Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large‐Scale Exome Sequencing
ABSTRACT Objective Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%), the etiology in most patients remains elusive. Moreover, understanding correlations between clinical manifestati...
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2025-08-01
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| Online Access: | https://doi.org/10.1002/acn3.70100 |
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| author | Mirja Thomsen Fabian Ott Sebastian Loens Gamze Kilic‐Berkmen Ai Huey Tan Shen‐Yang Lim Ebba Lohmann Kaja M. Schröder Lea Ipsen Lena A. Nothacker Linn Welzel Alexandra S. Rudnik Frauke Hinrichs Thorsten Odorfer Kirsten E. Zeuner Friederike Schumann Andrea A. Kühn Simone Zittel Marius Moeller Robert Pfister Christoph Kamm Anthony E. Lang Yi Wen Tay Ana Luísa deAlmeida Marcelino Marie Vidailhet Emmanuel Roze Joel S. Perlmutter Jeanne S. Feuerstein Victor S. C. Fung Florence Chang Richard L. Barbano Steven Bellows Aparna A. Wagle Shukla Alberto J. Espay Mark S. LeDoux Brian D. Berman Stephen Reich Andres Deik Andre Franke Michael Wittig Sören Franzenburg Jens Volkmann Norbert Brüggemann H. A. Jinnah Tobias Bäumer Christine Klein Hauke Busch Katja Lohmann |
| author_facet | Mirja Thomsen Fabian Ott Sebastian Loens Gamze Kilic‐Berkmen Ai Huey Tan Shen‐Yang Lim Ebba Lohmann Kaja M. Schröder Lea Ipsen Lena A. Nothacker Linn Welzel Alexandra S. Rudnik Frauke Hinrichs Thorsten Odorfer Kirsten E. Zeuner Friederike Schumann Andrea A. Kühn Simone Zittel Marius Moeller Robert Pfister Christoph Kamm Anthony E. Lang Yi Wen Tay Ana Luísa deAlmeida Marcelino Marie Vidailhet Emmanuel Roze Joel S. Perlmutter Jeanne S. Feuerstein Victor S. C. Fung Florence Chang Richard L. Barbano Steven Bellows Aparna A. Wagle Shukla Alberto J. Espay Mark S. LeDoux Brian D. Berman Stephen Reich Andres Deik Andre Franke Michael Wittig Sören Franzenburg Jens Volkmann Norbert Brüggemann H. A. Jinnah Tobias Bäumer Christine Klein Hauke Busch Katja Lohmann |
| author_sort | Mirja Thomsen |
| collection | DOAJ |
| description | ABSTRACT Objective Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%), the etiology in most patients remains elusive. Moreover, understanding correlations between clinical manifestations and genetic variants has become increasingly complex. Methods Exome sequencing was conducted on 1924 genetically unsolved, mainly late‐onset isolated dystonia patients, recruited primarily from two dystonia registries (DysTract and the Dystonia Coalition). Rare variants in genes previously linked to dystonia (n = 406) were examined, confirmed via Sanger sequencing, and analyzed for segregation when possible. Results We identified 137 distinct likely pathogenic/pathogenic variants (according to ACMG criteria) across 51 genes in 163/1924 patients, including 153/1895 index patients (diagnostic yield 8.1%). The strongest predictors of a genetic diagnosis were generalized dystonia (28.6% yield) and age at onset (20.4% yield in patients with onset < 30 years). Notably, 56.2% of these variants were novel, with recurrent variants in EIF2AK2, VPS16, KCNMA1, and SLC2A1. Additionally, 321 index patients (16.9%) harbored variants of uncertain significance in 102 genes. The most frequently implicated genes included VPS16, THAP1, GCH1, SGCE, GNAL, and KMT2B. Presumably pathogenic variants in less well‐established dystonia genes were also found, including KCNMA1, KIF1A, and ZMYND11. At least six variants (in ADCY5, GNB1, IR2BPL, KCNN2, KMT2B, and VPS16) occurred de novo, supporting pathogenicity. Interpretation This study provides valuable insights into the genetic landscape of dystonia, underscores the utility of exome sequencing for diagnosis, substantiates several candidate genes, and expands the phenotypic spectrum of some genes to include prominent, sometimes isolated dystonia. |
| format | Article |
| id | doaj-art-9ac7f4ecc7d7456ebe8b5a2a42e1860b |
| institution | Kabale University |
