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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 867-877 |
| Number of pages | 11 |
| Journal | Annals of neurology |
| Volume | 88 |
| Issue number | 5 |
| DOIs | |
| State | Published - Nov 1 2020 |
Funding
The authors would like to thank the patients and their families who took part in our study. This study was funded by a research grant from the Else Kr\u00F6ner-Fresenius-Stiftung as well as by in-house institutional funding from Technische Universit\u00E4t M\u00FCnchen, Munich, Germany, Helmholtz Zentrum M\u00FCnchen, Munich, Germany, Medizinische Universit\u00E4t Innsbruck, Innsbruck, Austria, and Charles University, Prague, Czech Republic (PROGRES Q27). This study was also funded by the Czech Ministry of Education under grant AZV: NV19-04-00233 and under the frame of EJP RD, the European Joint Programme on Rare Diseases (EJP RD COFUND-EJP No. 825575), as well as the Slovak Grant and Development Agency under contract APVV-18-0547 and the Slovak Research and Grant Agency under contract number VEGA 1/0596/19 to M.S. M.A.K. and D.S. are funded by a National Institute for Health Research (NIHR) Research Professorship. M.A.K.'s research group also benefits from funding from the Sir Jules Thorn Trust and Rosetrees Trust. M.Z. was supported by an internal research program at Helmholtz Zentrum M\u00FCnchen, Munich, Germany (\u201CPhysician Scientists for Groundbreaking Projects\u201D). K.R.K. is supported by a research award from the Aligning Science Across Parkinson's initiative, Michael J. Fox Foundation, as well as a donation through the Paul Ainsworth Family Foundation. S.W. is supported by the Ministry of Science, Research and the Arts of Baden-W\u00FCrttemberg, and the European Social Fund (ESF) of Baden-W\u00FCrttemberg (31-7635 41/67/1). CMS is a National Health and Medical Research Council Practitioner Fellow (#1136800). M.A.T. reports grants from The Netherlands Organisation for Health Research and Development ZonMW Topsubsidie (91218013), the European Fund for Regional Development from the European Union (01492947), and the province of Friesland, Dystonia Medical Research Foundation, from Stichting Wetenschapsfonds Dystonie Vereniging, from Fonds Psychische Gezondheid, from Phelps Stichting, and an unrestricted grants from Actelion and AOP Orphan Pharmaceuticals AG. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. This study was funded by a research grant from the Else Kr\u00F6ner\u2010Fresenius\u2010Stiftung as well as by in\u2010house institutional funding from Technische Universit\u00E4t M\u00FCnchen, Munich, Germany, Helmholtz Zentrum M\u00FCnchen, Munich, Germany, Medizinische Universit\u00E4t Innsbruck, Innsbruck, Austria, and Charles University, Prague, Czech Republic (PROGRES Q27). This study was also funded by the Czech Ministry of Education under grant AZV: NV19\u201004\u201000233 and under the frame of EJP RD, the European Joint Programme on Rare Diseases (EJP RD COFUND\u2010EJP No. 825575), as well as the Slovak Grant and Development Agency under contract APVV\u201018\u20100547 and the Slovak Research and Grant Agency under contract number VEGA 1/0596/19 to M.S. M.A.K. and D.S. are funded by a National Institute for Health Research (NIHR) Research Professorship. M.A.K.'s research group also benefits from funding from the Sir Jules Thorn Trust and Rosetrees Trust. M.Z. was supported by an internal research program at Helmholtz Zentrum M\u00FCnchen, Munich, Germany (\u201CPhysician Scientists for Groundbreaking Projects\u201D). K.R.K. is supported by a research award from the Aligning Science Across Parkinson's initiative, Michael J. Fox Foundation, as well as a donation through the Paul Ainsworth Family Foundation. S.W. is supported by the Ministry of Science, Research and the Arts of Baden\u2010W\u00FCrttemberg, and the European Social Fund (ESF) of Baden\u2010W\u00FCrttemberg (31\u20107635 41/67/1). CMS is a National Health and Medical Research Council Practitioner Fellow (#1136800). M.A.T. reports grants from The Netherlands Organisation for Health Research and Development ZonMW Topsubsidie (91218013), the European Fund for Regional Development from the European Union (01492947), and the province of Friesland, Dystonia Medical Research Foundation, from Stichting Wetenschapsfonds Dystonie Vereniging, from Fonds Psychische Gezondheid, from Phelps Stichting, and an unrestricted grants from Actelion and AOP Orphan Pharmaceuticals AG.
ASJC Scopus subject areas
- Neurology
- Clinical Neurology