Epidemiology of DYT1 dystonia: Estimating prevalence via genetic ascertainment

OBJECTIVE: To estimate the prevalence of TOR1A sequence variants associated with DYT1 dystonia. METHODS: We determined the frequency of the common trinucleotide deletion that causes DYT1 in the Genome Aggregation Database and the Penn Medicine Biobank, totaling exomes from over 135,000 individuals. We also evaluated the prevalence of other possible pathogenic variants in this gene and asked whether the D216H polymorphism is linked to a higher diagnostic rate for dystonia independent of the DYT1-causing mutation. RESULTS: The estimated range of prevalence of the most common pathogenic variant that causes DYT1 is ∼17.6–26.1 carriers per 100,000 individuals. Based on the different data sets used, we predict that there are between 54,366 and 80,891 mutation carriers in the United States, which, due to the reduced penetrance of this variant, would translate into 16,475–24,513 DYT1 patients. CONCLUSIONS: Our data provide a prevalence estimate of the most common DYT1 mutation in the general population. This information is specifically important for those with interest in the development of precision therapeutics for dystonia.