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

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

OnderzoeksoutputAcademicpeer review

18 Citaten (Scopus)
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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.

Originele taal-2English
Pagina's (van-tot)867-877
Aantal pagina's11
TijdschriftAnnals of Neurology
Nummer van het tijdschrift5
Vroegere onlinedatum18-aug-2020
StatusPublished - nov-2020

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