GABRA1 and STXBP1: Novel genetic causes of Dravet syndrome

被引：211

作者：

Carvill, Gemma L. ^{[1
]}

Weckhuysen, Sarah ^{[3
,4
,5
]}

McMahon, Jacinta M. ^{[6
]}

Hartmann, Corinna ^{[1
,7
]}

Moller, Rikke S. ^{[8
]}

Hjalgrim, Helle ^{[8
,9
]}

Cook, Joseph ^{[1
]}

Geraghty, Eileen ^{[1
]}

O'Roak, Brian J. ^{[10
]}

Petrou, Steve ^{[11
]}

Clarke, Alison ^{[11
]}

Gill, Deepak ^{[12
]}

Sadleir, Lynette G. ^{[13
]}

Muhle, Hiltrud ^{[7
]}

von Spiczak, Sarah ^{[7
]}

Nikanorova, Marina ^{[8
,9
]}

Hodgson, Bree L. ^{[14
]}

Gazina, Elena V. ^{[11
]}

Suls, Arvid ^{[4
]}

Shendure, Jay ^{[2
]}

Dibbens, Leanne M. ^{[14
]}

De Jonghe, Peter ^{[4
,15
]}

Helbig, Ingo ^{[7
]}

Berkovic, Samuel F. ^{[6
]}

Scheffer, Ingrid E. ^{[6
,11
,16
]}

Mefford, Heather C. ^{[1
]}

机构：

[1] Univ Washington, Dept Pediat, Div Med Genet, Seattle, WA 98195 USA

[2] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[3] VIB, Dept Mol Genet, Neurogenet Grp, Antwerp, Belgium

[4] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, Antwerp, Belgium

[5] Epilepsy Ctr Kempenhaeghe, Oosterhout, Netherlands

[6] Univ Melbourne, Austin Hlth, Dept Med, Epilepsy Res Ctr, Melbourne, Vic 3010, Australia

[7] Univ Kiel, Univ Med Ctr, Dept Neuropediat, Kiel, Germany

[8] Danish Epilepsy Ctr, Dianalund, Denmark

[9] Univ Southern Denmark, Inst Reg Hlth Serv, Odense, Denmark

[10] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA

[11] Florey Inst, Melbourne, Vic, Australia

[12] Childrens Hosp Westmead, TY Nelson Dept Neurol, Sydney, NSW, Australia

[13] Univ Otago, Sch Med & Hlth Sci, Dept Paediat, Wellington, New Zealand

[14] Univ S Australia, Sch Pharm & Med Sci, Epilepsy Res Program, Adelaide, SA 5001, Australia

[15] Univ Antwerp Hosp, Div Neurol, Antwerp, Belgium

[16] Univ Melbourne, Royal Childrens Hosp, Dept Paediat, Melbourne, Vic 3010, Australia

来源：

NEUROLOGY | 2014年 / 82卷 / 14期

基金：

英国医学研究理事会;

关键词：

DE-NOVO MUTATIONS; FEBRILE SEIZURES PLUS; INFANTILE EPILEPTIC ENCEPHALOPATHY; SEVERE MYOCLONIC EPILEPSY; GENERALIZED EPILEPSY; SCN1B; SUBUNIT; ONSET; SPECTRUM; PATIENT;

D O I：

10.1212/WNL.0000000000000291

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 approximate to 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.

引用

页码：1245 / 1253

页数：9

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