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.
Bibliographical noteFunding Information:
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 FoundationNewScholar 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).