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De novo mutations in epileptic encephalopathies

Nature volume 501, pages 217221 (12 September 2013) | Download Citation


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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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).

Author information


  1. Department of Biostatistics and Bioinformatics, Duke Clinical Research Institute, and Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina 27710, USA.

    • Andrew S. Allen
  2. Epilepsy Research Centre, Department of Medicine, University of Melbourne (Austin Health), Heidelberg, Victoria 3084, Australia.

    • Samuel F. Berkovic
    •  & Slavé Petrovski
  3. Centre of Excellence in Neuromics and CHUM Research Center, Université de Montréal, CHUM-Hôpital Notre-Dame Montréal, Quebec H2L 4M1, Canada.

    • Patrick Cossette
  4. Department of Neurology, Beaumont Hospital and Royal College of Surgeons, Dublin 9, Ireland.

    • Norman Delanty
  5. Department of Neurology and Pediatrics, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

    • Dennis Dlugos
    •  & Anu Venkat
  6. Department of Genome Sciences, University of Washington School of Medicine, Seattle, and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.

    • Evan E. Eichler
  7. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    • Michael P. Epstein
  8. Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA.

    • Tracy Glauser
  9. Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina 27708, USA.

    • David B. Goldstein
    • , Yujun Han
    • , Erin L. Heinzen
    • , Yuki Hitomi
    • , Yi-Fan Lu
    • , Slavé Petrovski
    •  & Elizabeth K. Ruzzo
  10. Department of Neurology, The Royal Children's Hospital Melbourne, Parkville, 3052 Victoria, Australia.

    • Katherine B. Howell
  11. Centre for Clinical Translation Division of Brain Sciences, Imperial College London, London SW7 2AZ, UK.

    • Michael R. Johnson
  12. Comprehensive Epilepsy Center, Department of Neurology, NYU School of Medicine, New York, New York 10016, USA.

    • Ruben Kuzniecky
    • , Jacqueline French
    •  & Daniel Friedman
  13. Department of Neurology, University of California, San Francisco, San Francisco, California 94143, USA.

    • Daniel H. Lowenstein
    • , Maura R. Z. Madou
    • , Heidi E. Kirsch
    •  & Joseph Sullivan
  14. Department of Molecular and Clinical Pharmacology, University of Liverpool, Clinical Sciences Centre, Lower Lane, Liverpool L9 7LJ, UK.

    • Anthony G. Marson
  15. Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington 98115, USA.

    • Heather C. Mefford
  16. University of California, San Francisco, California 94143, USA.

    • Sahar Esmaeeli Nieh
  17. Departments of Medicine and Neurology, The Royal Melbourne Hospital, Parkville, Victoria 3146, Australia.

    • Terence J. O'Brien
    •  & Slavé Petrovski
  18. Departments of Epidemiology and Neurology, and the G. H. Sergievsky Center, Columbia University; and Division of Epidemiology, New York State Psychiatric Institute, New York, New York 10032, USA.

    • Ruth Ottman
  19. Division of Epilepsy and Clinical Neurophysiology, Department of Neurology Boston Children’s Hospital, Boston, Massachusetts 02115, USA.

    • Annapurna Poduri
  20. Epilepsy Research Centre, Department of Medicine, University of Melbourne (Austin Health), Heidelberg, Victoria 3084, Australia.

    • Ingrid E. Scheffer
  21. Florey Institute and Department of Pediatrics, Royal Children’s Hospital, University of Melbourne, Victoria 3052, Australia.

    • Ingrid E. Scheffer
  22. Departments of Neurology, Pediatrics and Institute of Human Genetics, University of California, San Francisco, San Francisco, California 94158, USA.

    • Elliott H. Sherr
  23. Department of Neurology, Boston Children’s Hospital Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Christopher J. Yuskaitis
  24. Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

    • Bassel Abou-Khalil
    •  & Juliann M. Paolicchi
  25. Department of Clinical Pharmacy, UCSF School of Pharmacy, Department of Neurology, UCSF School of Medicine, San Francisco, California 94143, USA.

    • Brian K. Alldredge
  26. Department of Neurology, Cleveland Clinic Lerner College of Medicine & Epilepsy Center of the Cleveland Clinic Neurological Institute, Cleveland, Ohio 44195, USA.

    • Jocelyn F. Bautista
  27. Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467, USA.

    • Alex Boro
  28. Divison of Epilepsy, Mayo Clinic, Rochester, Minnesota 55905, USA.

    • Gregory D. Cascino
  29. Epilepsy Center, Neurology Division, Ramos Mejía Hospital, Buenos Aires 1221, Argentina.

