Evidence map›Paper›PMID 40533913›Full record

ArticleAnnals of clinical and translational neurology2025

Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large-Scale Exome Sequencing.

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 and 38 more

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Article in Annals of clinical and translational neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.

0numbers the graph read from it
0cells of the map it votes in
13citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

13 citing papers in PubMed.

  1. Article
  2. Genetic Etiologies of Dystonia with Anarthria/Aphonia.Movement disorders clinical practice · 2026
    Article
  3. Review
  4. Article
  5. Article
  6. Collaborative Genomics for Dystonia in Central and Eastern Europe: Successes Achieved, New Frontiers Ahead.Movement disorders : official journal of the Movement Disorder Society · 2026
    Article
  7. Article
  8. Rare but Relevant? Assessing Variants in Dystonia-Linked Genes in Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026
    Article
  9. Expanding the Genetic and Phenotypic Spectrum of DYT-VPS16: The Importance of Splice-Site Variants.Movement disorders : official journal of the Movement Disorder Society · 2026
    Article
  10. Article
  11. Article
  12. Article
  13. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

48 authors.

Mirja ThomsenInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.ORCID 0009-0004-1148-5493
Fabian OttMedical Systems Biology Division, Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
Sebastian LoensInstitute of Systems Motor Science, University of Lübeck, Lübeck, Germany.
Gamze Kilic-BerkmenDepartment of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
Ai Huey TanDivision of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.ORCID 0000-0002-2979-3839
Shen-Yang LimDivision of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Ebba LohmannHertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Kaja M SchröderInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Lea IpsenInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Lena A NothackerInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Linn WelzelInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Alexandra S RudnikInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Frauke HinrichsInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Thorsten OdorferDepartment of Neurology, University Hospital Würzburg, Würzburg, Germany.
Kirsten E ZeunerDepartment of Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Friederike SchumannDepartment of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Andrea A KühnDepartment of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Simone ZittelDepartment of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Marius MoellerMedical Systems Biology Division, Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
Robert PfisterNeurological Practice, Neusäß, Germany.
Christoph KammDepartment of Neurology, University Medical Center Rostock, Rostock, Germany.
Anthony E LangEdmond J. Safra Program in Parkinson's Disease, the Rossy PSP Centre and Department of Medicine (Neurology), Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
Yi Wen TayDivision of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Ana Luísa de Almeida MarcelinoDepartment of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.ORCID 0000-0002-3291-7222
Marie VidailhetSorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, and Center of Excellence of Neurodegenerative Disease (CoEN), AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
Emmanuel RozeSorbonne University, Paris Brain Institute (ICM), Inserm, CNRS, and Center of Excellence of Neurodegenerative Disease (CoEN), AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
Joel S PerlmutterDepartments of Neurology, Radiology and Neuroscience, Washington University, St. Louis, Missouri, USA.
Jeanne S FeuersteinDepartment of Neurology, University of Colorado, Aurora, Colorado, USA.
Victor S C FungMovement Disorders Unit, Department of Neurology, Westmead Hospital & Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Florence ChangMovement Disorders Unit, Department of Neurology, Westmead Hospital & Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Richard L BarbanoDepartment of Neurology, University of Rochester, Rochester, New York, USA.
Steven BellowsBaylor College of Medicine, Department of Neurology, Houston, Texas, USA.
Aparna A Wagle ShuklaDepartment of Neurology, University of Florida, Gainesville, Florida, USA.
Alberto J EspayJames J and Joan A Gardner Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA.ORCID 0000-0002-3389-136X
Mark S LeDouxDepartment of Psychology, University of Memphis, Veracity Neuroscience LLC, Memphis, Tennessee, USA.
Brian D BermanDepartment of Neurology, Virginia Commonwealth University, Richmond, Virginia, USA.ORCID 0000-0002-0602-9942
Stephen ReichNeurology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Andres DeikDepartment of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Andre FrankeInstitute of Clinical Molecular Biology, Christian-Albrechts-Universität and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Michael WittigInstitute of Clinical Molecular Biology, Christian-Albrechts-Universität and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Sören FranzenburgInstitute of Clinical Molecular Biology, Christian-Albrechts-Universität and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Jens VolkmannDepartment of Neurology, University Hospital Würzburg, Würzburg, Germany.
Norbert BrüggemannInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.
H A JinnahDepartment of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
Tobias BäumerInstitute of Systems Motor Science, University of Lübeck, Lübeck, Germany.
Christine KleinInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Hauke BuschMedical Systems Biology Division, Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
Katja LohmannInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.

Funding

Dystonia Coalition- Pilot ProjectU54NS116025 · NINDS · EMORY UNIVERSITY · PI JINNAH, HYDER A · 2019 to 2023
$7.1M
Dystonia CoalitionU54TR001456 · NCATS · EMORY UNIVERSITY · PI JINNAH, HYDER A · 2015 to 2016
$2.5M
Deutsche Forschungsgemeinschaft 407495230Deutsche Forschungsgemeinschaft 423957469Deutsche Forschungsgemeinschaft EXC 2167-390884018Deutsche Forschungsgemeinschaft LO1555/10-1NCATS NIH HHS U54 TR001456NIH HHS NS067501NIH HHS NS116025NIH HHS TR001456NINDS NIH HHS U54 NS116025The University of Malaya Parkinson's Disease and Movement Disorders Research Program PV035-2017
6 · The paper itself

Abstract

objectiveDystonia 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.

methodsExome 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.

resultsWe 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.

interpretationThis 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.

Indexed as

DystoniaDystonic DisordersGenetic VariationAdolescentAdultAgedChildExome SequencingFemaleHumansMaleMiddle AgedPhenotypeRegistriesYoung Adultdystoniaexome sequencinggenetic heterogeneitypathogenic variants

Identifiers

PMID40533913
PMCPMC12343315

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.