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| Lysosomal storage disorder v1.76 | CLCN7 | Arina Puzriakova Added comment: Comment on list classification: Rating Amber as two individuals have been reported and with the same variant. Although there is some functional support, an additional independent case would help corroborate this association and indicate whether this is a variant specific phenotype. Different heterozygous CLCN7 variants have been linked to AD osteopetrosis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lysosomal storage disorder v1.75 | CLCN7 |
Arina Puzriakova gene: CLCN7 was added gene: CLCN7 was added to Lysosomal storage disorder. Sources: Literature watchlist tags were added to gene: CLCN7. Mode of inheritance for gene: CLCN7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CLCN7 were set to 31155284 Phenotypes for gene: CLCN7 were set to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541 Mode of pathogenicity for gene: CLCN7 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: CLCN7 was set to AMBER Added comment: Nicoli et al., 2019 (PMID: 31155284) reported on two unrelated individuals from different ethnic backgrounds with the same de novo gain-of-function missense variant (c.2144A>G, p.Tyr715Cys) in the CLCN7 gene. Both children had generalised cutaneous hypopigmentation without ocular involvement, delayed myelination and motor development, and organomegaly. Biopsies showed that both probands had cytoplasmic inclusions, characteristic of those seen in lysosomal-storage disorders. Human phenotypes were recapitulated by a mouse model harbouring the knock-in Clcn7 variant. This gene-disease relationship is listed in OMIM (MIM# 618541) but is not yet in G2P. Sources: Literature |
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| Lysosomal storage disorder v1.71 | VPS16 |
Arina Puzriakova gene: VPS16 was added gene: VPS16 was added to Lysosomal storage disorder. Sources: Literature Q2_21_rating, Q2_21_MOI 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 30, OMIM:619291; Dystonia Associated with Lysosomal Abnormalities (monoallelic) Review for gene: VPS16 was set to GREEN Added comment: 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 |
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| Lysosomal storage disorder v1.41 | IDUA | Sarah Leigh Phenotypes for gene: IDUA were changed from Mucopolysaccharidosis Ih 607014; Mucopolysaccharidosis Is 607016; Mucopolysaccharidosis Ih/s 607015 to Mucopolysaccharidosis Ih OMIM:607014; Hurler syndrome MONDO:0011758; Mucopolysaccharidosis Is OMIM:607016; Scheie syndrome MONDO:0011760; Mucopolysaccharidosis Ih/s OMIM:607015; Hurler-Scheie syndromeMONDO:0011759 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lysosomal storage disorder v0.3 | IDUA | Emma Ashton reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lysosomal storage disorder v0.3 | IDUA | Carol Hardy reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Mucopolysaccharidosis Ih 607014, Mucopolysaccharidosis Ih/s 607015, Mucopolysaccharidosis Is 607016; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lysosomal storage disorder v0.2 | IDUA |
Ivone Leong gene: IDUA was added gene: IDUA was added to Lysosomal storage disorder. Sources: North London GLH,Expert Review Green,Wessex and West Midlands GLH,NHS GMS Mode of inheritance for gene: IDUA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IDUA were set to Mucopolysaccharidosis Ih 607014; Mucopolysaccharidosis Is 607016; Mucopolysaccharidosis Ih/s 607015 |
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