Rare Variant Burden in Known Dystonia Genes in Population Controls and Sporadic Dystonia Patients

Background: Rare mutations in genes associated with Mendelian forms of disease are a potential mechanism for sporadic disease. The need to assess the clinical significance of such variants is increasing as personalized medicine and genome sequencing increases. Objective: To evaluate the rate of rare, functional variants in dystonia genes in the general population to improve interpretation of the clinical relevance of potentially pathogenic variants in dystonia cases. Methods: We performed an aggregated collapsing analysis of exome sequence that considered rare coding variants in genes previously associated with dystonia, a rare neurological movement disorder, on 2,372 population controls of European ethnicity. We then performed a pilot study in sporadic dystonia to assess whether there was a substantially greater incidence of individuals with rare variation in dystonia genes. Results: Nearly half of population controls had a rare coding variant when 148 genes associated with a dystonia phenotype were considered. When the subset of genes causing isolated dystonia (14 genes) was evaluated, 3-4% of controls harbored rare qualifying variants. Our pilot study of case exomes was powered to identify a five-fold higher or greater rate of qualifying variants in isolated dystonia genes in sporadic dystonia cases compared to population controls; we did not find such an enrichment. Conclusions: We provide the first systematic analysis of rare variation in dystonia genes considered collectively. Our findings emphasize the need to consider the overall frequency of variants in rare disease-related genes in the general population when considering their potential role in clinical presentations.