Lysosomal storage disorder
Gene: VPS16The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 14 Mar 2022, 2:12 p.m. | Last Modified: 1 Jun 2023, 3:54 p.m.
Panel Version: 3.1
Comment on mode of inheritance: Biallelic variants are associated with a phenotype resembling a lysosomal storage disease. There are sufficient families (3) and functional data showing defects in the endolysosomal trafficking system to support inclusion for this allelic requirement.
Monoallelic variants are linked to dystonia but only one study performed further analyses that suggested lysosomal dysfunction. Therefore while possible, it is unclear whether the 'Lysosomal storage disorder' panel would be applied in these cases.
VPS16 will be flagged for GMS review with regards to the most appropriate MOI on this panel (biallelic or both bilalleic/monoallelic)Created: 14 Jun 2021, 11:36 a.m. | Last Modified: 14 Jun 2021, 11:36 a.m.
Panel Version: 1.73
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.
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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: LiteratureCreated: 14 Jun 2021, 11:11 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Mucopolysaccharidosis-like syndrome (biallelic); Dystonia 30, OMIM:619291; Dystonia Associated with Lysosomal Abnormalities (monoallelic)
Publications
Tag Q2_21_rating was removed from gene: VPS16. Tag Q2_21_MOI was removed from gene: VPS16.
Source Expert Review Green was added to VPS16. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Phenotypes for gene: VPS16 were changed from Mucopolysaccharidosis-like syndrome (biallelic); Dystonia 30, OMIM:619291; Dystonia Associated with Lysosomal Abnormalities (monoallelic) to Mucopolysaccharidosis-like syndrome (biallelic); Dystonia Associated with Lysosomal Abnormalities (monoallelic); Dystonia 30, OMIM:619291
Gene: vps16 has been classified as Amber List (Moderate Evidence).
Mode of inheritance for gene: VPS16 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
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