise Daugherty gene: FUT8 was added
gene: FUT8 was added to Undiagnosed metabolic disorders. Sources: Expert Review
Mode of inheritance for gene: FUT8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUT8 were set to 29304374
Phenotypes for gene: FUT8 were set to Congenital disorder of glycosylation with defective fucosylation, 618005
Review for gene: FUT8 was set to GREEN
Added comment: Adding to Undiagnosed metabolic disorders panel after reviewing panels for GMS, as recommended by the Genomics England clinical team, to benefit the 100K participants. Enough evidence to support gene-disease association and relevance to this panel to rate this gene Green.
Sources: Expert Review
Undiagnosed metabolic disorders v1.106 UQCRQ Sarah Leigh Added comment: Comment on list classification: Amber review collated by Carl Fratter (May 2019) on behalf of GMS mitochondrial specialist test group: One variant reported in a consanguineous Israeli Bedouin kindred with Mitochondrial complex III deficiency, nuclear type 4 (615159)(PMID: 18439546).
Undiagnosed metabolic disorders v1.104 UQCRB Sarah Leigh reviewed gene: UQCRB: Rating: ; Mode of pathogenicity: None; Publications: 28604960, 18439546; Phenotypes: Mitochondrial complex III deficiency, nuclear type 3 615158; Mode of inheritance: None
Undiagnosed metabolic disorders v1.104 MANBA Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in 6 unrelated cases.
Undiagnosed metabolic disorders v1.103 ASAH1 Sarah Leigh Phenotypes for gene: ASAH1 were changed from Farber disease (Sphingolipidoses); Fetal hydrops; Intellectual disability to Spinal muscular atrophy with progressive myoclonic epilepsy 159950; Farber lipogranulomatosis 228000; Fetal hydrops; Intellectual disability
Undiagnosed metabolic disorders v1.102 ASAH1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 7 variants reported in 6 cases of Farber lipogranulomatosis 228000 and 5 variants in 3 cases of Spinal muscular atrophy with progressive myoclonic epilepsy 159950.
Undiagnosed metabolic disorders v1.98 PGAM2 Sarah Leigh Added comment: Comment on list classification: Additional case with biallelic variant and rhabdomyolysis
Undiagnosed metabolic disorders v1.97 PGAM2 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.97 NDUFA1 Ellen McDonagh Added comment: Comment on mode of inheritance: Changed from 'Both monoallelic and biallelic' to X-linked, as encoded on the X-chromosome. One study reports a female with a heterozygous variant who developed a very mild form of complex I deficiency due to skewed X inactivation [PMID: 21596602].
Undiagnosed metabolic disorders v1.97 NDUFA1 Ellen McDonagh Mode of inheritance for gene: NDUFA1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Undiagnosed metabolic disorders v1.95 ATAD3A Ivone Leong Added comment: Comment on list classification: New gene added by external expert and reviewed by curation team and the clinical team: Sufficient evidence has been provided by the external expert review for this gene to be rated green.
Other aspects of the phenotype may warrant for this gene to be included on alternative specific panels (i.e. intellectual disability); however, not enough evidence is available at the moment. Therefore, this gene has also been added to the "watchlist" so that more cases can be collected.
Undiagnosed metabolic disorders v1.94 ATAD3A Ivone Leong Added comment: Comment on mode of pathogenicity: There is a recurrent missense variant thought to act in a dominant negative manner.
Undiagnosed metabolic disorders v1.94 ATAD3A Ivone Leong Mode of pathogenicity for gene: ATAD3A was changed from None to Other
Undiagnosed metabolic disorders v1.93 ATAD3A Ivone Leong Added comment: Comment on mode of inheritance: As the carrier parents of the biallelic cases do not appear to have any phenotype, have given this a biallelic mode of inheritance.
Undiagnosed metabolic disorders v1.93 ATAD3A Ivone Leong Mode of inheritance for gene: ATAD3A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.92 SLC35A1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green as agreed with Helen Brittain following review of 2018 paper (PMID:30115659) and promotion to Green on the 'Congenital disorders of glycosylation' panel. In addition to the 'leaky' polymorphism reported in PMID:15576474, there are 3 cases (PMIDs 23873973, 28856833, 30115659) to support causation of glycosylation disorder.
Undiagnosed metabolic disorders v1.90 ATAD3A Julia Baptista gene: ATAD3A was added
gene: ATAD3A was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: ATAD3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 27640307
Phenotypes for gene: ATAD3A were set to Lactic acidosis; Methylglutaconic aciduria; Neurological abnormalities; Cerebellar hypoplasia; Optic atrophy; Hypertrophic cardiomyopathy; Scoliosis; Spinal muscular atrophy
Review for gene: ATAD3A was set to GREEN
gene: ATAD3A was marked as current diagnostic
Added comment: A raised plasma lactate was reported in 4/7 families and methylglutaconic aciduria in 3/7 families (PMID: 27640307). Multiple patients with a diagnosis are described as having "severe metabolic disease".
