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

Blok LS, Rousseau J, Twist J, Ehresmann S, Takaku M, Venselaar H, Rodan LH, Nowak CB, Douglas J, Swoboda KJ, Steeves MA, Sahai I, Stumpel CTRM, Stegmann APA, Wheeler P, Willing M, Fiala E, Kochhar A, Gibson WT, Cohen ASA, Agbahovbe R, Innes AM, Au PYB, Rankin J, Anderson IJ, Skinner SA, Louie RJ, Warren HE, Afenjar A, Keren B, Nava C, Buratti J, Isapof A, Rodriguez D, Lewandowski R, Propst J, Van Essen T, Choi M, Lee S, Chae JH, Price S, Schnur RE, Douglas G, Wentzensen IM, Zweier C, Reis A, Bialer MG, Moore C, Koopmans M, Brilstra EH, Monroe GR, Van Gassen KL, Van Binsbergen E, Newbury-Ecob R, Bownass L, Bader I, Mayr JA, Wortmann SB, Jakielski KJ, Strand EA, Kloth K, Bierhals T, Roberts JD, Petrovich RM, Machida S, Kurumizaka H, Lelieveld S, Pfundt R, Jansen S, Deriziotis P, Faive L, Thevenon J, Assoum M, Shriberg L, Kleefstra T, Brunner HG, Wade PA, Fisher SE, Campeau PM (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 9

Journal Issue: 1

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.

Authors with CRIS profile

Involved external institutions

Waseda University / 早稲田大学 Japan (JP) Boston Children's Hospital United States (USA) (US) GeneDX United States (USA) (US) University of Calgary Canada (CA) Massachusetts General Hospital United States (USA) (US) Valley Children's Healthcare United States (USA) (US) British Columbia Children's Hospital Canada (CA) Radboud University Nijmegen Netherlands (NL) National Institute of Environmental Health Sciences United States (USA) (US) Université de Montréal Canada (CA) Maastricht University Netherlands (NL) Northwell Health United States (USA) (US) Virginia Commonwealth University (VCU) United States (USA) (US) Universiteit Utrecht (UU) / Utrecht University Netherlands (NL) Oxford University Hospitals NHS Foundation Trust United Kingdom (GB) Paracelsus Medizinische Privatuniversität Austria (AT) Salzburger Landeskliniken (SALK) Austria (AT) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) St. Michael's Hospital Canada (CA) University of Paris 6 - Pierre et Marie Curie / Université Paris VI Pierre et Marie Curie (UPMC) France (FR) Mayo Clinic United States (USA) (US) Greenwood Genetic Center United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Assistance Publique-Hôpitaux de Paris (AP-HP) France (FR) University of Tennessee (UTK) United States (USA) (US) University of Wisconsin - Madison United States (USA) (US) Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. (MPG) / Max Planck Society for the Advancement of Science Germany (DE) Augustana College United States (USA) (US) Université Bourgogne Franche-Comté France (FR) Washington University United States (USA) (US) Nemours Children's Hospital United States (USA) (US) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) Royal Devon & Exeter NHS Foundation Trust United Kingdom (GB)

How to cite

APA:

Blok, L.S., Rousseau, J., Twist, J., Ehresmann, S., Takaku, M., Venselaar, H.,... Campeau, P.M. (2018). CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-06014-6

MLA:

Blok, Lot Snijders, et al. "CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language." Nature Communications 9.1 (2018).

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