| issn | 2328-9503 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj-art-9ac7f4ecc7d7456ebe8b5a2a42e1860b2025-08-20T04:01:48ZengWileyAnnals of Clinical and Translational Neurology2328-95032025-08-011281648165910.1002/acn3.70100Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large‐Scale Exome SequencingMirja Thomsen0Fabian Ott1Sebastian Loens2Gamze Kilic‐Berkmen3Ai Huey Tan4Shen‐Yang Lim5Ebba Lohmann6Kaja M. Schröder7Lea Ipsen8Lena A. Nothacker9Linn Welzel10Alexandra S. Rudnik11Frauke Hinrichs12Thorsten Odorfer13Kirsten E. Zeuner14Friederike Schumann15Andrea A. Kühn16Simone Zittel17Marius Moeller18Robert Pfister19Christoph Kamm20Anthony E. Lang21Yi Wen Tay22Ana Luísa deAlmeida Marcelino23Marie Vidailhet24Emmanuel Roze25Joel S. Perlmutter26Jeanne S. Feuerstein27Victor S. C. Fung28Florence Chang29Richard L. Barbano30Steven Bellows31Aparna A. Wagle Shukla32Alberto J. Espay33Mark S. LeDoux34Brian D. Berman35Stephen Reich36Andres Deik37Andre Franke38Michael Wittig39Sören Franzenburg40Jens Volkmann41Norbert Brüggemann42H. A. Jinnah43Tobias Bäumer44Christine Klein45Hauke Busch46Katja Lohmann47Institute of Neurogenetics University of Lübeck Lübeck GermanyMedical Systems Biology Division, Institute of Experimental Dermatology University of Lübeck Lübeck GermanyInstitute of Systems Motor Science University of Lübeck Lübeck GermanyDepartment of Neurology Emory University School of Medicine Atlanta Georgia USADivision of Neurology, Department of Medicine Faculty of Medicine, University of Malaya Kuala Lumpur MalaysiaDivision of Neurology, Department of Medicine Faculty of Medicine, University of Malaya Kuala Lumpur MalaysiaHertie Institute for Clinical Brain Research, University of Tübingen Tübingen GermanyInstitute of Neurogenetics University of Lübeck Lübeck GermanyInstitute of Neurogenetics University of Lübeck Lübeck GermanyInstitute of Neurogenetics University of Lübeck Lübeck GermanyInstitute of Neurogenetics University of Lübeck Lübeck GermanyInstitute of Neurogenetics University of Lübeck Lübeck GermanyInstitute of Neurogenetics University of Lübeck Lübeck GermanyDepartment of Neurology University Hospital Würzburg Würzburg GermanyDepartment of Neurology University Hospital Schleswig‐Holstein, Campus Kiel Kiel GermanyDepartment of Neurology Charité—Universitätsmedizin Berlin Berlin GermanyDepartment of Neurology Charité—Universitätsmedizin Berlin Berlin GermanyDepartment of Neurology University Medical Center Hamburg‐Eppendorf Hamburg GermanyMedical Systems Biology Division, Institute of Experimental Dermatology University of Lübeck Lübeck GermanyNeurological Practice Neusäß GermanyDepartment of Neurology University Medical Center Rostock Rostock GermanyEdmond J. Safra Program in Parkinson's Disease, the Rossy PSP Centre and Department of Medicine (Neurology), Toronto Western Hospital University of Toronto Toronto Ontario CanadaDivision of Neurology, Department of Medicine Faculty of Medicine, University of Malaya Kuala Lumpur MalaysiaDepartment of Neurology Charité—Universitätsmedizin Berlin Berlin GermanySorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, and Center of Excellence of Neurodegenerative Disease (CoEN), AP‐HP, Pitié‐Salpêtrière Hospital Paris FranceSorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, and Center of Excellence of Neurodegenerative Disease (CoEN), AP‐HP, Pitié‐Salpêtrière Hospital Paris FranceDepartments of Neurology, Radiology and Neuroscience Washington University St. Louis Missouri USADepartment of Neurology University of Colorado Aurora Colorado USAMovement Disorders Unit, Department of Neurology Westmead Hospital & Sydney Medical School, University of Sydney Sydney New South Wales AustraliaMovement Disorders Unit, Department of Neurology Westmead Hospital & Sydney Medical School, University of Sydney Sydney New South Wales AustraliaDepartment of Neurology University of Rochester Rochester New York USABaylor College of Medicine Department of Neurology Houston Texas USADepartment of Neurology University of Florida Gainesville Florida USAJames J and Joan A Gardner Center for Parkinson's Disease and Movement Disorders University of Cincinnati Cincinnati Ohio USADepartment of Psychology University of Memphis, Veracity Neuroscience LLC Memphis Tennessee USADepartment of Neurology Virginia Commonwealth University Richmond Virginia USANeurology University of Maryland School of Medicine Baltimore Maryland USADepartment of Neurology Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania USAInstitute of Clinical Molecular Biology Christian‐Albrechts‐Universität and University Hospital Schleswig‐Holstein, Campus Kiel Kiel GermanyInstitute of Clinical Molecular Biology Christian‐Albrechts‐Universität