Sources: Literature
Undiagnosed metabolic disorders v1.90 RRM2B Rebecca Foulger Phenotypes for gene: RRM2B were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Mitochondrial Ribonucelotide Reductase subunit 2 deficiency (Disorders of purine metabolism); Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; Progressive external ophthalmoplegia with mitochondrial DNA deletions (autosomal dominant); 5,613077Mitochondrial DNA depletion syndrome 8B (MNGIE type), 612075; Mitochondrial DNA Depletion Syndrome (recessive) to Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Mitochondrial Ribonucelotide Reductase subunit 2 deficiency (Disorders of purine metabolism); Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5, 613077; Mitochondrial DNA depletion syndrome 8B (MNGIE type), 612075; Mitochondrial DNA Depletion Syndrome (recessive)
Undiagnosed metabolic disorders v1.88 TWNK Rebecca Foulger Phenotypes for gene: TWNK were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) ; Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia, autosomal dominant, 3, 609286Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions (monoallelic); Mitochondrial Membrane Protein-Associated Neurodegeneration (biallelic); Mitochondrial DNA Depletion Syndrome (biallelic) to Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia, autosomal dominant, 3, 609286; Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions (monoallelic); Mitochondrial Membrane Protein-Associated Neurodegeneration (biallelic); Mitochondrial DNA Depletion Syndrome (biallelic)
Undiagnosed metabolic disorders v1.87 SLC25A4 Rebecca Foulger Phenotypes for gene: SLC25A4 were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Disorders of mitochondrial protein transport; Progressive external ophthalmoplegia with mitochondrial DNA deletions 3, 609283Mitochondrial DNA depletion syndrome 12 (cardiomyopathic type), 615418; Progressive External Ophthalmoplegia with Mitochondrial DNADeletions to Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Disorders of mitochondrial protein transport; Progressive external ophthalmoplegia with mitochondrial DNA deletions 3, 609283; Mitochondrial DNA depletion syndrome 12 (cardiomyopathic type), 615418; Progressive External Ophthalmoplegia with Mitochondrial DNADeletions
Undiagnosed metabolic disorders v1.86 SCO2 Rebecca Foulger Phenotypes for gene: SCO2 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Isolated complex IV deficiency; Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1, 604377Myopia 6, 608908; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Isolated complex IV deficiency; Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1, 604377; Myopia 6, 608908; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency
Undiagnosed metabolic disorders v1.82 GLS Saikat Santra reviewed gene: GLS: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29468182; Phenotypes: Intellectual disability, Ataxia, Optic Atrophy; Mode of inheritance: None
Undiagnosed metabolic disorders v1.82 UPB1 Saikat Santra reviewed gene: UPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24526388, 25638458, 22525402; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.82 BCAT2 Saikat Santra reviewed gene: BCAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25653144; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.82 GAMT Saikat Santra reviewed gene: GAMT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Creatine deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.82 DHCR7 Saikat Santra reviewed gene: DHCR7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dysmorphism, Cataract; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.82 RPIA Sarah Leigh commented on gene: RPIA: Review by Konstantinos Varvagiannis for the Genetic Epilepsy syndromes panel. 9 Dec 2018, 1:44 a.m.
Panel version: 0.1488
Biallelic pathogenic variants in RPIA cause Ribose 5-phosphate isomerase deficiency, MIM 608611. PMID: 14988808 is the first report on the disorder with molecular (incl. genetic) confirmation of the diagnosis. A patient initially investigated for early developmental delay, leukoencephalopathy, seizures with onset at 4 years, with subsequent neurologic regression and peripheral neuropathy at the age of 7, was suspected to have a disorder of the pentose phosphate pathway on the basis of highly elevated polyols on brain MRS and body fluid analysis. Reduced ribose 5-phosphate isomerase activity was shown in fibroblasts. Genetic testing demonstrated the presence of a missense (NM_144563.2:c.404C>T or p.Ala135Val - previously referred to as A61V) as well as a frameshift variant (NM_144563.2:c.762delG or p.Asn255Ilefs). Additional extensive supportive functional studies were published a few years later (PMID: 20499043). [This patient was initially described in PMID: 10589548]. PMID: 28801340 is a report on a second patient. This individual presented with delayed early development (independent walking and speech achieved at 2 and 5 years respectively), seizures and regression at the age of 7 with MRI white matter abnormalities. Review of magnetic resonance spectroscopy (MRS) was suggestive of elevated polyols (arabitol and ribitol). In line with this, genetic testing revealed a homozygous missense variant in RPIA (NM_144563.2:c.592T>C or p.Phe198Leu). Urine analysis confirmed elevated excretion of polyols, thus confirming the diagnosis. PMID: 30088433 reports on a boy with neonatal onset leukoencephalopathy and developmental delay having undergone early metabolic testing and aCGH (the latter at the age of 16 months). Persistance of his delay motivated exome sequencing at the age of approx. 4.5 years which demonstrated 2 RPIA variants (NM_144563.2:c.253G>A or p.Ala85Thr and NM_144563.2:c.347-1G>A). Measurement of ribitol and arabitol in urine demonstrated significant elevations (>20x) consistent with this diagnosis. 2 of the 3 patients described in the literature presented seizures. As a result this gene can be considered for inclusion in this panel as amber. [This gene is also present in the Undiagnosed metabolic disorders gene panel as red. Please consider upgrade based on these further publications.]. Sources: Literature
Undiagnosed metabolic disorders v1.79 ATXN7_CAG Louise Daugherty Added comment: Comment on list classification: Removed STR from Panel. This STR was not listed on the recent GMC STRs document supplied by Arianna Tucci.
Undiagnosed metabolic disorders v1.79 ATXN7_CAG Louise Daugherty Str: atxn7_cag has been removed from the panel.
