2. Academic Validation
  3. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome

GABRA1 and STXBP1: novel genetic causes of Dravet syndrome

  • Neurology. 2014 Apr 8;82(14):1245-53. doi: 10.1212/WNL.0000000000000291.
Gemma L Carvill 1,  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
Affiliations

Affiliation

  • 1 From the Division of Genetic Medicine, Department of Pediatrics (G.L.C., C.H., J.C., E.G., H.C.M.), and the Department of Genome Sciences (J.S.), University of Washington, Seattle; Neurogenetics Group (S.W.), Department of Molecular Genetics, VIB, Antwerp; Laboratory of Neurogenetics (S.W., A.S., P.D.J.), Institute Born-Bunge, University of Antwerp, Belgium; Epilepsy Centre Kempenhaeghe (S.W.), Oosterhout, the Netherlands; Epilepsy Research Centre (J.M.M., S.F.B., I.E.S.), Department of Medicine, University of Melbourne, Austin Health, Australia; Department of Neuropediatrics (C.H., H.M., S.v.S., I.H.), University Medical Center, Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany; Danish Epilepsy Centre (R.S.M., H.H., M.N.), Dianalund; Institute for Regional Health Services (H.H., M.N.), University of Southern Denmark, Odense, Denmark; Department of Molecular and Medical Genetics (B.J.O.), Oregon Health and Science University, Portland; Florey Institute (S.P., A.C., E.V.G., I.E.S.), Victoria; TY Nelson Department of Neurology (D.G.), The Children's Hospital at Westmead, Sydney, NSW, Australia; Department of Paediatrics (L.G.S.), School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand; Epilepsy Research Program (B.L.H., L.M.D.), School of Pharmacy and Medical Sciences, University of South Australia, Adelaide; Division of Neurology (P.D.J.), Antwerp University Hospital, Belgium; and the Department of Paediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital, Australia.
PMID: 24623842 DOI: 10.1212/WNL.0000000000000291
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.

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