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De novo mutations in epileptic encephalopathies


Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown1. 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 disorders2.

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Figure 1: Heat map illustrating the probability of observing the specified number of de novo mutations in genes with the specified estimated mutation rate.
Figure 2: A protein–protein interaction network of genes with de novo mutations found in infantile spasms and Lennox–Gastaut syndrome patients studied.

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  1. Berg, A. T. et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51, 676–685 (2010)

    Article  Google Scholar 

  2. Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012)

    Article  CAS  Google Scholar 

  3. EPICURE Consortium et al. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. Hum. Mol. Genet. 21, 5359–5372 (2012)

  4. Heinzen, E. L. et al. Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy. Am. J. Hum. Genet. 91, 293–302 (2012)

    Article  CAS  Google Scholar 

  5. Mulley, J. C. & Mefford, H. C. Epilepsy and the new cytogenetics. Epilepsia 52, 423–432 (2011)

    Article  Google Scholar 

  6. Kasperaviciute, D. et al. Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study. Brain 133, 2136–2147 (2010)

    Article  Google Scholar 

  7. Vissers, L. E. et al. A de novo paradigm for mental retardation. Nature Genet. 42, 1109–1112 (2010)

    Article  CAS  Google Scholar 

  8. Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012)

    Article  CAS  ADS  Google Scholar 

  9. Kalscheuer, V. M. et al. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am. J. Hum. Genet. 72, 1401–1411 (2003)

    Article  CAS  Google Scholar 

  10. Claes, L. et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am. J. Hum. Genet. 68, 1327–1332 (2001)

    Article  CAS  Google Scholar 

  11. Saitsu, H. et al. De novo mutations in the gene encoding STXBP1 (MUNC18–1) cause early infantile epileptic encephalopathy. Nature Genet. 40, 782–788 (2008)

    Article  CAS  Google Scholar 

  12. Otsuka, M. et al. STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome—result of Japanese cohort study. Epilepsia 51, 2449–2452 (2010)

    Article  CAS  Google Scholar 

  13. Veeramah, K. R. et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am. J. Hum. Genet. 90, 502–510 (2012)

    Article  CAS  Google Scholar 

  14. Kamiya, K. et al. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. J. Neurosci. 24, 2690–2698 (2004)

    Article  CAS  Google Scholar 

  15. Tanaka, M., DeLorey, T. M., Delgado-Escueta, A. & Olsen, R. W. in Jasper's Basic Mechanisms of the Epilepsies (eds Noebels, J. L. et al.) (2012)

  16. DeLorey, T. M. et al. Mice lacking the β3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J. Neurosci. 18, 8505–8514 (1998)

    Article  CAS  Google Scholar 

  17. Timal, S. et al. Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing. Hum. Mol. Genet. 21, 4151–4161 (2012)

    Article  CAS  Google Scholar 

  18. de Ligt, J. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012)

    Article  CAS  ADS  Google Scholar 

  19. O’Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012)

    Article  ADS  Google Scholar 

  20. Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012)

    Article  CAS  ADS  Google Scholar 

  21. Petrovski, S. et al. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Gen (in the press) (2013)

  22. Klassen, T. et al. Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 145, 1036–1048 (2011)

    Article  CAS  Google Scholar 

  23. Lemke, J. R. et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 53, 1387–1398 (2012)

    Article  CAS  Google Scholar 

  24. Rauch, A. et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380, 1674–1682 (2012)

    Article  CAS  Google Scholar 

  25. Hitomi, Y. et al. Mutations in TNK2 in severe autosomal recessive infantile-onset epilepsy. Ann. Neurol. (2013)

  26. Lee, J. H. et al. De novo somatic mutations in components of the PI3K–AKT3-mTOR pathway cause hemimegalencephaly. Nature Genet. 44, 941–945 (2012)

    Article  CAS  Google Scholar 

  27. Gleeson, J. G. et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92, 63–72 (1998)

    Article  CAS  Google Scholar 

  28. Fox, J. W. et al. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron 21, 1315–1325 (1998)

    Article  CAS  Google Scholar 

  29. The EPGP Collaborative. The Epilepsy Phenome/Genome Project. Clin. Trials 10, 568–586 (2013)

  30. Kryukov, G. V., Pennacchio, L. A. & Sunyaev, S. R. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727–739 (2007)

    Article  CAS  Google Scholar 

  31. Kong, A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012)

    Article  CAS  ADS  Google Scholar 

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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,, 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).

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Authors and Affiliations



Initial design of EPGP: B.K.A., O.D., D.D., M.P.E., R.Kuz., D.H.L., R.O., E.H.S. and M.R.W. EPGP patient recruitment and phenotyping: B.A.-K., J.F.B., S.F.B., G.C., D.C., P.Cr., O.D., D.D., M.F., N.B.F., D.F., E.B.G., T.G., S.G., S.R.H., J.H., S.L.H., H.E.K., R.C.K., E.H.K., R.Kup., R.Kuz., D.H.L., S.M.M., P.V.M., E.J.N., J.M.Pao., J.M.Par., K.P., A.P., I.E.S., J.J.S., R.S., J.Si., M.C.S., L.L.T., A.V., E.P.G.V., G.K.V.A., J.L.W. and P.W.-W. Phenotype data analysis: B.A.-K., B.K.A., A.B., G.C., O.D., D.D., J.F., T.G., S.J., A.K., R.C.K., R.Kuz., D.H.L., R.O., J.M.Pao., A.P., I.E.S., R.A.S., E.H.S., J.J.S., J.Su., P.W.-W. and M.R.W. Initial design of Epi4K: S.F.B., P.Co., N.D., D.D., E.E.E., M.P.E., T.G., D.B.G., E.L.H., M.R.J., R.Kuz., D.H.L., A.G.M., H.C.M., T.J.O., R.O., A.P., I.E.S. and E.H.S. Epileptic encephalopathy phenotyping strategy: S.F.B., P.Co., D.D., R.Kuz., D.H.L., R.O., I.E.S. and E.H.S. Encephalopathy phenotyping: D.D., K.B.H., M.R.Z.M., H.C.M., A.P., I.E.S., E.H.S. and C.J.Y. Sequence data analysis and statistical interpretation: A.S.A., D.B.G., Y.Ha., E.L.H., S.E.N., S.P., E.K.R. and E.H.S. Functional evaluation of identified mutations: D.B.G., E.L.H., Y.Hi. and Y.-F.L. Writing of manuscript: A.S.A., S.F.B., D.D., D.B.G., Y.Ha., E.L.H., M.R.J., D.H.L., H.C.M., R.O., A.P., S.P., E.K.R., I.E.S. and E.H.S.

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The author declare no competing financial interests.

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Exome sequence data will be available in dbGAP (Epi4K: Gene Discovery in 4,000 Epilepsy Genomes).

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This file contains Supplementary Tables 1-15, Supplementary Figures 1-7, Supplementary Methods, Text, Data and Notes and Supplementary References. (PDF 3880 kb)

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Epi4K Consortium., Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013).

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