Undiagnosed metabolic disorders v1.78 ISCA-37440-Loss Louise Daugherty Region: ISCA-37440-Loss was added
Region: ISCA-37440-Loss was added to Undiagnosed metabolic disorders. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37440-Loss was set to BIALLELIC, autosomal or pseudoautosomal
Publications for Region: ISCA-37440-Loss were set to 11524703; 18234729; 16385448
Phenotypes for Region: ISCA-37440-Loss were set to mild/moderate mental retardation; facial dysmorphism; Hypotonia-cystinuria syndrome (HCS); 2p21 deletion syndrome; rapid weight gain in late childhood; failure to thrive; growth hormone deficiency; 606407; lactic acidemia; respiratory chain complex IV deficiency; hyperphagia; minor facial dysmorphism; severe somatic and developmental delay; nephrolithiasis; cystinuria; neonatal seizures; hypotonia
Undiagnosed metabolic disorders PEX11A Louise Daugherty edited their review of PEX11A
Undiagnosed metabolic disorders ABCG2 Sarah Leigh edited their review of ABCG2
Undiagnosed metabolic disorders CD320 Sarah Leigh edited their review of CD320
Undiagnosed metabolic disorders CD320 Sarah Leigh edited their review of CD320
Undiagnosed metabolic disorders MTHFD1 Sarah Leigh marked MTHFD1 as ready
Undiagnosed metabolic disorders SLC52A3 Sarah Leigh edited their review of SLC52A3
Undiagnosed metabolic disorders SLC52A2 Sarah Leigh edited their review of SLC52A2
Undiagnosed metabolic disorders SLC52A1 Sarah Leigh edited their review of SLC52A1
Undiagnosed metabolic disorders MTHFD1 Sarah Leigh reviewed MTHFD1
Undiagnosed metabolic disorders HCFC1 Sarah Leigh edited their review of HCFC1
Undiagnosed metabolic disorders GLRA1 Sarah Leigh edited their review of GLRA1
Undiagnosed metabolic disorders GABRG2 Sarah Leigh edited their review of GABRG2
Undiagnosed metabolic disorders CTH Sarah Leigh marked CTH as ready
Undiagnosed metabolic disorders CTH Sarah Leigh commented on CTH
Undiagnosed metabolic disorders SETX Sarah Leigh edited their review of SETX
Undiagnosed metabolic disorders WFS1 Sarah Leigh edited their review of WFS1
Undiagnosed metabolic disorders WFS1 Sarah Leigh edited their review of WFS1
Undiagnosed metabolic disorders WFS1 Sarah Leigh edited their review of WFS1
Undiagnosed metabolic disorders WFS1 Sarah Leigh edited their review of WFS1
Undiagnosed metabolic disorders WFS1 Sarah Leigh edited their review of WFS1
Undiagnosed metabolic disorders WDR45 Sarah Leigh edited their review of WDR45
Undiagnosed metabolic disorders WDR45 Sarah Leigh edited their review of WDR45
Undiagnosed metabolic disorders WDR45 Sarah Leigh edited their review of WDR45
Undiagnosed metabolic disorders WDR45 Sarah Leigh edited their review of WDR45
Undiagnosed metabolic disorders VPS33B Sarah Leigh edited their review of VPS33B
Undiagnosed metabolic disorders VPS33B Sarah Leigh edited their review of VPS33B
Undiagnosed metabolic disorders VPS33B Sarah Leigh edited their review of VPS33B
Undiagnosed metabolic disorders VPS33B Sarah Leigh edited their review of VPS33B
Undiagnosed metabolic disorders VIPAS39 Sarah Leigh edited their review of VIPAS39
Undiagnosed metabolic disorders VIPAS39 Sarah Leigh edited their review of VIPAS39
Undiagnosed metabolic disorders UMOD Sarah Leigh edited their review of UMOD
Undiagnosed metabolic disorders UMOD Sarah Leigh edited their review of UMOD
Undiagnosed metabolic disorders TREX1 Sarah Leigh edited their review of TREX1
Undiagnosed metabolic disorders TREX1 Sarah Leigh edited their review of TREX1
Undiagnosed metabolic disorders TREX1 Sarah Leigh edited their review of TREX1
Undiagnosed metabolic disorders TREX1 Sarah Leigh edited their review of TREX1
Undiagnosed metabolic disorders TPP1 Sarah Leigh edited their review of TPP1
Undiagnosed metabolic disorders TPP1 Sarah Leigh edited their review of TPP1
Undiagnosed metabolic disorders TH Sarah Leigh edited their review of TH
Undiagnosed metabolic disorders TH Sarah Leigh edited their review of TH
Undiagnosed metabolic disorders TH Sarah Leigh edited their review of TH
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders SUMF1 Sarah Leigh edited their review of SUMF1
Undiagnosed metabolic disorders SUMF1 Sarah Leigh edited their review of SUMF1
Undiagnosed metabolic disorders SUMF1 Sarah Leigh edited their review of SUMF1
Undiagnosed metabolic disorders SPTLC2 Sarah Leigh edited their review of SPTLC2
Undiagnosed metabolic disorders SPTLC2 Sarah Leigh edited their review of SPTLC2
Undiagnosed metabolic disorders SPTLC1 Sarah Leigh edited their review of SPTLC1
Undiagnosed metabolic disorders SPTLC1 Sarah Leigh edited their review of SPTLC1
Undiagnosed metabolic disorders SPR Sarah Leigh edited their review of SPR
Undiagnosed metabolic disorders WFS1 Sarah Leigh edited their review of WFS1
Undiagnosed metabolic disorders SPR Sarah Leigh edited their review of SPR
Undiagnosed metabolic disorders WFS1 Sarah Leigh edited their review of WFS1
Undiagnosed metabolic disorders SPR Sarah Leigh edited their review of SPR
