VPS16-related dystonia-associated variant alleles identified to date comprise mostly heterozygous loss-of-function (predicted protein-truncating or whole-gene deletion) variants:
• Heterozygous frameshift variants
• Heterozygous nonsense variants
• Heterozygous splice-site variants
• Whole-gene deletions
• Missense variants identified to date are mostly of uncertain significance
The suspected pathogenic mechanisms in VPS16-related dystonia is haploinsufficiency of the gene (consistent with the observation of whole-gene deletions and early truncating variants that are expected to trigger nonsense-mediated mRNA decay). VPS16 haploinsufficiency may impact on the function of the “HOPS” (homotypic fusion and vacuole protein sorting) complex, with impairments of endosome-lysosome and/or authophagosome-lysosome fusion processes. As such, VPS16-related dystonia may be regarded as a type of “lysosomal pathology”-associated dystonia (in addition to other endolysosomal/autophagic dysfunction-associated movement disorders such as ATP13A2-, IRF2PBL-, and VAC14-, and VPS41-related conditions).
Testing for VPS16-related dystonia is usually done with next-generation sequencing methods (panel-exome, or genome analysis) because of allelic heterogeneity, as well as genetic and clinical variability of dystonic disorders.
VPS16