Dora Steel1,2, Michael Zech3,4, Chen Zhao3, Katy E S Barwick1, Derek Burke5, Diane Demailly6, Kishore R Kumar7,8,9,10, Giovanna Zorzi11, Nardo Nardocci11, Rauan Kaiyrzhanov12, Matias Wagner3,4, Arcangela Iuso3,4, Riccardo Berutti4, Matej Škorvánek13,14, Ján Necpál15, Ryan Davis7,9,10, Sarah Wiethoff16,17, Kshitij Mankad18, Sniya Sudhakar18, Arianna Ferrini1, Suvasini Sharma19, Erik-Jan Kamsteeg20, Marina A Tijssen21, Corien Verschuuren22,23, Martje E van Egmond21,22, Joanna M Flowers24, Meriel McEntagart25, Arianna Tucci26, Philippe Coubes6, Bernabe I Bustos27, Paulina Gonzalez-Latapi27, Stephen Tisch28, Paul Darveniza28, Kathleen M Gorman29,30, Kathryn J Peall31, Kai Bötzel32, Jan C Koch33, Tomasz Kmieć34, Barbara Plecko35, Sylvia Boesch36, Bernhard Haslinger37, Robert Jech38, Barbara Garavaglia11, Nick Wood16, Henry Houlden12, Paul Gissen39, Steven J Lubbe27, Carolyn M Sue7,9,10,40, Laura Cif6, Niccolò E Mencacci27, Glenn Anderson41, Manju A Kurian1,2, Juliane Winkelmann3,4,42,43. 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.
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.
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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