Undiagnosed metabolic disorders WFS1 Sarah Leigh edited their review of WFS1
Undiagnosed metabolic disorders SMPD1 Sarah Leigh edited their review of SMPD1
Undiagnosed metabolic disorders WFS1 Sarah Leigh edited their review of WFS1
Undiagnosed metabolic disorders SMPD1 Sarah Leigh edited their review of SMPD1
Undiagnosed metabolic disorders WDR45 Sarah Leigh edited their review of WDR45
Undiagnosed metabolic disorders WDR45 Sarah Leigh edited their review of WDR45
Undiagnosed metabolic disorders WDR45 Sarah Leigh edited their review of WDR45
Undiagnosed metabolic disorders SLC6A3 Sarah Leigh edited their review of SLC6A3
Undiagnosed metabolic disorders SLC6A3 Sarah Leigh edited their review of SLC6A3
Undiagnosed metabolic disorders VPS33B Sarah Leigh edited their review of VPS33B
Undiagnosed metabolic disorders SLC6A3 Sarah Leigh edited their review of SLC6A3
Undiagnosed metabolic disorders VPS33B Sarah Leigh edited their review of VPS33B
Undiagnosed metabolic disorders VPS33B Sarah Leigh edited their review of VPS33B
Undiagnosed metabolic disorders SLC30A10 Sarah Leigh edited their review of SLC30A10
Undiagnosed metabolic disorders SLC30A10 Sarah Leigh edited their review of SLC30A10
Undiagnosed metabolic disorders VIPAS39 Sarah Leigh edited their review of VIPAS39
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders UMOD Sarah Leigh edited their review of UMOD
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders SLC17A5 Sarah Leigh edited their review of SLC17A5
Undiagnosed metabolic disorders TREX1 Sarah Leigh edited their review of TREX1
Undiagnosed metabolic disorders SLC17A5 Sarah Leigh edited their review of SLC17A5
Undiagnosed metabolic disorders TREX1 Sarah Leigh edited their review of TREX1
Undiagnosed metabolic disorders SLC17A5 Sarah Leigh edited their review of SLC17A5
Undiagnosed metabolic disorders TREX1 Sarah Leigh edited their review of TREX1
Undiagnosed metabolic disorders SLC17A5 Sarah Leigh edited their review of SLC17A5
Undiagnosed metabolic disorders TPP1 Sarah Leigh edited their review of TPP1
Undiagnosed metabolic disorders SETX Sarah Leigh edited their review of SETX
Undiagnosed metabolic disorders TH Sarah Leigh edited their review of TH
Undiagnosed metabolic disorders SETX Sarah Leigh edited their review of SETX
Undiagnosed metabolic disorders TH Sarah Leigh edited their review of TH
Undiagnosed metabolic disorders SETX Sarah Leigh edited their review of SETX
Undiagnosed metabolic disorders TH Sarah Leigh reviewed TH
Undiagnosed metabolic disorders SDHC Sarah Leigh edited their review of SDHC
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders SDHC Sarah Leigh edited their review of SDHC
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders SDHC Sarah Leigh edited their review of SDHC
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders SDHAF2 Sarah Leigh edited their review of SDHAF2
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders SDHAF2 Sarah Leigh edited their review of SDHAF2
Undiagnosed metabolic disorders TCN2 Sarah Leigh edited their review of TCN2
Undiagnosed metabolic disorders SDHAF2 Sarah Leigh edited their review of SDHAF2
Undiagnosed metabolic disorders SC5D Sarah Leigh edited their review of SC5D
Undiagnosed metabolic disorders SC5D Sarah Leigh edited their review of SC5D
Undiagnosed metabolic disorders RNASET2 Sarah Leigh edited their review of RNASET2
Undiagnosed metabolic disorders SUMF1 Sarah Leigh edited their review of SUMF1
Undiagnosed metabolic disorders RNASET2 Sarah Leigh edited their review of RNASET2
Undiagnosed metabolic disorders SUMF1 Sarah Leigh edited their review of SUMF1
Undiagnosed metabolic disorders RNASEH2C Sarah Leigh edited their review of RNASEH2C
Undiagnosed metabolic disorders RNASEH2C Sarah Leigh edited their review of RNASEH2C
Undiagnosed metabolic disorders RNASEH2C Sarah Leigh edited their review of RNASEH2C
Undiagnosed metabolic disorders SPTLC2 Sarah Leigh edited their review of SPTLC2
Undiagnosed metabolic disorders RNASEH2B Sarah Leigh edited their review of RNASEH2B
Undiagnosed metabolic disorders RNASEH2B Sarah Leigh edited their review of RNASEH2B
Undiagnosed metabolic disorders SPTLC1 Sarah Leigh edited their review of SPTLC1
Undiagnosed metabolic disorders RNASEH2B Sarah Leigh edited their review of RNASEH2B
Undiagnosed metabolic disorders RNASEH2A Sarah Leigh edited their review of RNASEH2A
Undiagnosed metabolic disorders SPR Sarah Leigh edited their review of SPR
Undiagnosed metabolic disorders RNASEH2A Sarah Leigh edited their review of RNASEH2A
Undiagnosed metabolic disorders SPR Sarah Leigh edited their review of SPR
Undiagnosed metabolic disorders RNASEH2A Sarah Leigh edited their review of RNASEH2A
Undiagnosed metabolic disorders SMPD1 Sarah Leigh edited their review of SMPD1
Undiagnosed metabolic disorders PSPH Sarah Leigh edited their review of PSPH
Undiagnosed metabolic disorders PSPH Sarah Leigh edited their review of PSPH
Undiagnosed metabolic disorders PRPS1 Sarah Leigh edited their review of PRPS1
