The disease is caused by heterozygous loss-of-function 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, i.e., the disease is caused by heterozygous dosage loss. VPS16 haploinsufficiency may negatively impact on lysosomal function. 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