GABRA1 and STXBP1: novel genetic causes of Dravet syndrome

Abstract

Objective: To determine the genes underlying Dravet syndrome in patients who do not have an SCN1A mutation on routine testing.

Methods: We performed whole-exome sequencing in 13 SCN1A-negative patients with Dravet syndrome and 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 STXBP1 in 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 STXBP1 make a significant contribution to Dravet syndrome after SCN1A abnormalities have been excluded. Our results have important implications for diagnostic testing, clinical management, and genetic counseling of patients with this devastating disorder and their families.

Figure 1. GABRA1 mutations in epilepsy and effects on γ-aminobutyric acid (GABA) response

(A) The amino acid locations of the 8 mutations identified in patients with Dravet syndrome (purple) and other epilepsy syndromes (green). There is no clear genotype–phenotype correlation with respect to either nature or localization of the mutation and severity of phenotype. (B) Maximal current response (1 mM GABA) of the wild-type (WT) and p.Gly251Ser mutant. (C) GABA dose-response curves of the WT and p.Gly251Ser mutant in Xenopus laevis oocytes. CAE = childhood absence epilepsy; EE = epileptic encephalopathy; GGE/FS = genetic generalized epilepsies/febrile seizures; JME = juvenile myoclonic epilepsy.