    • Damian Consalvo
  30. Medical Epilepsy Program & EEG & Child Neurology, Children’s Hospital of Pittsburgh of UPMC, Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA.

    • Patricia Crumrine
  31. NYU and Saint Barnabas Epilepsy Centers, NYU School of Medicine, New York, New York 10016, USA.

    • Orrin Devinsky
  32. Department of Neurology, Epilepsy Care Center, University of Minnesota Medical School, Minneapolis 55414, USA.

    • Miguel Fiol
  33. FE Dreifuss Comprehensive Epilepsy Program, University of Virginia, Charlottesville, Virginia 22908, USA.

    • Nathan B. Fountain
  34. Division of Neurology, Saint Barnabas Medical Center, Livingston, New Jersey 07039, USA.

    • Eric B. Geller
    •  & Peter Widdess-Walsh
  35. Department of Neurology, Comprehensive Epilepsy Program, University of Michigan Health System, Ann Arbor, Michigan 48109, USA.

    • Simon Glynn
  36. Comprehensive Epilepsy Center, Montefiore Medical Center, Bronx, New York 10467, USA.

    • Sheryl R. Haut
  37. The Kaiser Permanente Group, Oakland, California 94618, USA.

    • Jean Hayward
  38. Neurology and Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    • Sandra L. Helmers
  39. Pediatrics & Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Sucheta Joshi
  40. Department of Neurological Sciences, Rush Epilepsy Center, Rush University Medical Center, Chicago, Illinois 60612, USA.

    • Andres Kanner
    •  & Michael C. Smith
  41. Department of Radiology, University of California, San Francisco, California 94143, USA.

    • Heidi E. Kirsch
  42. Neurology, University of Texas Medical School, Houston, Texas 77030, USA.

    • Robert C. Knowlton
  43. Neurology and Pediatrics, Child Neurology, Pediatric Neurology Residency Program, Johns Hopkins Hospital, Baltimore, Maryland 21287, USA.

    • Eric H. Kossoff
  44. Epilepsy Program, Children’s Hospital & Research Center Oakland, Oakland, California 94609, USA.

    • Rachel Kuperman
  45. Clinical Neurology, Children’s Hospital Epilepsy Center of New Orleans, New Orleans, Louisiana 70118, USA.

    • Shannon M. McGuire
  46. Comprehensive Epilepsy Center, Oregon Health and Science University, Portland, Oregon 97239, USA.

    • Paul V. Motika
  47. Departments of Neurology and Pediatrics, University of Washington School of Medicine, Seattle Children’s Hospital, Seattle, Washington 98105, USA.

    • Edward J. Novotny
  48. Weill Cornell Medical Center, New York, New York 10065, USA.

    • Juliann M. Paolicchi
  49. Department of Neurology and Neuroscience Graduate Program, University of Michigan Medical Center, Ann Arbor, Michigan 49108, USA.

    • Jack M. Parent
  50. Ann Arbor Veterans Administration Healthcare System, Ann Arbor, Michigan 48105, USA.

    • Jack M. Parent
  51. Departments of Neurology and Pediatrics, University of Colorado School of Medicine, Children’s Hospital Colorado, Denver, Colorado 80045, USA.

    • Kristen Park
  52. University of Michigan, Pediatric Neurology, Ann Arbor, Michigan 48109, USA.

    • Renée A. Shellhaas
  53. Department of Neurology, Mayo Clinic, Jacksonville, Florida 32224, USA.

    • Jerry J. Shih
  54. Division of Pediatric Neurology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA.

    • Rani Singh
  55. Department of Neurology, Mayo Clinic, Scottsdale, Arizona 85259, USA.

    • Joseph Sirven
  56. Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

    • Liu Lin Thio
  57. Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland 21287, USA.

    • Eileen P. G. Vining
  58. Division of Child & Adolescent Neurology, Departments of Pediatrics, University of Texas Medical School, Houston, Texas 77030, USA.

    • Gretchen K. Von Allmen
  59. Department of Neurology, Division of Pediatric Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

    • Judith L. Weisenberg
  60. Department of Neurology and the G.H. Sergievsky Center, Columbia University, New York, New York 10032, USA.

    • Melodie R. Winawer


  1. Epi4K Consortium

  2. Epilepsy Phenome/Genome Project



    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.

    Competing interests

    The author declare no competing financial interests.

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

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      Supplementary Information

      This file contains Supplementary Tables 1-15, Supplementary Figures 1-7, Supplementary Methods, Text, Data and Notes and Supplementary References.

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