High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

  • Am J Hum Genet. 2017 Nov 2;101(5):664-685. doi: 10.1016/j.ajhg.2017.09.008.
Fadi F Hamdan  1 ,  Candace T Myers  2 ,  Patrick Cossette  3 ,  Philippe Lemay  1 ,  Dan Spiegelman  4 ,  Alexandre Dionne Laporte  4 ,  Christina Nassif  1 ,  Ousmane Diallo  4 ,  Jean Monlong  5 ,  Maxime Cadieux-Dion  6 ,  Sylvia Dobrzeniecka  7 ,  Caroline Meloche  7 ,  Kyle Retterer  8 ,  Megan T Cho  8 ,  Jill A Rosenfeld  9 ,  Weimin Bi  10 ,  Christine Massicotte  1 ,  Marguerite Miguet  1 ,  Ledia Brunga  11 ,  Brigid M Regan  12 ,  Kelly Mo  12 ,  Cory Tam  12 ,  Amy Schneider  13 ,  Georgie Hollingsworth  13 ,  Deciphering Developmental Disorders Study  14 ,  David R FitzPatrick  15 ,  Alan Donaldson  16 ,  Natalie Canham  17 ,  Edward Blair  18 ,  Bronwyn Kerr  19 ,  Andrew E Fry  20 ,  Rhys H Thomas  21 ,  Joss Shelagh  22 ,  Jane A Hurst  23 ,  Helen Brittain  23 ,  Moira Blyth  24 ,  Robert Roger Lebel  25 ,  Erica H Gerkes  26 ,  Laura Davis-Keppen  27 ,  Quinn Stein  28 ,  Wendy K Chung  29 ,  Sara J Dorison  30 ,  Paul J Benke  31 ,  Emily Fassi  32 ,  Nicole Corsten-Janssen  26 ,  Erik-Jan Kamsteeg  33 ,  Frederic T Mau-Them  34 ,  Ange-Line Bruel  34 ,  Alain Verloes  35 ,  Katrin Õunap  36 ,  Monica H Wojcik  37 ,  Dara V F Albert  38 ,  Sunita Venkateswaran  39 ,  Tyson Ware  40 ,  Dean Jones  41 ,  Yu-Chi Liu  42 ,  Shekeeb S Mohammad  43 ,  Peyman Bizargity  9 ,  Carlos A Bacino  44 ,  Vincenzo Leuzzi  45 ,  Simone Martinelli  46 ,  Bruno Dallapiccola  47 ,  Marco Tartaglia  47 ,  Lubov Blumkin  48 ,  Klaas J Wierenga  49 ,  Gabriela Purcarin  49 ,  James J O'Byrne  50 ,  Sylvia Stockler  50 ,  Anna Lehman  51 ,  Boris Keren  52 ,  Marie-Christine Nougues  53 ,  Cyril Mignot  52 ,  Stéphane Auvin  54 ,  Caroline Nava  52 ,  Susan M Hiatt  55 ,  Martina Bebin  56 ,  Yunru Shao  9 ,  Fernando Scaglia  9 ,  Seema R Lalani  9 ,  Richard E Frye  57 ,  Imad T Jarjour  58 ,  Stéphanie Jacques  59 ,  Renee-Myriam Boucher  60 ,  Emilie Riou  61 ,  Myriam Srour  62 ,  Lionel Carmant  63 ,  Anne Lortie  64 ,  Philippe Major  64 ,  Paola Diadori  64 ,  François Dubeau  4 ,  Guy D'Anjou  64 ,  Guillaume Bourque  5 ,  Samuel F Berkovic  13 ,  Lynette G Sadleir  65 ,  Philippe M Campeau  66 ,  Zoha Kibar  67 ,  Ronald G Lafrenière  7 ,  Simon L Girard  68 ,  Saadet Mercimek-Mahmutoglu  69 ,  Cyrus Boelman  70 ,  Guy A Rouleau  4 ,  Ingrid E Scheffer  71 ,  Heather C Mefford  2 ,  Danielle M Andrade  12 ,  Elsa Rossignol  63 ,  Berge A Minassian  72 ,  Jacques L Michaud  73
Affiliations
  • 1. Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
  • 2. Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
  • 3. Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC H2X 0A9, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada.
  • 4. Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A2B4, Canada.
  • 5. McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 1A4, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
  • 6. Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC H2X 0A9, Canada; Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Kansas City, Kansas City, MO 64108, USA.
  • 7. Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC H2X 0A9, Canada.
  • 8. GeneDx, Gaithersburg, MD 20877, USA.
  • 9. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 10. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA.
  • 11. Program in Genetics and Genome Biology, Division of Neurology, Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada.
  • 12. Division of Neurology, Epilepsy Genetics Program, Krembil Neuroscience Centre, Toronto Western Hospital, University of Toronto, Toronto, ON M5G 2C4, Canada.
  • 13. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
  • 14. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • 15. MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
  • 16. Clinical Genetics Service, University Hospitals Bristol NHS Foundation Trust, St. Michael's Hospital, St. Michael's Hill, Bristol BS2 8DT, UK.
  • 17. North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Northwick Park Hospital, Watford Road, Harrow HA1 3UJ, UK.
  • 18. Oxford Centre for Genomic Medicine, ACE building Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK.
  • 19. Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
  • 20. Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.
  • 21. MRC Centre for Neuropsychiatric Genetics & Genomics, Hadyn Ellis Building, Cathays, Cardiff University, Cardiff CF24 4HQ, UK.
  • 22. West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
  • 23. North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
  • 24. Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK.
  • 25. Department of Pediatrics, Section of Medical Genetics, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • 26. University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, the Netherlands.
  • 27. University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57117, USA.
  • 28. Augustana-Sanford Genetic Counseling Graduate Program, Sioux Falls, SD 57197, USA.
  • 29. Departments of Medicine and Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
  • 30. Baptist Hospital, Miami, FL 33176 USA.
