Mutations in the gene CHD3 can cause a language disorder with cognitive delays and a larger head.

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 van 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 van Gassen, Ellen van 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, Philippe M Campeau


We studied individuals with mutations in CHD3. They tended to have a delayed development, especially their language development, and later on various degrees of intellectual disability. Some characteristics were in common between many individuals, such as a larger head, a flat facial profile, eyes more set apart, joint laxity and hernias. We studied the effect of the mutations in vitro. Several decreased the ability of CHD3 to remodel nucleosomes, while others had no in vitro effect or in fact increased the activity.


We defined the clinical characteristics of individuals with dysfunctional CHD3, thus allowing us to better know this genetic condition, and also allowing us to start to understand what happens in the cells and eventually in the neurons of such individuals.

Altmetric Statistics

Author Comments

Dr. Philippe M Campeau, MD, FCCMG
Dr. Philippe M Campeau, MD, FCCMG
University of Montreal
We will now try to understand what are the consequences of this CHD3 dysregulation on gene expression and regulation in neurons, and we will continue expanding the phenotypic spectrum of this condition.Dr. Philippe M Campeau, MD, FCCMG



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

Nat Commun 2018 11 5;9(1):4619. Epub 2018 Nov 5.

CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.

Link to publicationChromatin 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.

Download full-text PDF

Publisher Site Listing
November 2018
1350 Reads
10.742 Impact Factor

Publication Analysis

Top Keywords

chromatin remodeling
impaired speech
novo chd3
chd3 mutations
alterations chromatin
speech language
macrocephaly impaired
individuals novo
mutations overlapping
phenotypes mutations
domain encoded
encoded protein
atpase/helicase domain
cluster atpase/helicase
characterizing individuals
mutations cluster
overlapping phenotypes
approach collecting
gain comprehensive


(Supplied by CrossRef)

CG Marfella et al.
Mutat. Res. 2007

DC Hargreaves et al.
Cell Res. 2011

L Ho et al.
Nature 2010

GL Carvill et al.
Nat. Genet. 2013

LE Vissers et al.
Nat. Genet. 2004

BJ O'Roak et al.
Nature 2012

R Bernier et al.
Cell 2014

K Weiss et al.
Am. J. Hum. Genet. 2016

GO Pilarowski et al.
J. Med. Genet. 2017

Y Zhang et al.
Cell 1998

T Woodage et al.
Proc. Natl. Acad. Sci. U.S.A. 1997

Similar Publications