2. Academic Validation
  3. Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities

Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities

  • Ann Neurol. 2020 Nov;88(5):867-877. doi: 10.1002/ana.25879.
Dora Steel # 1 2,  Michael Zech # 3 4,  Chen Zhao 3,  Katy E S Barwick 1,  Derek Burke 5,  Diane Demailly 6,  Kishore R Kumar 7 8 9 10,  Giovanna Zorzi 11,  Nardo Nardocci 11,  Rauan Kaiyrzhanov 12,  Matias Wagner 3 4,  Arcangela Iuso 3 4,  Riccardo Berutti 4,  Matej Škorvánek 13 14,  Ján Necpál 15,  Ryan Davis 7 9 10,  Sarah Wiethoff 16 17,  Kshitij Mankad 18,  Sniya Sudhakar 18,  Arianna Ferrini 1,  Suvasini Sharma 19,  Erik-Jan Kamsteeg 20,  Marina A Tijssen 21,  Corien Verschuuren 22 23,  Martje E van Egmond 21 22,  Joanna M Flowers 24,  Meriel McEntagart 25,  Arianna Tucci 26,  Philippe Coubes 6,  Bernabe I Bustos 27,  Paulina Gonzalez-Latapi 27,  Stephen Tisch 28,  Paul Darveniza 28,  Kathleen M Gorman 29 30,  Kathryn J Peall 31,  Kai Bötzel 32,  Jan C Koch 33,  Tomasz Kmieć 34,  Barbara Plecko 35,  Sylvia Boesch 36,  Bernhard Haslinger 37,  Robert Jech 38,  Barbara Garavaglia 11,  Nick Wood 16,  Henry Houlden 12,  Paul Gissen 39,  Steven J Lubbe 27,  Carolyn M Sue 7 9 10 40,  Laura Cif 6,  Niccolò E Mencacci 27,  Glenn Anderson 41,  Manju A Kurian 1 2,  Juliane Winkelmann 3 4 42 43,  Genomics England Research Consortium
Affiliations

Affiliations

  • 1 Department of Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
  • 2 Department of Neurology, Great Ormond Street Hospital, London, UK.
  • 3 Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
  • 4 Institute of Human Genetics, Technical University of Munich, Munich, Germany.
  • 5 Enzyme Laboratory, Great Ormond Street Hospital for Children, London, UK.
  • 6 Unités des Pathologies Cérébrales Résistantes, Département de Neurochirurgie, Centre Hospitalier Universitaire, Montpellier, France.
  • 7 Department of Neurogenetics, Kolling Institute of Medical Research, University of Sydney and Northern Sydney Local Health District, Sydney, New South Wales, Australia.
  • 8 Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, New South Wales, Australia.
  • 9 Translational Genomics, Kinghorn Centre for Clinical Genomics, Garvan Institute for Medical Research, Sydney, New South Wales, Australia.
  • 10 Department of Neurogenetics, University of Sydney and Northern Sydney Local Health District, Sydney, New South Wales, Australia.
  • 11 Department of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • 12 Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London, UK.
  • 13 Department of Neurology, P. J. Safarik University, Kosice, Slovak Republic.
  • 14 Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic.
  • 15 Department of Neurology, Zvolen Hospital, Zvolen, Slovakia.
  • 16 UCL Queen Square Institute of Neurology, London, UK.
  • 17 Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Tübingen, Germany.
  • 18 Department of Radiology, Great Ormond Street Hospital for Children, London, UK.
  • 19 Neurology Division, Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India.
  • 20 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 21 Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 22 Expertise Center Movement Disorders Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 23 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 24 Department of Neurology, St. George's Hospital, London, UK.
  • 25 Department of Clinical Genetics, St. George's Hospital, London, UK.
  • 26 Genomics England, London, UK.
  • 27 Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 28 Department of Neurology, St. Vincent's Hospital, Sydney, Australia.
  • 29 Department of Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.
  • 30 UCD School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
  • 31 University of Cardiff, Cardiff, Wales, UK.
  • 32 Department of Neurology, Ludwig Maximilian University, Munich, Germany.
  • 33 Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
  • 34 Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, Poland.
  • 35 Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria.
  • 36 Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
  • 37 Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • 38 Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
  • 39 Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.
  • 40 Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, New South Wales, Australia.
  • 41 Department of Histopathology, Great Ormond Street Hospital for Children, London, UK.
  • 42 Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.
  • 43 Munich Cluster for Systems Neurology, Munich, Germany.
  • # Contributed equally.
PMID: 32808683 DOI: 10.1002/ana.25879
Abstract

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.

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