Undiagnosed metabolic disorders SLC6A3 Sarah Leigh edited their review of SLC6A3
Undiagnosed metabolic disorders PRPS1 Sarah Leigh edited their review of PRPS1
Undiagnosed metabolic disorders SLC6A3 Sarah Leigh edited their review of SLC6A3
Undiagnosed metabolic disorders PRPS1 Sarah Leigh edited their review of PRPS1
Undiagnosed metabolic disorders PRPS1 Sarah Leigh edited their review of PRPS1
Undiagnosed metabolic disorders PRKAG2 Sarah Leigh edited their review of PRKAG2
Undiagnosed metabolic disorders PRKAG2 Sarah Leigh edited their review of PRKAG2
Undiagnosed metabolic disorders SLC30A10 Sarah Leigh edited their review of SLC30A10
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders POR Sarah Leigh edited their review of POR
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders POR Sarah Leigh edited their review of POR
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders POR Sarah Leigh edited their review of POR
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders SLC2A1 Sarah Leigh edited their review of SLC2A1
Undiagnosed metabolic disorders PLA2G6 Sarah Leigh edited their review of PLA2G6
Undiagnosed metabolic disorders PLA2G6 Sarah Leigh edited their review of PLA2G6
Undiagnosed metabolic disorders PLA2G6 Sarah Leigh edited their review of PLA2G6
Undiagnosed metabolic disorders PLA2G6 Sarah Leigh edited their review of PLA2G6
Undiagnosed metabolic disorders PINK1 Sarah Leigh edited their review of PINK1
Undiagnosed metabolic disorders SLC17A5 Sarah Leigh edited their review of SLC17A5
Undiagnosed metabolic disorders PINK1 Sarah Leigh edited their review of PINK1
Undiagnosed metabolic disorders SLC17A5 Sarah Leigh edited their review of SLC17A5
Undiagnosed metabolic disorders SLC17A5 Sarah Leigh edited their review of SLC17A5
Undiagnosed metabolic disorders PHGDH Sarah Leigh edited their review of PHGDH
Undiagnosed metabolic disorders PHGDH Sarah Leigh edited their review of PHGDH
Undiagnosed metabolic disorders PGK1 Sarah Leigh edited their review of PGK1
Undiagnosed metabolic disorders PGK1 Sarah Leigh edited their review of PGK1
Undiagnosed metabolic disorders PGK1 Sarah Leigh edited their review of PGK1
Undiagnosed metabolic disorders SETX Sarah Leigh edited their review of SETX
Undiagnosed metabolic disorders PFKM Sarah Leigh edited their review of PFKM
Undiagnosed metabolic disorders SETX Sarah Leigh edited their review of SETX
Undiagnosed metabolic disorders PFKM Sarah Leigh edited their review of PFKM
Undiagnosed metabolic disorders SDHC Sarah Leigh edited their review of SDHC
Undiagnosed metabolic disorders SDHC Sarah Leigh edited their review of SDHC
Undiagnosed metabolic disorders PANK2 Sarah Leigh edited their review of PANK2
Undiagnosed metabolic disorders PANK2 Sarah Leigh edited their review of PANK2
Undiagnosed metabolic disorders SDHAF2 Sarah Leigh edited their review of SDHAF2
Undiagnosed metabolic disorders PANK2 Sarah Leigh edited their review of PANK2
Undiagnosed metabolic disorders SDHAF2 Sarah Leigh edited their review of SDHAF2
Undiagnosed metabolic disorders OCRL Sarah Leigh edited their review of OCRL
Undiagnosed metabolic disorders SC5D Sarah Leigh edited their review of SC5D
Undiagnosed metabolic disorders RNASET2 Sarah Leigh edited their review of RNASET2
Undiagnosed metabolic disorders OCRL Sarah Leigh edited their review of OCRL
Undiagnosed metabolic disorders OCRL Sarah Leigh edited their review of OCRL
Undiagnosed metabolic disorders RNASEH2C Sarah Leigh edited their review of RNASEH2C
Undiagnosed metabolic disorders OCRL Sarah Leigh edited their review of OCRL
Undiagnosed metabolic disorders NPC2 Sarah Leigh edited their review of NPC2
Undiagnosed metabolic disorders RNASEH2C Sarah Leigh edited their review of RNASEH2C
Undiagnosed metabolic disorders NPC2 Sarah Leigh edited their review of NPC2
Undiagnosed metabolic disorders NPC1 Sarah Leigh edited their review of NPC1
Undiagnosed metabolic disorders NPC1 Sarah Leigh edited their review of NPC1
Undiagnosed metabolic disorders NPC1 Sarah Leigh edited their review of NPC1
Undiagnosed metabolic disorders RNASEH2B Sarah Leigh edited their review of RNASEH2B
Undiagnosed metabolic disorders RNASEH2B Sarah Leigh edited their review of RNASEH2B
Undiagnosed metabolic disorders RNASEH2A Sarah Leigh edited their review of RNASEH2A
Undiagnosed metabolic disorders RNASEH2A Sarah Leigh edited their review of RNASEH2A
Undiagnosed metabolic disorders MMACHC Sarah Leigh edited their review of MMACHC
Undiagnosed metabolic disorders MMACHC Sarah Leigh edited their review of MMACHC
Undiagnosed metabolic disorders PSPH Sarah Leigh edited their review of PSPH
Undiagnosed metabolic disorders MAOA Sarah Leigh edited their review of MAOA
Undiagnosed metabolic disorders PRPS1 Sarah Leigh edited their review of PRPS1
Undiagnosed metabolic disorders MAOA Sarah Leigh edited their review of MAOA
Undiagnosed metabolic disorders PRPS1 Sarah Leigh edited their review of PRPS1
