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