RESUMO
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 (nâ¯=â¯1), ATM (nâ¯=â¯1), GNAL (nâ¯=â¯2), GLB1 (nâ¯=â¯1), KMT2B (nâ¯=â¯2), PRKN (nâ¯=â¯2), PRRT2 (nâ¯=â¯1), SGCE (nâ¯=â¯2), and THAP1 (nâ¯=â¯1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (pâ¯=â¯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.