Loss‐of‐function variants in HOPS complex genes VPS16 and VPS41 cause early‐onset dystonia associated with lysosomal abnormalities

Objectives\ud The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognised. We aimed to investigate this paucity of diagnoses.\ud \ud Methods\ud We undertook weighted burden analysis of whole‐exome sequencing data from 138 individuals with unresolved generalised dystonia of suspected genetic aetiology, followed by additional case‐finding from international databases, first for the gene implicated by the burden analysis (VPS16), then for other functionally related genes. Electron microscopy was performed on patient‐derived cells.\ud \ud Results\ud Analysis revealed a significant burden for VPS16 (Fisher's exact test p‐value, 6.9x10−9). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome‐lysosome fusion. A total of 18 individuals harbouring heterozygous loss‐of‐function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early‐onset progressive dystonia with predominant cervical, bulbar, orofacial and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss‐of‐function variants in VPS41, another HOPS‐complex encoding genes, in an individual with infantile‐onset generalised dystonia. Electron microscopy of patient‐derived lymphocytes and fibroblasts from both VPS16 and VPS41 patients showed vacuolar abnormalities suggestive of impaired lysosomal function.\ud \ud Interpretation\ud Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, though variants in different subunits display different phenotypic and inheritance characteristics.