and University Hospital Schleswig‐Holstein, Campus Kiel Kiel GermanyInstitute of Clinical Molecular Biology Christian‐Albrechts‐Universität and University Hospital Schleswig‐Holstein, Campus Kiel Kiel GermanyDepartment of Neurology University Hospital Würzburg Würzburg GermanyInstitute of Neurogenetics University of Lübeck Lübeck GermanyDepartment of Neurology Emory University School of Medicine Atlanta Georgia USAInstitute of Systems Motor Science University of Lübeck Lübeck GermanyInstitute of Neurogenetics University of Lübeck Lübeck GermanyMedical Systems Biology Division, Institute of Experimental Dermatology University of Lübeck Lübeck GermanyInstitute of Neurogenetics University of Lübeck Lübeck GermanyABSTRACT Objective Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%), the etiology in most patients remains elusive. Moreover, understanding correlations between clinical manifestations and genetic variants has become increasingly complex. Methods Exome sequencing was conducted on 1924 genetically unsolved, mainly late‐onset isolated dystonia patients, recruited primarily from two dystonia registries (DysTract and the Dystonia Coalition). Rare variants in genes previously linked to dystonia (n = 406) were examined, confirmed via Sanger sequencing, and analyzed for segregation when possible. Results We identified 137 distinct likely pathogenic/pathogenic variants (according to ACMG criteria) across 51 genes in 163/1924 patients, including 153/1895 index patients (diagnostic yield 8.1%). The strongest predictors of a genetic diagnosis were generalized dystonia (28.6% yield) and age at onset (20.4% yield in patients with onset < 30 years). Notably, 56.2% of these variants were novel, with recurrent variants in EIF2AK2, VPS16, KCNMA1, and SLC2A1. Additionally, 321 index patients (16.9%) harbored variants of uncertain significance in 102 genes. The most frequently implicated genes included VPS16, THAP1, GCH1, SGCE, GNAL, and KMT2B. Presumably pathogenic variants in less well‐established dystonia genes were also found, including KCNMA1, KIF1A, and ZMYND11. At least six variants (in ADCY5, GNB1, IR2BPL, KCNN2, KMT2B, and VPS16) occurred de novo, supporting pathogenicity. Interpretation This study provides valuable insights into the genetic landscape of dystonia, underscores the utility of exome sequencing for diagnosis, substantiates several candidate genes, and expands the phenotypic spectrum of some genes to include prominent, sometimes isolated dystonia.https://doi.org/10.1002/acn3.70100dystoniaexome sequencinggenetic heterogeneitypathogenic variants |
| spellingShingle | Mirja Thomsen Fabian Ott Sebastian Loens Gamze Kilic‐Berkmen Ai Huey Tan Shen‐Yang Lim Ebba Lohmann Kaja M. Schröder Lea Ipsen Lena A. Nothacker Linn Welzel Alexandra S. Rudnik Frauke Hinrichs Thorsten Odorfer Kirsten E. Zeuner Friederike Schumann Andrea A. Kühn Simone Zittel Marius Moeller Robert Pfister Christoph Kamm Anthony E. Lang Yi Wen Tay Ana Luísa deAlmeida Marcelino Marie Vidailhet Emmanuel Roze Joel S. Perlmutter Jeanne S. Feuerstein Victor S. C. Fung Florence Chang Richard L. Barbano Steven Bellows Aparna A. Wagle Shukla Alberto J. Espay Mark S. LeDoux Brian D. Berman Stephen Reich Andres Deik Andre Franke Michael Wittig Sören Franzenburg Jens Volkmann Norbert Brüggemann H. A. Jinnah Tobias Bäumer Christine Klein Hauke Busch Katja Lohmann Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large‐Scale Exome Sequencing Annals of Clinical and Translational Neurology dystonia exome sequencing genetic heterogeneity pathogenic variants |
| title | Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large‐Scale Exome Sequencing |
| title_full | Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large‐Scale Exome Sequencing |
| title_fullStr | Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large‐Scale Exome Sequencing |
| title_full_unstemmed | Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large‐Scale Exome Sequencing |
| title_short | Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large‐Scale Exome Sequencing |
| title_sort | genetic diversity and expanded phenotypes in dystonia insights from large scale exome sequencing |
| topic | dystonia exome sequencing genetic heterogeneity pathogenic variants |
| url | https://doi.org/10.1002/acn3.70100 |
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