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 T R M; Stegmann, Alexander P A; 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 H; Monroe, Glen R; van Gassen, Koen L I; Van Binsbergen, Ellen; Newbury-Ecob, Ruth; Bownass, Lucy; Bader, Ingrid; Mayr, Johannes A; Wortmann, Saskia B; 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 E; Campeau, Philippe M     «

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 T R M; Stegmann, Alexander P A; 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, Hann...     »

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.      «

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...     »