  • 31. Joe DiMaggio Children's Hospital, Hollywood, FL 33021, USA.
  • 32. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 33. Department of Human Genetics, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 34. Centre de Génétique des Anomalies du Développement, Centre Hospitalier Universitaire de Dijon, 21000 Dijon, France; Équipe INSERM 1231, Génétique des Anomalies du Développement, Université de Bourgogne, 21000 Dijon, France.
  • 35. Genetics Department, Assistance Publique - Hôpitaux de Paris, Robert-Debré University Hospital, 75000 Paris, France.
  • 36. Department of Clinical Genetics, United Laboratories, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu 51014, Estonia.
  • 37. Division of Genetics and Genomics and Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 38. Nationwide Children's Hospital and Ohio State University, Department of Pediatrics, Division of Neurology, Columbus, OH 43205, USA.
  • 39. Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
  • 40. University of Tasmania, Royal Hobart Hospital, Department of Paediatrics, Hobart, TAS 7000, Australia.
  • 41. School of Medicine, University of Tasmania, Hobart, TAS 7000, Australia.
  • 42. Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
  • 43. Children's Hospital at Westmead Clinical School, University of Sydney, Westmead, NSW 2145, Australia.
  • 44. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 45. Dipartimento di Pediatria e di Neuropsichiatria Infantile, Università La Sapienza, 00185 Rome, Italy.
  • 46. Dipartimento di Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, 00161 Rome, Italy.
  • 47. Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.
  • 48. Metabolic Neurogenetic Clinic and Pediatric Movement Disorders Clinic, Wolfson Medical Center, Holon 5822012, Israel.
  • 49. University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
  • 50. University of British Columbia, BC Children's Hospital, Vancouver, BC V6H 3N1, Canada.
  • 51. Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 52. Département de Génétique, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique "Déficiences Intellectuelles et Autisme," Université Pierre et Marie Curie, Hôpital de la Pitié-Salpêtrière, Paris 75013, France; Sorbonne Universités, Université Pierre et Marie Curie (Université Paris 06), UMRS 1127, INSERM U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Épinière, Paris 75013, France.
  • 53. Assistance Publique - Hôpitaux de Paris, Hôpital d'Enfants Armand Trousseau, Service de Neuropédiatrie, Paris 75012, France.
  • 54. Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR 1141, Paris 75019, France; Assistance Publique - Hôpitaux de Paris, Hôpital Robert Debré, Service de Neurologie Pédiatrique, Paris 75019, France.
  • 55. HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
  • 56. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 57. Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Arkansas Children's Research Institute, Little Rock, AR 72205, USA.
  • 58. Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030, USA.
  • 59. Centre Hospitalier Rouyn-Noranda, Rouyn-Noranda, QC J9X 2B2, Canada.
  • 60. Division of Neurology, Centre Hospitalier Universitaire de Québec, Quebec, QC G1V 4G2, Canada.
  • 61. Department of Pediatrics, Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
  • 62. Department of Pediatrics, McGill University, Montreal, QC H3A 1A4, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 1A4, Canada.
  • 63. Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T1C5, Canada.
  • 64. Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T1C5, Canada.
  • 65. Department of Pediatrics and Child Health, University of Otago, Wellington 9016, New Zealand.
  • 66. Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T1C5, Canada.
  • 67. Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada.
  • 68. Centre Hospitalier de l'Université de Montréal Research Center, Montreal, QC H2X 0A9, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Chicoutimi, QC G7H 2B1, Canada.
  • 69. Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • 70. Division of Neurology, BC Children's Hospital, Vancouver, BC V6H 3N1, Canada.
  • 71. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia; Department of Pediatrics, University of Melbourne Royal Children's Hospital, Parkville, VIC 3052, Australia; Florey Institute of Neuroscience and Mental Health, Melbourne, VIC 3084, Australia.
  • 72. Program in Genetics and Genome Biology, Division of Neurology, Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada; Division of Child Neurology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX 75390, USA. Electronic address: [email protected].
  • 73. Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T1C5, Canada. Electronic address: [email protected].
PMID: 29100083 DOI: 10.1016/j.ajhg.2017.09.008
Abstract

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome Sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted Sequencing in another series of individuals with DEE and by mining various Sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in Other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

Keywords
CLTC; DHDDS; GABBR2; GABRB2; NTRK2; NUS1; RAB11; SNAP25; epileptic encephalopathy.