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

Genomics England Research Consortium, Steel, D., Zech, M., Zhao, C., Barwick, K. E., Burke, D., Demailly, D., Kumar, K. R., Zorzi, G., Nardocci, N., Kaiyrzhanov, R., Wagner, M., Iuso, A., Berutti, R., Škorvánek, M., Necpál, 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., Bötzel, K., Koch, J. C., Kmieć, 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., 18-Aug-2020, In : Annals of Neurology. 88, 5, p. 867-877 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • 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 Sudhakar
  • Arianna 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

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.

Original languageEnglish
Pages (from-to)867-877
Number of pages11
JournalAnnals of Neurology
Issue number5
Publication statusE-pub ahead of print - 18-Aug-2020

ID: 132894042