Nature · 2013

De novo mutations in epileptic encephalopathies.

СтатьяResearch Support, American Recovery and Reinvestment ActПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен

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Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen Andrew S, Berkovic Samuel F, Cossette Patrick, Delanty Norman, Dlugos Dennis, Eichler Evan E, Epstein Michael P, Glauser Tracy, Goldstein David B, Han Yujun, Heinzen Erin L, Hitomi Yuki, Howell Katherine B, Johnson Michael R, Kuzniecky Ruben, Lowenstein Daniel H, Lu Yi-Fan, Madou Maura R Z, Marson Anthony G, Mefford Heather C, Esmaeeli Nieh Sahar, O'Brien Terence J, Ottman Ruth, Petrovski Slavé, Poduri Annapurna, Ruzzo Elizabeth K, Scheffer Ingrid E, Sherr Elliott H, Yuskaitis Christopher J, Abou-Khalil Bassel, Alldredge Brian K, Bautista Jocelyn F, Berkovic Samuel F, Boro Alex, Cascino Gregory D, Consalvo Damian, Crumrine Patricia, Devinsky Orrin, Dlugos Dennis, Epstein Michael P, Fiol Miguel, Fountain Nathan B, French Jacqueline, Friedman Daniel, Geller Eric B, Glauser Tracy, Glynn Simon, Haut Sheryl R, Hayward Jean, Helmers Sandra L, Joshi Sucheta, Kanner Andres, Kirsch Heidi E, Knowlton Robert C, Kossoff Eric H, Kuperman Rachel, Kuzniecky Ruben, Lowenstein Daniel H, McGuire Shannon M, Motika Paul V, Novotny Edward J, Ottman Ruth, Paolicchi Juliann M, Parent Jack M, Park Kristen, Poduri Annapurna, Scheffer Ingrid E, Shellhaas Renée A, Sherr Elliott H, Shih Jerry J, Singh Rani, Sirven Joseph, Smith Michael C, Sullivan Joseph, Lin Thio Liu, Venkat Anu, Vining Eileen P G, Von Allmen Gretchen K, Weisenberg Judith L, Widdess-Walsh Peter, Winawer Melodie R

Аннотация

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

Предметные рубрики MeSH

Child Development Disorders, Pervasive Cohort Studies Exome Female Fragile X Messenger Ribonucleoprotein 1 Genetic Predisposition to Disease Humans Infant Intellectual Disability Lennox Gastaut Syndrome Male Mutation Mutation Rate N-Acetylglucosaminyltransferases Probability Receptors, GABA-A Spasms, Infantile

De novo mutations in epileptic encephalopathies.

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH