GABRA1 and STXBP1: Novel genetic causes of Dravet syndrome

GL Carvill, S Weckhuysen, JM McMahon, C Hartmann… - Neurology, 2014 - AAN Enterprises
GL Carvill, S Weckhuysen, JM McMahon, C Hartmann, RS Møller, H Hjalgrim, J Cook…
Neurology, 2014AAN Enterprises
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 …
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.
American Academy of Neurology