Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large-Scale Exome Sequencing.
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Thomsen Mirja, Ott Fabian, Loens Sebastian, Kilic-Berkmen Gamze, Tan Ai Huey, Lim Shen-Yang, Lohmann Ebba, Schröder Kaja M, Ipsen Lea, Nothacker Lena A, Welzel Linn, Rudnik Alexandra S, Hinrichs Frauke, Odorfer Thorsten, Zeuner Kirsten E, Schumann Friederike, Kühn Andrea A, Zittel Simone, Moeller Marius, Pfister Robert, Kamm Christoph, Lang Anthony E, Tay Yi Wen, de Almeida Marcelino Ana Luísa, Vidailhet Marie, Roze Emmanuel, Perlmutter Joel S, Feuerstein Jeanne S, Fung Victor S C, Chang Florence, Barbano Richard L, Bellows Steven, Wagle Shukla Aparna A, Espay Alberto J, LeDoux Mark S, Berman Brian D, Reich Stephen, Deik Andres, Franke Andre, Wittig Michael, Franzenburg Sören, Volkmann Jens, Brüggemann Norbert, Jinnah H A, Bäumer Tobias, Klein Christine, Busch Hauke, Lohmann Katja
Аннотация
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.