Undiagnosed metabolic disorders PRPS1 Sarah Leigh edited their review of PRPS1
Undiagnosed metabolic disorders MAN2B1 Sarah Leigh edited their review of MAN2B1
Undiagnosed metabolic disorders MAN2B1 Sarah Leigh edited their review of MAN2B1
Undiagnosed metabolic disorders PRKAG2 Sarah Leigh edited their review of PRKAG2
Undiagnosed metabolic disorders MAN2B1 Sarah Leigh edited their review of MAN2B1
Undiagnosed metabolic disorders POR Sarah Leigh edited their review of POR
Undiagnosed metabolic disorders POR Sarah Leigh edited their review of POR
Undiagnosed metabolic disorders LBR Sarah Leigh edited their review of LBR
Undiagnosed metabolic disorders PLA2G6 Sarah Leigh edited their review of PLA2G6
Undiagnosed metabolic disorders LBR Sarah Leigh edited their review of LBR
Undiagnosed metabolic disorders PLA2G6 Sarah Leigh edited their review of PLA2G6
Undiagnosed metabolic disorders LAMP2 Sarah Leigh edited their review of LAMP2
Undiagnosed metabolic disorders PLA2G6 Sarah Leigh edited their review of PLA2G6
Undiagnosed metabolic disorders LAMP2 Sarah Leigh edited their review of LAMP2
Undiagnosed metabolic disorders LAMP2 Sarah Leigh edited their review of LAMP2
Undiagnosed metabolic disorders PINK1 Sarah Leigh edited their review of PINK1
Undiagnosed metabolic disorders LAMP2 Sarah Leigh edited their review of LAMP2
Undiagnosed metabolic disorders L2HGDH Sarah Leigh edited their review of L2HGDH
Undiagnosed metabolic disorders L2HGDH Sarah Leigh edited their review of L2HGDH
Undiagnosed metabolic disorders PHGDH Sarah Leigh edited their review of PHGDH
Undiagnosed metabolic disorders HSD17B10 Sarah Leigh edited their review of HSD17B10
Undiagnosed metabolic disorders PGK1 Sarah Leigh edited their review of PGK1
Undiagnosed metabolic disorders HSD17B10 Sarah Leigh edited their review of HSD17B10
Undiagnosed metabolic disorders PGK1 Sarah Leigh edited their review of PGK1
Undiagnosed metabolic disorders HPS1 Sarah Leigh edited their review of HPS1
Undiagnosed metabolic disorders HPS1 Sarah Leigh edited their review of HPS1
Undiagnosed metabolic disorders HPRT1 Sarah Leigh edited their review of HPRT1
Undiagnosed metabolic disorders PFKM Sarah Leigh edited their review of PFKM
Undiagnosed metabolic disorders HPRT1 Sarah Leigh edited their review of HPRT1
Undiagnosed metabolic disorders HEXB Sarah Leigh edited their review of HEXB
Undiagnosed metabolic disorders HEXB Sarah Leigh edited their review of HEXB
Undiagnosed metabolic disorders PANK2 Sarah Leigh edited their review of PANK2
Undiagnosed metabolic disorders HEXA Sarah Leigh edited their review of HEXA
Undiagnosed metabolic disorders PANK2 Sarah Leigh edited their review of PANK2
Undiagnosed metabolic disorders HEXA Sarah Leigh edited their review of HEXA
Undiagnosed metabolic disorders HADH Sarah Leigh edited their review of HADH
Undiagnosed metabolic disorders HADH Sarah Leigh edited their review of HADH
Undiagnosed metabolic disorders OCRL Sarah Leigh edited their review of OCRL
Undiagnosed metabolic disorders OCRL Sarah Leigh edited their review of OCRL
Undiagnosed metabolic disorders OCRL Sarah Leigh edited their review of OCRL
Undiagnosed metabolic disorders NPC2 Sarah Leigh edited their review of NPC2
Undiagnosed metabolic disorders NPC1 Sarah Leigh edited their review of NPC1
Undiagnosed metabolic disorders NPC1 Sarah Leigh edited their review of NPC1
Undiagnosed metabolic disorders GK Sarah Leigh edited their review of GK
Undiagnosed metabolic disorders GK Sarah Leigh edited their review of GK
Undiagnosed metabolic disorders GCH1 Sarah Leigh edited their review of GCH1
Undiagnosed metabolic disorders GCH1 Sarah Leigh edited their review of GCH1
Undiagnosed metabolic disorders MMACHC Sarah Leigh edited their review of MMACHC
Undiagnosed metabolic disorders GCH1 Sarah Leigh edited their review of GCH1
Undiagnosed metabolic disorders MAOA Sarah Leigh edited their review of MAOA
Undiagnosed metabolic disorders GALT Sarah Leigh edited their review of GALT
Undiagnosed metabolic disorders GALT Sarah Leigh edited their review of GALT
Undiagnosed metabolic disorders MAN2B1 Sarah Leigh edited their review of MAN2B1
Undiagnosed metabolic disorders MAN2B1 Sarah Leigh edited their review of MAN2B1
Undiagnosed metabolic disorders GALC Sarah Leigh edited their review of GALC
Undiagnosed metabolic disorders GALC Sarah Leigh edited their review of GALC
Undiagnosed metabolic disorders GAA Sarah Leigh edited their review of GAA
Undiagnosed metabolic disorders GAA Sarah Leigh edited their review of GAA
Undiagnosed metabolic disorders G6PC3 Sarah Leigh edited their review of G6PC3
Undiagnosed metabolic disorders G6PC3 Sarah Leigh edited their review of G6PC3
Undiagnosed metabolic disorders LBR Sarah Leigh edited their review of LBR
Undiagnosed metabolic disorders FUCA1 Sarah Leigh edited their review of FUCA1
Undiagnosed metabolic disorders LAMP2 Sarah Leigh edited their review of LAMP2
Undiagnosed metabolic disorders FUCA1 Sarah Leigh edited their review of FUCA1
