Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Kishore R. Kumar*, Ryan L. Davis, Michel C. Tchan, G. M. Wali, Neil Mahant, Karl Ng, Katya Kotschet, Sue Faye Siow, Jason Gu, Zachary Walls, Ce Kang, Gautam Wali, Stan Levy, Chung Sen Phua, Con Yiannikas, Paul Darveniza, Florence C. F. Chang, Hugo Morales-Briceño, Dominic B. Rowe, Alex DrewVelimir Gayevskiy, Mark J. Cowley, Andre E. Minoche, Stephen Tisch, Michael Hayes, Sarah Kummerfeld, Victor S. C. Fung, Carolyn M. Sue

*Corresponding author for this work

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    Introduction: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. Methods: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. Results: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). Conclusion: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.

    Original languageEnglish
    Pages (from-to)111-118
    Number of pages8
    JournalParkinsonism and Related Disorders
    Publication statusPublished - 1 Dec 2019

    Bibliographical note

    Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


    • Dystonia
    • Genetic diagnosis
    • GNAL
    • KMT2B
    • Whole genome sequencing


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