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| Likely inborn error of metabolism - targeted testing not possible v4.114 | VPS16 |
Sarah Leigh gene: VPS16 was added gene: VPS16 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other Q4_23_promote_green tags were added to gene: VPS16. Mode of inheritance for gene: VPS16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS16 were set to 33938619; 34013567 Phenotypes for gene: VPS16 were set to Mucopolysaccharidosis-like syndrome (biallelic); Dystonia Associated with Lysosomal Abnormalities (monoallelic); Dystonia 30, OMIM:619291 Review for gene: VPS16 was set to GREEN Added comment: Copied from Lysosomal storage disorder panel: Four individuals from three families were identified (PMIDs: 33938619; 34013567) exhibiting a mucopolysaccharidosis (MPS)-like lysosomal storage phenotype with short stature, coarse facies, DD or regression, peripheral neuropathy, skeletal dysplasia, neutropenia, and high-normal glycosaminoglycan excretion. All harboured homozygous variants in VPS16 which segregated with disease, including a missense variant in a sib pair (c.540G>T; p.Trp180Cys) and a recurrent intronic variant (c.2272‐18C>A) in two supposedly unrelated patients (although both of Middle Eastern descent). Fibroblasts of the two patients with the intronic variant showed accumulation of lysosomal compartments and autophagosomes with significantly decreased VPS16 mRNA and protein levels, as well as HOPS/CORVET complexes. Cellular phenotypes were rescued upon re-expression of wild-type VPS16. ----- Heterozygous variants, as well as a homozygous missense variant (c.156C>A) found in a consanguineous Chinese family (PMID:27174565), have been found to cause dystonia with variable onset (OMIM:619291). It has been suggested that the discrepancies in patient phenotypes are due to different mechanisms of pathogenicity, where variants causing dystonia do not affect the levels of endolysosomal tethering (HOPS/CORVET) complexes. More research is needed to clarify the mechanisms underlying VPS16-related dystonia as only limited functional data is currently available - Steel et al. 2020 (PMID:32808683) did perform electron microscopic studies of lymphocytes and fibroblasts derived from 2 unrelated patients, which showed vacuolar abnormalities suggestive of impaired lysosomal function. Sources: Literature Arina Puzriakova (Genomics England Curator), 14 Jun 2021 Sources: Other |
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| Likely inborn error of metabolism - targeted testing not possible v4.101 | EDEM3 |
Sarah Leigh gene: EDEM3 was added gene: EDEM3 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other Q4_23_promote_green tags were added to gene: EDEM3. Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EDEM3 were set to 34143952 Phenotypes for gene: EDEM3 were set to Congenital disorder of glycosylation, type 2V, OMIM:619493 Review for gene: EDEM3 was set to GREEN Added comment: Reviews copied from entry on Congenital disorders of glycosylation panel. There is sufficient evidence to promote this gene to Green at the next GMS panel update. EDEM3 is associated with a relevant phenotype in OMIM (MIM# 619493) and G2P with a 'strong' confidence level assertion. 12 individuals from 7 unrelated families identified by Polla et al. 2021 (PMID: 34143952) with various biallelic variants in the EDEM3 gene. Clinical characteristics were predominant for DD (12/12), ID (6/7), hypotonia (6/12) and facial dysmorphisms. (Arina Puzriakova (Genomics England Curator), 18 Jul 2022). PMID: 34143952: 7 families (11 individuals) with 6x PTV and 2x missense variants with neurodevelopmental delay and variable facial dysmorphisms. The unaffected parents were all heterozygous carriers. Functional studies show loss of EDEM3 enzymatic activity. Sources: Literature (Zornitza Stark (Australian Genomics), 7 Aug 2021). Sources: Other |
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| Likely inborn error of metabolism - targeted testing not possible v4.44 | SLC22A5 | Sarah Leigh changed review comment from: 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: 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). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism - targeted testing not possible v4.42 | SLC22A5 | Sarah Leigh edited their review of gene: SLC22A5: Added comment: 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).; Changed rating: GREEN; Changed publications to: 10545605, 11261427; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism - targeted testing not possible v3.8 | CRLS1 |
Achchuthan Shanmugasundram gene: CRLS1 was added gene: CRLS1 was added to Inborn errors of metabolism. Sources: Literature Mode of inheritance for gene: CRLS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRLS1 were set to 35147173 Phenotypes for gene: CRLS1 were set to Combined oxidative phosphorylation deficiency 57, OMIM:620167 Review for gene: CRLS1 was set to GREEN Added comment: Three individuals from two unrelated families were identified with the same homozygous variant in CRLS1 (p.Ile109Asn). They presented with a mitochondrial disorder characterized by an evolving pattern of cardiomyopathy, encephalopathy, bilateral auditory neuropathy spectrum disorder, bull’s eye maculopathy, diabetes insipidus, autonomic instability and low complex IV activity in skeletal muscle. A fourth individual was identified with a compound heterozygous CRLS1 variant (p.Ala172Asp/ p.Leu217Phe) that presented with developmental regression beginning in late infancy, with acquired microcephaly, sensorineural hearing loss and impaired vision. Lipidomics in fibroblasts from 2 patients demonstrated that cardiolipin was reduced, cardiolipin acyl side chains had an abnormal distribution, and substrates of CRLS1 were abnormally elevated, including an elevation of phosphatidylglycerol. Sources: Literature |
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| Likely inborn error of metabolism - targeted testing not possible v2.328 | ARSK |
Arina Puzriakova gene: ARSK was added gene: ARSK was added to Inborn errors of metabolism. Sources: Literature Mode of inheritance for gene: ARSK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARSK were set to 34916232 Phenotypes for gene: ARSK were set to Mucopolysaccharidoses with short stature, coarse facial features and dysostosis multiplex Review for gene: ARSK was set to AMBER Added comment: Verheyen et al. 2022 (PMID: 34916232) reported four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Patients were affected with skeletal dysplasia, resembling spondyloepiphysial dysplasia. Reverse phenotyping in two individuals from one family revealed additional cardiac and ophthalmological abnormalities. Sources: Literature |
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| Likely inborn error of metabolism - targeted testing not possible v2.315 | UQCRC1 | Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on current evidence - three unrelated individuals with Parkinson's disease and heterozygous variants identified by one group (PMID: 33141179) but results have failed to be replicated in large European and Chinese cohorts (PMIDs: 33779694; 33248804) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism - targeted testing not possible v2.221 | CPT2 | Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS review. 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) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism - targeted testing not possible v2.198 | CLPB |
Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update. Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype overlapped with that observed in the recessive disease including neurodevelopmental delay, seizures, 3-MGA-uria, and neutropenia. Some functional studies of heterozygous variants were performed. |
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| Likely inborn error of metabolism - targeted testing not possible v2.49 | GLS_GCA |
Arina Puzriakova STR: GLS_GCA was added STR: GLS_GCA was added to Inborn errors of metabolism. Sources: Literature STR, NGS Not Validated, for-review tags were added to STR: GLS_GCA. Mode of inheritance for STR: GLS_GCA was set to BIALLELIC, autosomal or pseudoautosomal Publications for STR: GLS_GCA were set to 30970188 Phenotypes for STR: GLS_GCA were set to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 Review for STR: GLS_GCA was set to GREEN Added comment: GLS is associated with relevant phenotypes in OMIM, but currently is not in Gene2Phenoype. ---------- - PMID: 30970188 (2019) - Three unrelated cases who presented with an early-onset global developmental delay, progressive ataxia, and elevated levels of glutamine (MIM# 618412). One patient also showed cerebellar atrophy. All 3 individuals harboured a large trinucleotide (GCA) repeat expansion in the 5' UTR (length: 680-1,500-copy repeats). The repeat expansion was found in homozygosity in 1 case, and occurred in compound heterozygosity with an SNV in the other two cases (missense and frameshift variant, respectively). Functional analysis showed the repeat expansion results in reduced expression and glutaminase deficiency. Sources: Literature |
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| Likely inborn error of metabolism - targeted testing not possible v2.37 | SHMT2 |
Arina Puzriakova gene: SHMT2 was added gene: SHMT2 was added to Inborn errors of metabolism. Sources: Literature for-review tags were added to gene: SHMT2. Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHMT2 were set to 33015733 Phenotypes for gene: SHMT2 were set to Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, OMIM:619121 Review for gene: SHMT2 was set to GREEN Added comment: PMID: 33015733 (2020) - 5 individuals from 4 families with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. Clinical features include dysmorphism, congenital microcephaly, hypertrophic cardiomyopathy or atrial-septal defects, DD/ID and motor dysfunction, in the form of spastic paraparesis, ataxia, and/or peripheral neuropathy. SHMT2 encodes the mitochondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF. While plasma metabolites were within normal range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts, decrease in glycine/serine ratios, impaired folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction. Sources: Literature |
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| Likely inborn error of metabolism - targeted testing not possible v2.35 | HS2ST1 |
Ivone Leong gene: HS2ST1 was added gene: HS2ST1 was added to Inborn errors of metabolism. Sources: Literature for-review tags were added to gene: HS2ST1. 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 AMBER 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. This gene should be considered for Green gene rating status at the next review. Sources: Literature |
