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

Lot Snijders Blok, Justine Rousseau, Joanna Twist, Sophie Ehresmann, Motoki Takaku, Hanka Venselaar, Lance H. Rodan, Catherine B. Nowak, Jessica Douglas, Kathryn J. Swoboda, Marcie A. Steeves, Inderneel Sahai, Connie T. R. M. Stumpel, Alexander P. A. Stegmann, Patricia Wheeler, Marcia Willing, Elise Fiala, Aaina Kochhar, William T. Gibson, Ana S. A. Cohen, Ruky Agbahovbe, A. Micheil Innes, P. Y. Billie Au, Julia Rankin, Ilse J. Anderson, Steven A. Skinner, Raymond J. Louie, Hannah E. Warren, Alexandra Afenjar, Boris Keren, Caroline Nava, Julien Buratti, Arnaud Isapof, Diana Rodriguez, Raymond Lewandowski, Jennifer Propst, Ton Essen, Murim Choi, Sangmoon Lee, Jong H. Chae, Susan Price, Rhonda E. Schnur, Ganka Douglas, Ingrid M. Wentzensen, Christiane Zweier, André Reis, Martin G. Bialer, Christine Moore, Marije Koopmans, Eva H. Brilstra, Glen R. Monroe, Koen L. I. Gassen, Ellen Binsbergen, Ruth Newbury-Ecob, Lucy Bownass, Ingrid Bader, Johannes A. Mayr, Saskia B. Wortmann, Kathy J. Jakielski, Edythe A. Strand, Katja Kloth, Tatjana Bierhals, John D. Roberts, Robert M. Petrovich, Shinichi Machida, Hitoshi Kurumizaka, Stefan Lelieveld, Rolph Pfundt, Sandra Jansen, Pelagia Deriziotis, Laurence Faivre, Julien Thevenon, Mirna Assoum, Lawrence Shriberg, Tjitske Kleefstra, Han G. Brunner, Paul A. Wade, Simon E. Fisher () and Philippe M. Campeau ()
Additional contact information
Lot Snijders Blok: Radboud University Medical Center
Justine Rousseau: CHU Sainte-Justine Research Center
Joanna Twist: National Institute of Environmental Health Sciences
Sophie Ehresmann: CHU Sainte-Justine Research Center
Motoki Takaku: National Institute of Environmental Health Sciences
Hanka Venselaar: Radboud University Medical Center
Lance H. Rodan: Boston Children’s Hospital
Catherine B. Nowak: Boston Children’s Hospital
Jessica Douglas: Boston Children’s Hospital
Kathryn J. Swoboda: Massachusetts General Hospital and Harvard Medical School
Marcie A. Steeves: Massachusetts General Hospital
Inderneel Sahai: Massachusetts General Hospital
Connie T. R. M. Stumpel: Maastricht University Medical Center
Alexander P. A. Stegmann: Maastricht University Medical Center
Patricia Wheeler: Nemours Childrens Clinic
Marcia Willing: Washington University School of Medicine
Elise Fiala: Washington University School of Medicine
Aaina Kochhar: Valley Children’s Hospital
William T. Gibson: British Columbia Children’s Hospital Research Institute
Ana S. A. Cohen: British Columbia Children’s Hospital Research Institute
Ruky Agbahovbe: British Columbia Children’s Hospital Research Institute
A. Micheil Innes: University of Calgary
P. Y. Billie Au: University of Calgary
Julia Rankin: Royal Devon and Exeter NHS Foundation Trust (Heavitree)
Ilse J. Anderson: University of Tennessee Medical Center
Steven A. Skinner: Greenwood Genetic Center
Raymond J. Louie: Greenwood Genetic Center
Hannah E. Warren: Greenwood Genetic Center
Alexandra Afenjar: Armand Trousseau Hospital, GHUEP, AP-HP
Boris Keren: AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique
Caroline Nava: AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique
Julien Buratti: AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique
Arnaud Isapof: Armand Trousseau Hospital, GHUEP, AP-HP
Diana Rodriguez: Armand Trousseau Hospital, GHUEP, AP-HP, INSERM U1141
Raymond Lewandowski: Virginia Commonwealth University Health System
Jennifer Propst: Virginia Commonwealth University Health System
Ton Essen: University Medical Center Groningen
Murim Choi: Seoul National University College of Medicine
Sangmoon Lee: Seoul National University College of Medicine
Jong H. Chae: Seoul National University Children’s Hospital
Susan Price: Oxford University Hospitals NHS Foundation Trust
Rhonda E. Schnur: GeneDx
Ganka Douglas: GeneDx
Ingrid M. Wentzensen: GeneDx
Christiane Zweier: Friedrich-Alexander-Universität Erlangen-Nürnberg
André Reis: Friedrich-Alexander-Universität Erlangen-Nürnberg
Martin G. Bialer: Division of Medical Genetics and Genomics
Christine Moore: Division of Medical Genetics and Genomics
Marije Koopmans: Utrecht University
Eva H. Brilstra: Utrecht University
Glen R. Monroe: Utrecht University
Koen L. I. Gassen: Utrecht University
Ellen Binsbergen: Utrecht University
Ruth Newbury-Ecob: St Michael’s Hospital
Lucy Bownass: St Michael’s Hospital
Ingrid Bader: Paracelsus Medical University
Johannes A. Mayr: Salzburger Landeskliniken and Paracelsus Medical University
Saskia B. Wortmann: Salzburger Landeskliniken and Paracelsus Medical University
Kathy J. Jakielski: Augustana College
Edythe A. Strand: Mayo Clinic
Katja Kloth: University Medical Center Hamburg-Eppendorf
Tatjana Bierhals: University Medical Center Hamburg-Eppendorf
John D. Roberts: National Institute of Environmental Health Sciences
Robert M. Petrovich: National Institute of Environmental Health Sciences
Shinichi Machida: Waseda University
Hitoshi Kurumizaka: Waseda University
Stefan Lelieveld: Radboud University Medical Center
Rolph Pfundt: Radboud University Medical Center
Sandra Jansen: Radboud University Medical Center
Pelagia Deriziotis: Max Planck Institute for Psycholinguistics
Laurence Faivre: Université de Bourgogne-Franche Comté
Julien Thevenon: Université de Bourgogne-Franche Comté
Mirna Assoum: Université de Bourgogne-Franche Comté
Lawrence Shriberg: Phonology Project
Tjitske Kleefstra: Radboud University Medical Center
Han G. Brunner: Radboud University Medical Center
Paul A. Wade: National Institute of Environmental Health Sciences
Simon E. Fisher: Max Planck Institute for Psycholinguistics
Philippe M. Campeau: CHU Sainte-Justine Research Center

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06014-6

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