Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

被引：519

作者：

Carvill, Gemma L. ^{[1
]}

Heavin, Sinead B. ^{[2
]}

Yendle, Simone C. ^{[2
]}

McMahon, Jacinta M. ^{[2
]}

O'Roak, Brian J. ^{[3
]}

Cook, Joseph ^{[1
]}

Khan, Adiba ^{[1
]}

Dorschner, Michael O. ^{[4
,5
]}

Weaver, Molly ^{[4
,5
]}

Calvert, Sophie ^{[6
,7
]}

Malone, Stephen ^{[6
,7
]}

Wallace, Geoffrey ^{[6
,7
]}

Stanley, Thorsten ^{[8
]}

Bye, Ann M. E. ^{[9
]}

Bleasel, Andrew ^{[10
]}

Howell, Katherine B. ^{[11
]}

Kivity, Sara ^{[12
]}

Mackay, Mark T. ^{[11
,13
,14
]}

Rodriguez-Casero, Victoria ^{[15
]}

Webster, Richard ^{[16
]}

Korczyn, Amos ^{[17
]}

Afawi, Zaid ^{[18
]}

Zelnick, Nathanel ^{[19
]}

Lerman-Sagie, Tally ^{[20
,21
]}

Lev, Dorit ^{[20
]}

Moller, Rikke S. ^{[21
]}

Gill, Deepak ^{[16
]}

Andrade, Danielle M. ^{[22
]}

Freeman, Jeremy L. ^{[11
,13
]}

Sadleir, Lynette G. ^{[8
]}

Shendure, Jay ^{[3
]}

Berkovic, Samuel F. ^{[2
]}

Scheffer, Ingrid E. ^{[2
,11
,14
,23
]}

Mefford, Heather C. ^{[1
]}

机构：

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

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

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

[4] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

[5] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA

[6] Royal Childrens Hosp, Neurosci Childrens Hlth Queensland, Brisbane, Qld, Australia

[7] Univ Queensland, Mater Childrens Hosp, Neurosci Childrens Hlth Queensland, Brisbane, Qld 4101, Australia

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

[9] Univ New S Wales, Dept Paediat Neurol, Sydney Childrens Hosp, Sydney, NSW, Australia

[10] Univ Sydney, Westmead Hosp, Dept Neurol, Sydney, NSW 2006, Australia

[11] Royal Childrens Hosp, Dept Neurol, Melbourne, Vic, Australia

[12] Schneider Childrens Med Ctr Israel, Epilepsy Unit, Petah Tiqwa, Israel

[13] Murdoch Childrens Res Inst, Melbourne, Vic, Australia

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

[15] Monash Med Ctr, Melbourne, Vic, Australia

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

[17] Tel Aviv Univ, Dept Neurol, IL-69978 Tel Aviv, Israel

[18] Tel Aviv Univ, Sch Med, IL-69978 Tel Aviv, Israel

[19] Technion Israel Inst Technol, Fac Med, Carmel Med Ctr, Dept Pediat, Haifa, Israel

[20] Wolfson Med Ctr, Metab Neurogenet Serv, Holon, Israel

[21] Danish Epilepsy Ctr, Dianalund, Denmark

[22] Univ Toronto, Toronto Western Hosp, Dept Med, Div Neurol,Krembil Neurosci Program, Toronto, ON M5T 2S8, Canada

[23] Florey Inst, Melbourne, Vic, Australia

来源：

NATURE GENETICS | 2013年 / 45卷 / 07期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

AUTISM SPECTRUM DISORDERS; INTELLECTUAL DISABILITY; SODIUM-CHANNEL; MENTAL-RETARDATION; GENE SCN2A; MICRODELETION; SEIZURES; EPILEPSIES; PHENOTYPE; DELETIONS;

D O I：

10.1038/ng.2646

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.

引用

页码：825 / U158

页数：7

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