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Loss‐of‐Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities
Author(s) -
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 ErikJan,
Tijssen Marina A.,
Verschuuren Corien,
Egmond Martje E.,
Flowers Joanna M.,
McEntagart Meriel,
Tucci Arianna,
Coubes Philippe,
Bustos Bernabe I.,
GonzalezLatapi 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
Publication year - 2020
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25879
Subject(s) - phenotype , loss function , dystonia , biology , genetics , gene , exome sequencing , medicine , neuroscience
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 × 10 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 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