Undiagnosed metabolic disorders LAMP2 Sarah Leigh edited their review of LAMP2
Undiagnosed metabolic disorders FUCA1 Sarah Leigh edited their review of FUCA1
Undiagnosed metabolic disorders LAMP2 Sarah Leigh edited their review of LAMP2
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders L2HGDH Sarah Leigh edited their review of L2HGDH
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders HSD17B10 Sarah Leigh edited their review of HSD17B10
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders HPS1 Sarah Leigh edited their review of HPS1
Undiagnosed metabolic disorders FA2H Sarah Leigh edited their review of FA2H
Undiagnosed metabolic disorders HPRT1 Sarah Leigh edited their review of HPRT1
Undiagnosed metabolic disorders FA2H Sarah Leigh edited their review of FA2H
Undiagnosed metabolic disorders DHODH Sarah Leigh edited their review of DHODH
Undiagnosed metabolic disorders HEXB Sarah Leigh edited their review of HEXB
Undiagnosed metabolic disorders DHODH Sarah Leigh edited their review of DHODH
Undiagnosed metabolic disorders DHODH Sarah Leigh edited their review of DHODH
Undiagnosed metabolic disorders HEXA Sarah Leigh edited their review of HEXA
Undiagnosed metabolic disorders DHCR7 Sarah Leigh edited their review of DHCR7
Undiagnosed metabolic disorders HADH Sarah Leigh edited their review of HADH
Undiagnosed metabolic disorders DHCR7 Sarah Leigh edited their review of DHCR7
Undiagnosed metabolic disorders DHCR7 Sarah Leigh edited their review of DHCR7
Undiagnosed metabolic disorders DHCR7 Sarah Leigh edited their review of DHCR7
Undiagnosed metabolic disorders DHCR24 Sarah Leigh edited their review of DHCR24
Undiagnosed metabolic disorders DHCR24 Sarah Leigh edited their review of DHCR24
Undiagnosed metabolic disorders GK Sarah Leigh edited their review of GK
Undiagnosed metabolic disorders CYP27A1 Sarah Leigh edited their review of CYP27A1
Undiagnosed metabolic disorders GCH1 Sarah Leigh edited their review of GCH1
Undiagnosed metabolic disorders CYP27A1 Sarah Leigh edited their review of CYP27A1
Undiagnosed metabolic disorders GCH1 Sarah Leigh edited their review of GCH1
Undiagnosed metabolic disorders CYP27A1 Sarah Leigh edited their review of CYP27A1
Undiagnosed metabolic disorders CUBN Sarah Leigh edited their review of CUBN
Undiagnosed metabolic disorders CUBN Sarah Leigh edited their review of CUBN
Undiagnosed metabolic disorders CTSK Sarah Leigh edited their review of CTSK
Undiagnosed metabolic disorders GALT Sarah Leigh edited their review of GALT
Undiagnosed metabolic disorders CTSK Sarah Leigh edited their review of CTSK
Undiagnosed metabolic disorders CTSA Sarah Leigh edited their review of CTSA
Undiagnosed metabolic disorders GALC Sarah Leigh edited their review of GALC
Undiagnosed metabolic disorders CTSA Sarah Leigh edited their review of CTSA
Undiagnosed metabolic disorders CTSA Sarah Leigh edited their review of CTSA
Undiagnosed metabolic disorders GAA Sarah Leigh edited their review of GAA
Undiagnosed metabolic disorders CP Sarah Leigh edited their review of CP
Undiagnosed metabolic disorders G6PC3 Sarah Leigh edited their review of G6PC3
Undiagnosed metabolic disorders CP Sarah Leigh edited their review of CP
Undiagnosed metabolic disorders CLN6 Sarah Leigh edited their review of CLN6
Undiagnosed metabolic disorders FUCA1 Sarah Leigh edited their review of FUCA1
Undiagnosed metabolic disorders CLN6 Sarah Leigh edited their review of CLN6
Undiagnosed metabolic disorders FUCA1 Sarah Leigh edited their review of FUCA1
Undiagnosed metabolic disorders CLN3 Sarah Leigh edited their review of CLN3
Undiagnosed metabolic disorders CLN3 Sarah Leigh edited their review of CLN3
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders CISD2 Sarah Leigh edited their review of CISD2
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders CISD2 Sarah Leigh edited their review of CISD2
Undiagnosed metabolic disorders FGFR2 Sarah Leigh edited their review of FGFR2
Undiagnosed metabolic disorders ATP7A Sarah Leigh edited their review of ATP7A
Undiagnosed metabolic disorders FA2H Sarah Leigh edited their review of FA2H
Undiagnosed metabolic disorders ATP7A Sarah Leigh edited their review of ATP7A
Undiagnosed metabolic disorders ATP7A Sarah Leigh edited their review of ATP7A
Undiagnosed metabolic disorders ATP7A Sarah Leigh edited their review of ATP7A
Undiagnosed metabolic disorders DHODH Sarah Leigh edited their review of DHODH
Undiagnosed metabolic disorders DHODH Sarah Leigh edited their review of DHODH
Undiagnosed metabolic disorders ATP13A2 Sarah Leigh edited their review of ATP13A2
Undiagnosed metabolic disorders DHCR7 Sarah Leigh edited their review of DHCR7
Undiagnosed metabolic disorders DHCR7 Sarah Leigh edited their review of DHCR7
Undiagnosed metabolic disorders ATP13A2 Sarah Leigh edited their review of ATP13A2
Undiagnosed metabolic disorders DHCR7 Sarah Leigh edited their review of DHCR7
Undiagnosed metabolic disorders DHCR24 Sarah Leigh edited their review of DHCR24
