Merck

GABRA1 and STXBP1: novel genetic causes of Dravet syndrome.

Neurology (2014-03-14)
Gemma L Carvill, Sarah Weckhuysen, Jacinta M McMahon, Corinna Hartmann, Rikke S Møller, Helle Hjalgrim, Joseph Cook, Eileen Geraghty, Brian J O'Roak, Steve Petrou, Alison Clarke, Deepak Gill, Lynette G Sadleir, Hiltrud Muhle, Sarah von Spiczak, Marina Nikanorova, Bree L Hodgson, Elena V Gazina, Arvid Suls, Jay Shendure, Leanne M Dibbens, Peter De Jonghe, Ingo Helbig, Samuel F Berkovic, Ingrid E Scheffer, Heather C Mefford
ABSTRACT

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

MATERIALS
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