Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes

Mirja Thomsen, Katrin Marth, Sebastian Loens, Judith Everding, Johanna Junker, Friederike Borngräber, Fabian Ott, Silvia Jesús, Mathias Gelderblom, Thorsten Odorfer, Gregor Kuhlenbäumer, Han-Joon Kim, Eva Schaeffer, Jos Becktepe, Meike Kasten, Norbert Brüggemann, Robert Pfister, Katja Kollewe, Joachim K Krauss, Ebba LohmannFrauke Hinrichs, Daniela Berg, Beomseok Jeon, Hauke Busch, Eckart Altenmüller, Pablo Mir, Christoph Kamm, Jens Volkmann, Simone Zittel, Andreas Ferbert, Kirsten E Zeuner, Arndt Rolfs, Peter Bauer, Andrea A Kühn, Tobias Bäumer, Christine Klein, Katja Lohmann


BACKGROUND: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD).

OBJECTIVES: To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes.

METHODS: We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature.

RESULTS: We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic.

CONCLUSION: This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

ZeitschriftMovement disorders : official journal of the Movement Disorder Society
Seiten (von - bis)526-538
PublikationsstatusVeröffentlicht - 03.2024

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)
  • Querschnittsbereich: Medizinische Genetik


  • 206-06 Molekulare und Zelluläre Neurologie und Neuropathologie