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

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.

SUBMITTER: Snijders Blok L 

PROVIDER: S-EPMC6218476 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Snijders Blok Lot L   Rousseau Justine J   Twist Joanna J   Ehresmann Sophie S   Takaku Motoki M   Venselaar Hanka H   Rodan Lance H LH   Nowak Catherine B CB   Douglas Jessica J   Swoboda Kathryn J KJ   Steeves Marcie A MA   Sahai Inderneel I   Stumpel Connie T R M CTRM   Stegmann Alexander P A APA   Wheeler Patricia P   Willing Marcia M   Fiala Elise E   Kochhar Aaina A   Gibson William T WT   Cohen Ana S A ASA   Agbahovbe Ruky R   Innes A Micheil AM   Au P Y Billie PYB   Rankin Julia J   Anderson Ilse J IJ   Skinner Steven A SA   Louie Raymond J RJ   Warren Hannah E HE   Afenjar Alexandra A   Keren Boris B   Nava Caroline C   Buratti Julien J   Isapof Arnaud A   Rodriguez Diana D   Lewandowski Raymond R   Propst Jennifer J   van Essen Ton T   Choi Murim M   Lee Sangmoon S   Chae Jong H JH   Price Susan S   Schnur Rhonda E RE   Douglas Ganka G   Wentzensen Ingrid M IM   Zweier Christiane C   Reis André A   Reis André A   Bialer Martin G MG   Moore Christine C   Koopmans Marije M   Brilstra Eva H EH   Monroe Glen R GR   van Gassen Koen L I KLI   van Binsbergen Ellen E   Newbury-Ecob Ruth R   Bownass Lucy L   Bader Ingrid I   Mayr Johannes A JA   Wortmann Saskia B SB   Jakielski Kathy J KJ   Strand Edythe A EA   Kloth Katja K   Bierhals Tatjana T   Roberts John D JD   Petrovich Robert M RM   Machida Shinichi S   Kurumizaka Hitoshi H   Lelieveld Stefan S   Pfundt Rolph R   Jansen Sandra S   Deriziotis Pelagia P   Faivre Laurence L   Thevenon Julien J   Assoum Mirna M   Shriberg Lawrence L   Kleefstra Tjitske T   Brunner Han G HG   Wade Paul A PA   Fisher Simon E SE   Campeau Philippe M PM  

Nature communications 20181105 1

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  ...[more]

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