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
  • 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.