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

OBJECTIVES 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. METHODS 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. RESULTS 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. INTERPRETATION 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. This article is protected by copyright. All rights reserved.