Journal article
De novo mutations in epileptic encephalopathies
Andrew S Allen, Samuel F Berkovic, Patrick Cossette, Norman Delanty, Dennis Dlugos, Evan E Eichler, Michael P Epstein, Tracy Glauser, David B Goldstein, Yujun Han, Erin L Heinzen, Yuki Hitomi, Katherine B Howell, Michael R Johnson, Ruben Kuzniecky, Daniel H Lowenstein, Yi-Fan Lu, Maura RZ Madou, Anthony G Marson, Heather C Mefford Show all
NATURE | NATURE PUBLISHING GROUP | Published : 2013
DOI: 10.1038/nature12439
Abstract
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 i..
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Grants
Awarded by National Institute of Neurological Disorders and Stroke
Awarded by ARRA
Awarded by NIAID
Awarded by Ellison Medical Foundation New Scholar award
Awarded by SAID-Frederick, Inc.
Awarded by Center for HIV/AIDS Vaccine Immunology ("CHAVI") from the National Institute of Allergy and Infectious Diseases, National Institutes of Health
Awarded by NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Funding Acknowledgements
We are grateful to the patients, their families, clinical research coordinators and referring physicians for participating in the Epilepsy Phenome/Genome Project (EPGP) and providing the phenotype data and DNA samples used in this study. We thank the following professional and lay organizations for substantial assistance in publicizing EPGP and therefore enabling us to recruit participants effectively: AED Pregnancy Registry, American Epilepsy Society, Association of Child Neurology Nurses, California School Nurses Organization, Child Neurology Society, Citizens United for Research in Epilepsy, Dravet Syndrome Foundation, Epilepsy Alliance of Orange County, Epilepsy Foundation, Epilepsy Therapy Project, Finding a Cure for Epilepsy and Seizures, IDEA League, InfantileSpasms.com, Lennox-Gastaut Syndrome Foundation, PatientsLikeMe, People Against Childhood Epilepsy, PVNH Support & Awareness, and Seizures & Epilepsy Education. We thank the EPGP Administrative Core (C. Freyer, K. Schardein, R.N., M. S., R. Fahlstrom, M. P. H., S. Cristofaro, R.N., B.S.N. and K. McGovern), EPGP Bioinformatics Core (G. Nesbitt, K. McKenna, V. Mays), staff at the Coriell Institute - NINDS Genetics Repository (C. Tarn, A. Scutti), and members of the Duke Center for Human Genome Variation (B. Krueger, J. Bridgers, J. Keebler, H. Shin Kim, E. Campbell, K. Cronin, L. Hong and M. McCall) for their dedication and commitment to this work. We also thank S. Shinnar (Albert Einstein College of Medicine) and N. Risch (University of California, San Francisco) for valuable input into the creation of EPGP and Epi4K, and R. Stewart, K. Gwinn and R. Corriveau from the National Institute of Neurological Disorders and Stroke for their careful oversight and guidance of both EPGP and Epi4K. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (The Epilepsy Phenome/Genome Project NS053998; Epi4K Project 1-Epileptic Encephalopathies NS077364; Epi4K-Administrative Core NS077274; Epi4K-Sequencing, Biostatistics and Bioinformatics Core NS077303 and Epi4K-Phenotyping and Clinical Informatics Core NS077276); Finding a Cure for Epilepsy and Seizures; and the Richard Thalheimer Philanthropic Fund. We would like to acknowledge the following individuals and groups for their contribution of control samples: J. Hoover-Fong, N. Sobreira and D. Valle; The MURDOCK Study Community Registry and Biorepository (D. Murdock); S. Sisodiya; D. Attix; O. Chiba-Falek; V. Shashi; P. Lugar; W. Lowe; S. Palmer; D. Marchuk; Z. Farfel, D. Lancet, E. Pras; Q. Zhao; D. Daskalakis; R. Brown; E. Holtzman; R. Gbadegesin; M. Winn; S. Kerns; and H. Oster. The collection of control samples was funded in part by ARRA 1RC2NS070342, NIAID R56AI098588, the Ellison Medical Foundation New Scholar award AG-NS-0441-08, an award from SAID-Frederick, Inc. (M11-074), and with federal funds by the Center for HIV/AIDS Vaccine Immunology ("CHAVI") under a grant from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (UO1AIO67854).