Steel, Dora; Zech, Michael; Zhao, Chen; Barwick, Katy E S; Burke, Derek; Demailly, Diane; Kumar, Kishore R; Zorzi, Giovanna; Nardocci, Nardo; Kaiyrzhanov, Rauan; Wagner, Matias; Iuso, Arcangela; Berutti, Riccardo; Škorvánek, Matej; Necpál, Ján; Davis, Ryan; Wiethoff, Sarah; Mankad, Kshitij; Sudhakar, Sniya; Ferrini, Arianna; Sharma, Suvasini; Kamsteeg, Erik-Jan; Tijssen, Marina A; Verschuuren, Corien; van Egmond, Martje E; Flowers, Joanna M; McEntagart, Meriel; Tucci, Arianna; Coubes, Philippe; Bustos, Bernabe I; Gonzalez-Latapi, Paulina; Tisch, Stephen; Darveniza, Paul; Gorman, Kathleen M; Peall, Kathryn J; Bötzel, Kai; Koch, Jan C; Kmieć, Tomasz; Plecko, Barbara; Boesch, Sylvia; Haslinger, Bernhard; Jech, Robert; Garavaglia, Barbara; Wood, Nick; Houlden, Henry; Gissen, Paul; Lubbe, Steven J; Sue, Carolyn M; Cif, Laura; Mencacci, Niccolò E; Anderson, Glenn; Kurian, Manju A; Winkelmann, Juliane     «

Steel, Dora; Zech, Michael; Zhao, Chen; Barwick, Katy E S; Burke, Derek; Demailly, Diane; Kumar, Kishore R; Zorzi, Giovanna; Nardocci, Nardo; Kaiyrzhanov, Rauan; Wagner, Matias; Iuso, Arcangela; Berutti, Riccardo; Škorvánek, Matej; Necpál, Ján; Davis, Ryan; Wiethoff, Sarah; Mankad, Kshitij; Sudhakar, Sniya; Ferrini, Arianna; Sharma, Suvasini; Kamsteeg, Erik-Jan; Tijssen, Marina A; Verschuuren, Corien; van Egmond, Martje E; Flowers, Joanna M; McEntagart, Meriel; Tucci, Arianna; Coubes, Philippe;...     »

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 recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and 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, 6.9 × 109 ). 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 harboring 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 gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020; 88:867-877.      «

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 recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene impl...     »