GABRA1 and STXBP1: Novel genetic causes of Dravet syndrome

Objective: To determine the genes underlying Dravet syndromein patients who do not have an SCN1A mutation on routine testing. Methods: We performed whole- exome sequencingin 13 SCN1A -negative patients with Dravet syndromeand targeted resequencing in 67 additional patients to identify new genes for this disorder. Results: We detected disease-causing mutations in 2 novel genes for Dravet syndrome, with mutations in GABRA1 in 4 cases and STXBP1in 3. Furthermore, we identified 3 patients with previously undetected SCN1A mutations, suggesting that SCN1A mutations occur in even more than the currently accepted ∼75% of cases. Conclusions: We show that GABRA1 and STXBP1make a significant contribution to Dravet syndromeafter SCN1A abnormalities have been excluded. Our results have important implications for diagnostic testing, clinical management, and genetic counselingof patients with this devastating disorder and their families.