Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression

Background Paroxysmal dyskinesias (PDs), a clinically and genetically heterogeneous group of episodic movement disorders, include kinesigenic PD (PKD), exercise-induced PD (PED) and non-kinesigenic PD (PNKD). These disorders are all transmitted as autosomal dominant traits with incomplete penetrance. Several PD-related genetic disorders, including PKD and familial infantile convulsions with paroxysmal choreoathetosis (ICCA), mapped to the same region on chromosome 16. Independent genetic studies have recently revealed that PKD can be caused by loss-of-function mutations in the proline-rich transmembrane protein 2 gene (PRRT2). We tested the hypothesis that other forms of PDs are also due to PRRT2 mutations. Methods/results The whole genomic region of PRRT2 was sequenced in six Han Chinese families and 15 sporadic cases of PD-related phenotypes. The previously reported mutation, c.649dupC (p.R217Pfs*7), was found in two families with PKD, one family with ICCA, one family with PNKD-like phenotype, and two sporadic cases with PED. In an additional ICCA family, a novel frameshift mutation, c.904dupG (p.D302Gfs*38), was identified. A missense mutation, c.913G -> A (p.G305R), and a synonymous substitution, c.1011C -> T (p.G337G), were also detected in two sporadic PKD cases. Conclusion This study shows that PKD, ICCA and some other PD-related phenotypes are part of the same phenotypic spectrum, caused by mutations in PRRT2. This underscores the complexity of the phenotypic consequences of PRRT2 mutations.