2. Academic Validation
  3. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

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

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.

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