| Title: |
CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language |
| Authors: |
Snijders Blok, L; Rousseau, J; Twist, J; Ehresmann, S; Takaku, M; Venselaar, H; Rodan, LH; Nowak, CB; Douglas, J; Swoboda, KJ; Steeves, MA; Sahai, I; Stumpel, CTRM; Stegmann, APA; Wheeler, P; Willing, M; Fiala, E; Kochhar, A; Gibson, WT; Cohen, ASA; Agbahovbe, R; Innes, AM; Au, PYB; Rankin, J; Anderson, IJ; Skinner, SA; Louie, RJ; Warren, HE; Afenjar, A; Keren, B; Nava, C; Buratti, J; Isapof, A; Rodriguez, D; Lewandowski, R; Propst, J; van Essen, T; Choi, M; Lee, S; Chae, JH; Price, S; Schnur, RE; Douglas, G; Wentzensen, IM; Zweier, C; Reis, A; Bialer, MG; Moore, C; Koopmans, M; Brilstra, EH; Monroe, GR; van Gassen, KLI; van Binsbergen, E; Newbury-Ecob, R; Bownass, L; Bader, I; Mayr, JA; Wortmann, SB; Jakielski, KJ; Strand, EA; Kloth, K; Bierhals, T; Roberts, JD; Petrovich, RM; Machida, S; Kurumizaka, H; Lelieveld, S; Pfundt, R; Jansen, S; Deriziotis, P; Faivre, L; Thevenon, J; Assoum, M; Shriberg, L; Kleefstra, T; Brunner, HG; Wade, PA; Fisher, SE; Campeau, PM |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2018 |
| Collection: |
White Rose Research Online (Universities of Leeds, Sheffield & York) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
https://eprints.whiterose.ac.uk/id/eprint/158490/1/s41467-018-06014-6.pdf; Snijders Blok, L, Rousseau, J, Twist, J et al. (76 more authors) (2018) CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. Nature Communications, 9 (1). 4619. ISSN: 2041-1723 |
| Availability: |
https://eprints.whiterose.ac.uk/id/eprint/158490/ |
| Rights: |
cc_by_4 |
| Accession Number: |
edsbas.FFFD26E6 |
| Database: |
BASE |