Abstract

DYT1 early-onset isolated dystonia (DYT1 dystonia), a rare autosomal dominant (AD) primary dystonia, is categorized as a monogenic disease. While it is a well-known AD inherited disease, the relatively low penetrance rate implicates potential modifiers in play for disease progression. In this report, an affected individual with TOR1A gene (c.907_909delGAG, p.E303del) variant, was identified along with three additional AD carriers in the family. Since we failed to find the second hit variant from TOR1A (D216H, F323_Y328del and F205I) and major binding proteins, including TOR1AIP1 and 2 or HSPA8 proteins, subsequent whole exome sequencing on the patient, the carriers and a non-carrier family member were performed to screen for candidate modifiers of TOR1A (E303del). The result reveals that this patient distinctly carries one copy of TOR1A gene (c.907_909delGAG, p.E303del) and one or two copy of SYNE2 gene (c.1721T>C, c.12001T>C, and c.12002G>A), encoding I574T, W4001R, and W4001Ter variants. We propose that these SYNE2 variants are linked to earlier disease onset in this patient by impacting the protein-protein interaction between TOR1A and SYNE2. Our study suggests SYNE2 gene maybe a culprit to lower the threshold for DYT1 dystonia progression and provides one novel gene target for further screening diagnosis of DYT1 dystonia.