CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
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CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. / 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; DDD Study; 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.
In: NAT COMMUN, Vol. 9, No. 1, 05.11.2018, p. 4619.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
AU - Snijders Blok, Lot
AU - Rousseau, Justine
AU - Twist, Joanna
AU - Ehresmann, Sophie
AU - Takaku, Motoki
AU - Venselaar, Hanka
AU - Rodan, Lance H
AU - Nowak, Catherine B
AU - Douglas, Jessica
AU - Swoboda, Kathryn J
AU - Steeves, Marcie A
AU - Sahai, Inderneel
AU - Stumpel, Connie T R M
AU - Stegmann, Alexander P A
AU - Wheeler, Patricia
AU - Willing, Marcia
AU - Fiala, Elise
AU - Kochhar, Aaina
AU - Gibson, William T
AU - Cohen, Ana S A
AU - Agbahovbe, Ruky
AU - Innes, A Micheil
AU - Au, P Y Billie
AU - Rankin, Julia
AU - Anderson, Ilse J
AU - Skinner, Steven A
AU - Louie, Raymond J
AU - Warren, Hannah E
AU - Afenjar, Alexandra
AU - Keren, Boris
AU - Nava, Caroline
AU - Buratti, Julien
AU - Isapof, Arnaud
AU - Rodriguez, Diana
AU - Lewandowski, Raymond
AU - Propst, Jennifer
AU - van Essen, Ton
AU - Choi, Murim
AU - Lee, Sangmoon
AU - Chae, Jong H
AU - Price, Susan
AU - Schnur, Rhonda E
AU - Douglas, Ganka
AU - Wentzensen, Ingrid M
AU - Zweier, Christiane
AU - Reis, André
AU - Bialer, Martin G
AU - Moore, Christine
AU - Koopmans, Marije
AU - Brilstra, Eva H
AU - Monroe, Glen R
AU - van Gassen, Koen L I
AU - van Binsbergen, Ellen
AU - Newbury-Ecob, Ruth
AU - Bownass, Lucy
AU - Bader, Ingrid
AU - Mayr, Johannes A
AU - Wortmann, Saskia B
AU - Jakielski, Kathy J
AU - Strand, Edythe A
AU - Kloth, Katja
AU - Bierhals, Tatjana
AU - DDD Study
AU - Roberts, John D
AU - Petrovich, Robert M
AU - Machida, Shinichi
AU - Kurumizaka, Hitoshi
AU - Lelieveld, Stefan
AU - Pfundt, Rolph
AU - Jansen, Sandra
AU - Deriziotis, Pelagia
AU - Faive, Laurence
AU - Thevenon, Julien
AU - Assoum, Mirna
AU - Shriberg, Lawrence
AU - Kleefstra, Tjitske
AU - Brunner, Han G
AU - Wade, Paul A
AU - Fisher, Simon E
AU - Campeau, Philippe M
PY - 2018/11/5
Y1 - 2018/11/5
N2 - 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.
AB - 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.
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/s41467-018-06014-6
DO - 10.1038/s41467-018-06014-6
M3 - SCORING: Journal article
C2 - 30397230
VL - 9
SP - 4619
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -