CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
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Snijders Blok, Lot | Rousseau, Justine | Twist, Joanna | Ehresmann, Sophie | Takaku, Motoki | Venselaar, Hanka | Rodan, Lance, H | Nowak, Catherine, B. | Douglas, Jessica | Swoboda, Kathryn, J | Steeves, Marcie, A | Sahai, Inderneel | Stumpel, Connie | Stegmann, Alexander | Wheeler, Patricia | Willing, Marcia | Fiala, Elise | Kochhar, Aaina | Gibson, William, T | Cohen, Ana, S A | Agbahovbe, Ruky | Innes, A. Micheil | Au, P., y Billie | Rankin, Julia | Anderson, Ilse, J | Skinner, Steven, A | Louie, Raymond, J | Warren, Hannah, E | Afenjar, Alexandra | Keren, Boris | Nava, Caroline | Buratti, Julien | Isapof, Arnaud | Rodriguez, Diana | Lewandowski, Raymond | Propst, Jennifer | van Essen, Ton | Choi, Murim | Lee, Sangmoon | Chae, Jong, H | Price, Susan | Schnur, Rhonda, E | Douglas, Ganka | Wentzensen, Ingrid, M | Zweier, Christiane | Reis, André | Bialer, Martin, G | Moore, Christine | Koopmans, Marije | Brilstra, Eva | Monroe, Glen, R | van Gassen, Koen, L | van Binsbergen, Ellen | Newbury-Ecob, Ruth | Bownass, Lucy | Bader, Ingrid | Mayr, Johannes, A | Wortmann, Saskia | Jakielski, Kathy, J | Strand, Edythe, A | Kloth, Katja | Bierhals, Tatjana | Roberts, John, D | Petrovich, Robert, M | Machida, Shinichi | Kurumizaka, Hitoshi | Lelieveld, Stefan | Pfundt, Rolph | Jansen, Sandra | Deriziotis, Pelagia | Faive, Laurence | Thevenon, Julien | Assoum, Mirna | Shriberg, Lawrence | Kleefstra, Tjitske | Brunner, Han, G. | Wade, Paul, A | Fisher, Simon | Campeau, Philippe
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CCSD ; Nature Publishing Group -
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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.
