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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 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 x 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.

Type Journal
ISBN 1531-8249 (Electronic) 0364-5134 (Linking)
Authors Steel, D.; Zech, M.; Zhao, C.; Barwick, K. E. S.; Burke, D.; Demailly, D.; Kumar, K. R.; Zorzi, G.; Nardocci, N.; Kaiyrzhanov, R.; Wagner, M.; Iuso, A.; Berutti, R.; Skorvanek, M.; Necpal, J.; Davis, R.; Wiethoff, S.; Mankad, K.; Sudhakar, S.; Ferrini, A.; Sharma, S.; Kamsteeg, E. J.; Tijssen, M. A.; Verschuuren, C.; van Egmond, M. E.; Flowers, J. M.; McEntagart, M.; Tucci, A.; Coubes, P.; Bustos, B. I.; Gonzalez-Latapi, P.; Tisch, S.; Darveniza, P.; Gorman, K. M.; Peall, K. J.; Botzel, K.; Koch, J. C.; Kmiec, T.; Plecko, B.; Boesch, S.; Haslinger, B.; Jech, R.; Garavaglia, B.; Wood, N.; Houlden, H.; Gissen, P.; Lubbe, S. J.; Sue, C. M.; Cif, L.; Mencacci, N. E.; Anderson, G.; Kurian, M. A.; Winkelmann, J.; Genomics England Research, Consortium
Responsible Garvan Author Dr Kishore Kumar
Published Date 2020-11-01
Published Volume 88
Published Issue 5
Published Pages 867-877
Status Published in-print
DOI 10.1002/ana.25879
URL link to publisher's version