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Journal article
De novo mutations in epileptic encephalopathies
Nature (London), v 501(7466), pp 217-221
12 Sep 2013
PMID: 23934111
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown(1). 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 similar to 4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 x 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 x 10(-10) and P = 7.8 x 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(2).
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Details
- Title
- De novo mutations in epileptic encephalopathies
- Creators
- Epi4K Consortium (Collaboration)Andrew S. Allen - Duke UniversitySamuel F. Berkovic - The University of MelbournePatrick Cossette - Université de MontréalNorman Delanty - Royal College of Surgeons in IrelandDennis Dlugos - College Station Medical CenterEvan E. Eichler - University of WashingtonMichael P. Epstein - Emory UniversityTracy Glauser - College Station Medical CenterDavid B. Goldstein - Duke UniversityYujun Han - Duke UniversityErin L. Heinzen - Duke UniversityYuki Hitomi - Duke UniversityKatherine B. Howell - Royal Childrens Hosp Melbourne, Dept Neurol, Parkville, Vic 3052, AustraliaMichael R. Johnson - Ctr Clin Translat Div Brain Sci, London SW7 2AZ, EnglandRuben Kuzniecky - College Station Medical CenterDaniel H. Lowenstein - University of California, San FranciscoYi-Fan Lu - Duke UniversityMaura R. Z. Madou - University of California, San FranciscoAnthony G. Marson - University of LiverpoolHeather C. Mefford - University of WashingtonSahar Esmaeeli Nieh - University of California, San FranciscoTerence J. O'Brien - College Station Medical CenterRuth Ottman - Columbia UniversitySlave Petrovski - The University of MelbourneAnnapurna Poduri - Boston Childrens Hosp, Dept Neurol, Div Epilepsy & Clin Neurophysiol, Boston, MA 02115 USAElizabeth K. Ruzzo - Duke UniversityIngrid E. Scheffer - The University of MelbourneElliott H. Sherr - University of California, San FranciscoChristopher J. Yuskaitis - Harvard UniversityBassel Abou-Khalil - Vanderbilt UniversityBrian K. Alldredge - College Station Medical CenterJocelyn F. Bautista - College Station Medical CenterAlex Boro - Albert Einstein Coll Med, Montefiore Med Ctr, Dept Neurol, Bronx, NY 10467 USAGregory D. Cascino - Mayo Clin, Div Epilepsy, Rochester, MN 55905 USADamian Consalvo - Ramos Meji Hosp, Div Neurol, Epilepsy Ctr, RA-1221 Buenos Aires, DF, ArgentinaPatricia Crumrine - University of PittsburghOrrin Devinsky - College Station Medical CenterMiguel Fiol - University of MinnesotaNathan B. Fountain - University of VirginiaJacqueline French - College Station Medical CenterDaniel Friedman - College Station Medical CenterEric B. Geller - St Barnabas Hosp, Div Neurol, Livingston, NJ 07039 USASimon Glynn - Univ Michigan Hlth Syst, Dept Neurol, Comprehens Epilepsy Program, Ann Arbor, MI 48109 USASheryl R. Haut - The Bronx DefendersJean Hayward - Kaiser PermanenteSandra L. Helmers - Emory UniversitySucheta Joshi - University of MichiganAndres Kanner - Rush UniversityHeidi E. Kirsch - University of California, San FranciscoRobert C. Knowlton - College Station Medical CenterErich Kossoff - Johns Hopkins UniversityRachel Kuperman - Childrens Hosp, Epilepsy Program, Oakland, CA 94609 USAShannon M. McGuire - Childrens Hosp Epilepsy Ctr New Orleans, New Orleans, LA 70118 USAPaul V. Motika - Oregon Hlth & Sci Univ, Comprehens Epilepsy Ctr, Portland, OR 97239 USAEdward J. Novotny - University of WashingtonJuliann M. Paolicchi - Vanderbilt UniversityJack M. Parent - College Station Medical CenterKristen Park - College Station Medical CenterRenee A. Shellhaas - University of MichiganJerry J. Shih - Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USARani Singh - Univ Michigan Hlth Syst, Div Pediat Neurol, Ann Arbor, MI 48109 USAJoseph Sirven - Mayo Clin, Dept Neurol, Scottsdale, AZ 85259 USAMichael C. Smith - Rush UniversityJoseph Sullivan - Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USALiu Lin Thio - College Station Medical CenterAnu Venkat - College Station Medical CenterEileen P. G. Vining - Dept Neurol, Baltimore, MD 21287 USAGretchen K. Von Allmen - College Station Medical CenterJudith L. Weisenberg - College Station Medical CenterPeter Widdess-Walsh - St Barnabas Hosp, Div Neurol, Livingston, NJ 07039 USAMelodie R. Winawer - Columbia University
- Publication Details
- Nature (London), v 501(7466), pp 217-221
- Publisher
- Springer Nature
- Number of pages
- 7
- Grant note
- NS053998; NS077364; NS077274; NS077303; NS077276 / National Institute of Neurological Disorders and Stroke; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) 1RC2NS070342 / ARRA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA UO1AIO67854 / Center for HIV/AIDS Vaccine Immunology ("CHAVI") from the National Institute of Allergy and Infectious Diseases, National Institutes of Health R56AI098588 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) R56AI098588 / NIAID; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) M11-074 / SAID-Frederick, Inc. Richard Thalheimer Philanthropic Fund RC2NS070342 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) AG-NS-0441-08 / Ellison Medical Foundation New Scholar award; Lawrence Ellison Foundation UL1TR000005 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Medicine (Graduate)
- Web of Science ID
- WOS:000324244900040
- Scopus ID
- 2-s2.0-84884130368
- Other Identifier
- 991021838151304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity