CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

  • Nat Commun. 2018 Nov 5;9(1):4619. doi: 10.1038/s41467-018-06014-6.
Lot Snijders Blok  1  2  3 ,  Justine Rousseau  4 ,  Joanna Twist  5 ,  Sophie Ehresmann  4 ,  Motoki Takaku  5 ,  Hanka Venselaar  6 ,  Lance H Rodan  7 ,  Catherine B Nowak  7 ,  Jessica Douglas  7 ,  Kathryn J Swoboda  8 ,  Marcie A Steeves  9 ,  Inderneel Sahai  9 ,  Connie T R M Stumpel  10 ,  Alexander P A Stegmann  10 ,  Patricia Wheeler  11 ,  Marcia Willing  12 ,  Elise Fiala  12 ,  Aaina Kochhar  13 ,  William T Gibson  14  15 ,  Ana S A Cohen  14  15 ,  Ruky Agbahovbe  14  15 ,  A Micheil Innes  16 ,  P Y Billie Au  16 ,  Julia Rankin  17 ,  Ilse J Anderson  18 ,  Steven A Skinner  19 ,  Raymond J Louie  19 ,  Hannah E Warren  19 ,  Alexandra Afenjar  20 ,  Boris Keren  21  22 ,  Caroline Nava  21  22  23 ,  Julien Buratti  21 ,  Arnaud Isapof  24 ,  Diana Rodriguez  25 ,  Raymond Lewandowski  26 ,  Jennifer Propst  26 ,  Ton van Essen  27 ,  Murim Choi  28 ,  Sangmoon Lee  28 ,  Jong H Chae  29 ,  Susan Price  30 ,  Rhonda E Schnur  31 ,  Ganka Douglas  31 ,  Ingrid M Wentzensen  31 ,  Christiane Zweier  32 ,  André Reis  32 ,  Martin G Bialer  33 ,  Christine Moore  33 ,  Marije Koopmans  34 ,  Eva H Brilstra  34 ,  Glen R Monroe  34 ,  Koen L I van Gassen  34 ,  Ellen van Binsbergen  34 ,  Ruth Newbury-Ecob  35 ,  Lucy Bownass  35 ,  Ingrid Bader  36 ,  Johannes A Mayr  37 ,  Saskia B Wortmann  37  38  39 ,  Kathy J Jakielski  40 ,  Edythe A Strand  41 ,  Katja Kloth  42 ,  Tatjana Bierhals  42 ,  DDD study ,  John D Roberts  5 ,  Robert M Petrovich  5 ,  Shinichi Machida  43 ,  Hitoshi Kurumizaka  43 ,  Stefan Lelieveld  1 ,  Rolph Pfundt  1 ,  Sandra Jansen  1  3 ,  Pelagia Deriziotis  2 ,  Laurence Faivre  44  45 ,  Julien Thevenon  44  45 ,  Mirna Assoum  44  45 ,  Lawrence Shriberg  46 ,  Tjitske Kleefstra  1  3 ,  Han G Brunner  1  3  10 ,  Paul A Wade  5 ,  Simon E Fisher  47  48 ,  Philippe M Campeau  49  50
Affiliations
  • 1. Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6500HB, The Netherlands.
  • 2. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, 6500AH, The Netherlands.
  • 3. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, 6500HE, The Netherlands.
  • 4. CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.
  • 5. National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
  • 6. Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6500HB, The Netherlands.
  • 7. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
  • 8. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 9. Department of Medical Genetics, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 10. Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, 6202AZ, The Netherlands.
  • 11. Nemours Childrens Clinic, Orlando, FL 32827, USA.
  • 12. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 13. Valley Children's Hospital, Madera, CA 93636, USA.
  • 14. British Columbia Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.
  • 15. Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 16. Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 17. Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust (Heavitree), Exeter, EX2 5DW, UK.
  • 18. Division of Genetics, Department of Medicine, University of Tennessee Medical Center, Knoxville, TN 37920, USA.
  • 19. Greenwood Genetic Center, Greenwood, SC 29646, USA.
  • 20. GRC ConCer-LD, Sorbonne Universités, UPMC Univ Paris ; Department of Medical Genetics and Centre de Référence Malformations et maladies congénitales du cervelet et déficiences intellectuelles de causes rares, Armand Trousseau Hospital, GHUEP, AP-HP, Paris, 75012, France.
  • 21. AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, 75013, France.
  • 22. Groupe de Recherche Clinique (GRC) 'déficience intellectuelle et autisme' UPMC, Paris, 75005, France.
  • 23. INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, 75013, Paris, France.
  • 24. GRC ConCer-LD, Sorbonne Universités, UPMC Univ Paris 06; Department Child Neurology and Reference Center for Neuromuscular Diseases "Nord/Est/Ile-de-France", FILNEMUS, Armand Trousseau Hospital, GHUEP, AP-HP, Paris, 75012, France.
  • 25. GRC ConCer-LD, Sorbonne Universités, UPMC Univ Paris 06; Department of Child Neurology and National Reference Center for Neurogenetic Disorders, Armand Trousseau Hospital, GHUEP, AP-HP, INSERM U1141, 75012, Paris, France.
  • 26. Clinical Genetics Division, Virginia Commonwealth University Health System, Richmond, VA 23298, USA.
  • 27. Clinical Genetics Department, University Medical Center Groningen, Groningen, 9700RB, The Netherlands.
  • 28. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 08826, Republic of Korea.
  • 29. Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, 08826, Republic of Korea.
  • 30. Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7HE, UK.
  • 31. GeneDx, Gaithersburg, MD 20877, USA.
  • 32. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany.
  • 33. Northwell Health, Division of Medical Genetics and Genomics, Great Neck, NY 11021, USA.
  • 34. Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, 3508AB, The Netherlands.
  • 35. University Hospitals Bristol, Department of Clinical Genetics, St Michael's Hospital, Bristol, BS2 8EG, UK.
  • 36. Department of Clinical Genetics, University Children's Hospital, Paracelsus Medical University, Salzburg, A-5020, Austria.
  • 37. Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, A-5020, Austria.
  • 38. Institute of Human Genetics, Technische Universität München, Munich, 81675, Germany.
  • 39. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, 85764, Germany.
  • 40. Communication Sciences and Disorders, Augustana College, Rock Island, IL 61201, USA.
  • 41. Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
  • 42. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany.
  • 43. Waseda University, Tokyo, 169-8050, Japan.
  • 44. Equipe Génétique des Anomalies du Développement, Université de Bourgogne-Franche Comté, Dijon, 21070, France.
  • 45. Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon et Université de Bourgogne, Dijon, 21079, France.
  • 46. Waisman Center, Phonology Project, Madison, WI 53705-2280, USA.
  • 47. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, 6500AH, The Netherlands. [email protected].
  • 48. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, 6500HE, The Netherlands. [email protected].
  • 49. CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada. [email protected].
  • 50. Sainte-Justine Hospital, University of Montreal, Montreal, QC H3T 1C5, Canada. [email protected].
PMID: 30397230 DOI: 10.1038/s41467-018-06014-6
Abstract

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome Sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.