GABRA1 and STXBP1: Novel genetic causes of Dravet syndrome

GL Carvill; S Weckhuysen; JM McMahon; C Hartmann; RS Møller; H Hjalgrim; J Cook; E Geraghty; BJ O'Roak; S Petrou; A Clarke; D Gill; LG Sadleir; H Muhle; S Von Spiczak; M Nikanorova; BL Hodgson; EV Gazina; A Suls; J Shendure; LM Dibbens; P De Jonghe; I Helbig; SF Berkovic; IE Scheffer; HC Mefford

Journal article

GABRA1 and STXBP1: Novel genetic causes of Dravet syndrome

GL Carvill, S Weckhuysen, JM McMahon, C Hartmann, RS Møller, H Hjalgrim, J Cook, E Geraghty, BJ O'Roak, S Petrou, A Clarke, D Gill, LG Sadleir, H Muhle, S Von Spiczak, M Nikanorova, BL Hodgson, EV Gazina, A Suls, J Shendure Show all

Neurology | Published : 2014

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 contrib..

View full abstract

University of Melbourne Researchers

Sam Berkovic Author

Ingrid Scheffer Author

Grants

Awarded by National Institute of Neurological Disorders and Stroke

Funding Acknowledgements

Supported by funding from the NIH (NINDS 5R01NS069605). H. C. M. is a recipient of the Burroughs Wellcome Fund Career Award for Medical Scientists. I. E. S. and S. F. B. are supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant and Practitioner Fellowship (I. E. S.). L. G. S. is supported by a Health and Research Council of New Zealand project grant. The research is supported by the Fund for Scientific Research Flanders (FWO), Methusalem excellence grant of the Flemish Government, University of Antwerp, the Interuniversity Attraction Poles (IAP) program P6/43 of the Belgian Science Policy Office (BELSPO) and the Eurocores program EuroEPINOMICS of the European Science Foundation. The VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be) performed genetic analyses. A. S. is a postdoctoral fellow of the Fund for Scientific Research Flanders (FWO).