Undiagnosed metabolic disorders ATP13A2 Sarah Leigh edited their review of ATP13A2
Undiagnosed metabolic disorders CYP27A1 Sarah Leigh edited their review of CYP27A1
Undiagnosed metabolic disorders CYP27A1 Sarah Leigh edited their review of CYP27A1
Undiagnosed metabolic disorders CUBN Sarah Leigh edited their review of CUBN
Undiagnosed metabolic disorders CTSK Sarah Leigh edited their review of CTSK
Undiagnosed metabolic disorders ASPA Sarah Leigh edited their review of ASPA
Undiagnosed metabolic disorders ASPA Sarah Leigh edited their review of ASPA
Undiagnosed metabolic disorders CTSA Sarah Leigh edited their review of CTSA
Undiagnosed metabolic disorders ASAH1 Sarah Leigh edited their review of ASAH1
Undiagnosed metabolic disorders CTSA Sarah Leigh edited their review of CTSA
Undiagnosed metabolic disorders ASAH1 Sarah Leigh edited their review of ASAH1
Undiagnosed metabolic disorders ARSA Sarah Leigh edited their review of ARSA
Undiagnosed metabolic disorders ARSA Sarah Leigh edited their review of ARSA
Undiagnosed metabolic disorders ARSA Sarah Leigh edited their review of ARSA
Undiagnosed metabolic disorders CP Sarah Leigh edited their review of CP
Undiagnosed metabolic disorders AMN Sarah Leigh edited their review of AMN
Undiagnosed metabolic disorders CLN6 Sarah Leigh edited their review of CLN6
Undiagnosed metabolic disorders AMN Sarah Leigh edited their review of AMN
Undiagnosed metabolic disorders ALPL Sarah Leigh edited their review of ALPL
Undiagnosed metabolic disorders ALPL Sarah Leigh edited their review of ALPL
Undiagnosed metabolic disorders CLN3 Sarah Leigh edited their review of CLN3
Undiagnosed metabolic disorders ALPL Sarah Leigh edited their review of ALPL
Undiagnosed metabolic disorders ALG13 Sarah Leigh edited their review of ALG13
Undiagnosed metabolic disorders ALG13 Sarah Leigh edited their review of ALG13
Undiagnosed metabolic disorders CISD2 Sarah Leigh edited their review of CISD2
Undiagnosed metabolic disorders ALDH3A2 Sarah Leigh edited their review of ALDH3A2
Undiagnosed metabolic disorders ATP7A Sarah Leigh edited their review of ATP7A
Undiagnosed metabolic disorders ALDH3A2 Sarah Leigh edited their review of ALDH3A2
Undiagnosed metabolic disorders ATP7A Sarah Leigh edited their review of ATP7A
Undiagnosed metabolic disorders ATP7A Sarah Leigh edited their review of ATP7A
Undiagnosed metabolic disorders AGA Sarah Leigh edited their review of AGA
Undiagnosed metabolic disorders AGA Sarah Leigh edited their review of AGA
Undiagnosed metabolic disorders ATP13A2 Sarah Leigh edited their review of ATP13A2
Undiagnosed metabolic disorders AGA Sarah Leigh edited their review of AGA
Undiagnosed metabolic disorders ATP13A2 Sarah Leigh edited their review of ATP13A2
Undiagnosed metabolic disorders ADSL Sarah Leigh edited their review of ADSL
Undiagnosed metabolic disorders ADSL Sarah Leigh edited their review of ADSL
Undiagnosed metabolic disorders ADAR Sarah Leigh edited their review of ADAR
Undiagnosed metabolic disorders ASPA Sarah Leigh edited their review of ASPA
Undiagnosed metabolic disorders ADAR Sarah Leigh edited their review of ADAR
Undiagnosed metabolic disorders ADAR Sarah Leigh edited their review of ADAR
Undiagnosed metabolic disorders ASAH1 Sarah Leigh edited their review of ASAH1
Undiagnosed metabolic disorders ADA Sarah Leigh edited their review of ADA
Undiagnosed metabolic disorders ADA Sarah Leigh edited their review of ADA
Undiagnosed metabolic disorders ADA Sarah Leigh edited their review of ADA
Undiagnosed metabolic disorders ABHD12 Sarah Leigh edited their review of ABHD12
Undiagnosed metabolic disorders ARSA Sarah Leigh edited their review of ARSA
Undiagnosed metabolic disorders ABHD12 Sarah Leigh edited their review of ABHD12
Undiagnosed metabolic disorders ABHD12 Sarah Leigh edited their review of ABHD12
Undiagnosed metabolic disorders ARSA Sarah Leigh edited their review of ARSA
Undiagnosed metabolic disorders AMN Sarah Leigh edited their review of AMN
Undiagnosed metabolic disorders ALPL Sarah Leigh edited their review of ALPL
Undiagnosed metabolic disorders ALPL Sarah Leigh edited their review of ALPL
Undiagnosed metabolic disorders ALG13 Sarah Leigh edited their review of ALG13
Undiagnosed metabolic disorders ALDH3A2 Sarah Leigh edited their review of ALDH3A2
Undiagnosed metabolic disorders AGA Sarah Leigh edited their review of AGA
Undiagnosed metabolic disorders AGA Sarah Leigh edited their review of AGA
Undiagnosed metabolic disorders ADSL Sarah Leigh edited their review of ADSL
Undiagnosed metabolic disorders ADAR Sarah Leigh edited their review of ADAR
Undiagnosed metabolic disorders ADAR Sarah Leigh edited their review of ADAR
Undiagnosed metabolic disorders ADA Sarah Leigh edited their review of ADA
Undiagnosed metabolic disorders ADA Sarah Leigh edited their review of ADA
Undiagnosed metabolic disorders ABHD12 Sarah Leigh edited their review of ABHD12
Undiagnosed metabolic disorders ABHD12 Sarah Leigh edited their review of ABHD12