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.

Metadata

Item Type:	Article
Authors/Creators:	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 The DDD Study 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 Fisher, SE Campeau, PM
Copyright, Publisher and Additional Information:	© 2018, the author(s). This article is licensed under a Creative Commons Attribution 4.0 International License.
Dates:	Accepted: 27 July 2018 Published (online): 5 November 2018 Published: 5 November 2018
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) > Genetics (LIBACS) (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	11 Jul 2019 15:24
Last Modified:	11 Jul 2019 15:24
Status:	Published
Publisher:	Nature Research
Identification Number:	10.1038/s41467-018-06014-6
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:148483

Commentary/Response Threads

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, The DDD Study, 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, Fisher, SE and Campeau, PM CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. (deposited 11 Jul 2019 15:24) [Currently Displayed]
- Blok, LS, 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, The DDD Study, 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 and Campeau, PM Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. (deposited 12 Jul 2019 08:55)

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

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