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| Likely inborn error of metabolism - targeted testing not possible v2.25 | GALM |
Ivone Leong gene: GALM was added gene: GALM was added to Inborn errors of metabolism. Sources: Expert Review,Literature for-review tags were added to gene: GALM. Mode of inheritance for gene: GALM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GALM were set to 30451973; 30910422 Phenotypes for gene: GALM were set to Galactosemia IV, 618881 Review for gene: GALM was set to GREEN Added comment: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with an appropriate phenotype in OMIM but not in Gene2Phenotype. There is enough evidence for this gene to be Green. The gene has been given an Amber rating and will be promoted to Green at the next review. Review from Zornitza Stark (Australian Genomics) on the Cholestasis panel: Homozygous and compound heterozygous variants (missense, nonsense and frameshift) found in 8 Japanese patients from unrelated families with unexplained galactosaemia. (No variants in GALT, GALK1, and GALE). In vitro expression analysis and enzyme activity assay of the patients’ peripheral blood mononuclear cells showed total lack of or compromised expression of GALM protein. One homozygote for one of these variants p.(Gly142Arg) in gnomAD (African population). (Wada, Y. et al 2019; PMID: 30451973) Note only two individuals were reported as having transient cholestasis. Sources: Literature Zornitza Stark (Australian Genomics), 2 May 2020 Sources: Expert Review, Literature |
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| Likely inborn error of metabolism - targeted testing not possible v2.1 | PCYT2 |
Sarah Leigh edited their review of gene: PCYT2: Added comment: Vaz et al. (2019 - PMID: 31637422 - DDD study among the co-authors) report on 5 individuals - from 4 families - with biallelic PCYT2 mutations. The phenotype corresponded to a complex hererditary paraplegia with global DD, regression (4/5), ID (mild in 3/5, severe in 2/5), spastic para-/tetraparesis, epilepsy (5/5 - variable onset 2-16 yrs - focal or tonic-clonic seizures) and progressive cerebral and cerebellar atrophy. Exome sequencing in all revealed biallelic PCYT2 variants, confirmed with Sanger s. in probands and their parents (NM_001184917.2 - corresponding to the canonical transcript used as Ref below): - P1 (Fam1) : 2 missense SNVs in trans configuration, c.730C>T or p.His244Tyr and c.920C>T or p.Pro307Leu - P2 (Fam2 - consanguineous of White British origin), P3 (Fam3 - Consanguineous of Turkish origin), P4,5 (Fam4 - consanguineous, unspecified origin) : homozygosity for c.1129C>T or p.Arg377Ter) affecting the last exon of 8/12 transcripts, including the canonical one. Individuals with the same genotype displayed variable degrees of ID (eg P3 - severe / P2, P4,5 - mild ID). For sibs in Fam4, homozygosity for a missense SACS variant led to consideration of the respective disorder (AR spastic ataxia of Charlevoix-Saguenay) though the variant was predicted to be tolerated in silico and notably the MRI images not suggestive. All variants were absent from / had extremely low AF in public databases, with no homozygotes. Posphatidylethanolamine (PE) is a membrane lipid, particularly enriched in human brain (45% of phospholypid fraction). PE is synthesized either via the CDP-ethanolamine pathway or by decarboxylation of phosphatidylserine in mitochondria. PCYT2 encodes CTP:phosophoethanolamine cytidyltransferase (ET) which is an ubiquitously expressed rate-limiting enzyme for PE biosynthesis in the former pathway. In silico, the 2 missense variants - localizing in the CTP catalytic domain 2 - were predicted to be damaging, as well as to affect protein stability. Fibroblasts of 3 patients (P1, P2, P3) representing all variants were studied: - Enzymatic activity was shown to be significantly reduced (though not absent) compared to controls. Abnormalities were noted upon Western Blot incl. absence in all 3 patients studied of one of the 2 bands normally found in controls (probably representing the longer isoform), reduced intensity in all 3 of another band probably corresponding to a shorter isoform, and presence of an additional band of intermediate molec. mass in patients with the truncating variant. - RT-PCR on mRNA from patient fibroblasts did not reveal (significant) reduction compared to controls. - Lipidomic profile of patient fibroblasts was compatible with the location of the block in the phospholipid biosynthesis pathway and different from controls. The lipidomic profile had similarities with what has been reported for EPT1 deficiency, the enzyme directly downstream of ET. The SELENO1-related phenotype (/EPT1 deficiency) is also highly overlapping. CRISPR-Cas9 was used to generate pcyt2 partial or complete knockout (ko) zebrafish, targeting either the final (ex13) or another exon (ex3) respectively. mRNA expression was shown to be moderately reduced in the first case and severely reduced/absent in the second, compared to wt. Similarly, complete-ko (ex3) led to significantly lower survival, with impaired though somewhat better survival of partial-ko (ex13) zebrafish. Complete knockout of Pcyt2 in mice is embryonically lethal (PMID cited: 17325045) while heterozygous mice develop features of metabolic syndrome (PMID cited: 22764088). Given lethality in knockout zebrafish / mice and the residual activity (15-20%) in patient fibroblasts, the variants reported were thought to be hypomorphic and complete loss of function possibly incompatible with life. PCYT2 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID. As a result this gene could included in the ID / epilepsy panels with green (~/>3 indiv/fam/variants with the nonsense found in different populations, consistent phenotype, lipidomics, in silico/in vitro/in vivo evidence) or amber rating. [Please consider inclusion in other possibly relevant panels eg. for metabolic disorders, etc]. Sources: Literature Konstantinos Varvagiannis (Other), 11 Nov 2019; Changed rating: GREEN |
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| Likely inborn error of metabolism - targeted testing not possible v1.422 | UPB1 | Ellen McDonagh changed review comment from: Additional comments were provided by Dr Clare Beesley and colleagues (Great Ormond Street Hospital for Children NHS Foundation Trust) as part of the GMS Metabolic Specialist disease test group: 16 mutations reported in HGMD & several families have been reported in the literature. Heterologous expression of A85E mutant enzyme in E. coli yielded no residual activity (Van Kuilenburg et al., 2004, PMID: 15385443].; to: Additional comments were provided by Dr Clare Beesley and colleagues (Great Ormond Street Hospital for Children NHS Foundation Trust) as part of the GMS Metabolic Specialist disease test group: 16 mutations reported in HGMD & several families have been reported in the literature. Heterologous expression of A85E mutant enzyme in E. coli yielded no residual activity (Van Kuilenburg et al., 2004, PMID: 15385443). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism - targeted testing not possible v1.422 | UPB1 | Ellen McDonagh commented on gene: UPB1: Additional comments were provided by Dr Clare Beesley and colleagues (Great Ormond Street Hospital for Children NHS Foundation Trust) as part of the GMS Metabolic Specialist disease test group: 16 mutations reported in HGMD & several families have been reported in the literature. Heterologous expression of A85E mutant enzyme in E. coli yielded no residual activity (Van Kuilenburg et al., 2004, PMID: 15385443]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism - targeted testing not possible v1.345 | TAT |
Catherine Snow Added comment: Comment on publications: PMID: 28255985 Reports on 106 families, represented by 143 individuals, carrying a total of 36 genetic variants. Variants include large deletions, non‐synonymous and nonsense amino‐acid changes, frameshifts and splice variants. |
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| Likely inborn error of metabolism - targeted testing not possible v1.115 | DHDDS |
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 probable Gen2Phen gene for Retinitis pigmentosa 59 613861. One variant was reported in at least 15 families with retinitis pigmentosa, but only one compound individual with glycosylation defects was identifed so far (PMID 27343064). |
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| Likely inborn error of metabolism - targeted testing not possible v1.47 | IDUA |
Ivone Leong Source NHS GMS was added to IDUA. Source London North GLH was added to IDUA. |
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| Likely inborn error of metabolism - targeted testing not possible v0.16 | MRPS34 |
Sarah Leigh gene: MRPS34 was added gene: MRPS34 was added to Inborn errors of metabolism. Sources: Expert Review,Literature Mode of inheritance for gene: MRPS34 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPS34 were set to 28777931 Phenotypes for gene: MRPS34 were set to Combined oxidative phosphorylation deficiency 32 617664 Review for gene: MRPS34 was set to GREEN Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 4 variants reported in 3 unrelated cases. (Six individuals from four unrelated families reported in the literature with bi-allelic variants in this gene. Zornitza Stark (Australian Genomics), 30 Aug 2018) Sources: Expert Review, Literature |
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| Likely inborn error of metabolism - targeted testing not possible v0.4 | IDUA |
Ellen McDonagh gene: IDUA was added gene: IDUA was added to Inborn errors of metabolism. Sources: Expert Review Green Mode of inheritance for gene: IDUA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IDUA were set to 27604308 Phenotypes for gene: IDUA were set to Hurler syndrome; Mucopolysaccharidosis type 1H/S; MPS I, Hurler, Scheie disease (Mucopolysaccharidoses); Scheie syndrome; Hurler-Scheie syndrome; Mucopolysaccharidosis type 1S; Mucopolysaccharidosis type 1H; Mucopolysaccharidosis Ih/s, 607015; Mucopolysaccharidosis, Type I; Mucopolysaccharidosis Is, 607016; Mucopolysaccharidosis Ih, 607014 |
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| Likely inborn error of metabolism - targeted testing not possible v0.4 | ACAT1 |
Ellen McDonagh gene: ACAT1 was added gene: ACAT1 was added to Inborn errors of metabolism. Sources: Expert Review Green Mode of inheritance for gene: ACAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACAT1 were set to 27604308 Phenotypes for gene: ACAT1 were set to Cytosolic acetoacetyl-CoA thiolase deficiency (Disorders of ketone body metabolism); Fasting intolerance with acidosis, ? residual neurological problems; 3-Oxothiolase deficiency (Organic acidurias) |
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