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

Lot Snijders Blok; Justine Rousseau; Joanna Twist; Sophie Ehresmann; Motoki Takaku; Hanka Venselaar; Lance H. Rodan; Catherine B. Nowak; Jessica Douglas; Kathryn J. Swoboda; Marcie A. Steeves; Inderneel Sahai; Connie T. R. M. Stumpel; Alexander P. A. Stegmann; Patricia Wheeler; Marcia Willing; Elise Fiala; Aaina Kochhar; William T. Gibson; Ana S. A. Cohen; Ruky Agbahovbe; A. Micheil Innes; P. Y. Billie Au; Julia Rankin; Ilse J. Anderson; Steven A. Skinner; Raymond J. Louie; Hannah E. Warren; Alexandra Afenjar; Boris Keren; Caroline Nava; Julien Buratti; Arnaud Isapof; Diana Rodriguez; Raymond Lewandowski; Jennifer Propst; Ton van Essen; Murim Choi; Sangmoon Lee; Jong H. Chae; Susan Price; Rhonda E. Schnur; Ganka Douglas; Ingrid M. Wentzensen; Christiane Zweier; Andre Reis; Martin G. Bialer; Christine Moore; Sandra Jansen; Han G. Brunner; DDD Study; Philippe M. Campeau; Simon E. Fisher

doi:10.1038/s41467-018-06014-6

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

Lot Snijders Blok, Justine Rousseau, Joanna Twist, Sophie Ehresmann, Motoki Takaku, Hanka Venselaar, Lance H. Rodan, Catherine B. Nowak, Jessica Douglas, Kathryn J. Swoboda, Marcie A. Steeves, Inderneel Sahai, Connie T. R. M. Stumpel, Alexander P. A. Stegmann, Patricia Wheeler, Marcia Willing, Elise Fiala, Aaina Kochhar, William T. Gibson, Ana S. A. CohenRuky Agbahovbe, A. Micheil Innes, P. Y. Billie Au, Julia Rankin, Ilse J. Anderson, Steven A. Skinner, Raymond J. Louie, Hannah E. Warren, Alexandra Afenjar, Boris Keren, Caroline Nava, Julien Buratti, Arnaud Isapof, Diana Rodriguez, Raymond Lewandowski, Jennifer Propst, Ton van Essen, Murim Choi, Sangmoon Lee, Jong H. Chae, Susan Price, Rhonda E. Schnur, Ganka Douglas, Ingrid M. Wentzensen, Christiane Zweier, Andre Reis, Martin G. Bialer, Christine Moore, Sandra Jansen, Han G. Brunner, DDD Study, Philippe M. Campeau^*, Simon E. Fisher^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	4619
Number of pages	12
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06014-6
Publication status	Published - 5 Nov 2018

Keywords

DE-NOVO MUTATIONS
CHROMATIN REMODELING COMPLEX
INTELLECTUAL DISABILITY
DEACETYLASE COMPLEX
EXOME
DISORDER
FAMILY
GENE
NURD
DIAGNOSIS

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2 Erratum / corrigendum / retractions

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
Blok, L. S., Rousseau, J., Twist, J., Ehresmann, S., Takaku, M., Venselaar, H., Rodan, L. H., Nowak, C. B., Douglas, J., Swoboda, K. J., Steeves, M. A., Sahai, I., Stumpel, C. T. R. M., Stegmann, A. P. A., Wheeler, P., Willing, M., Fiala, E., Kochhar, A., Gibson, W. T., Cohen, A. S. A., & 33 othersAgbahovbe, R., Innes, A. M., Au, P. Y. B., Rankin, J., Anderson, I. J., Skinner, S. A., Louie, R. J., Warren, H. E., Afenjar, A., Keren, B., Nava, C., Buratti, J., Isapof, A., Rodriguez, D., Lewandowski, R., Propst, J., van Essen, T., Choi, M., Lee, S., Chae, J. H., Price, S., Schnur, R. E., Douglas, G., Wentzensen, I. M., Zweier, C., Reis, A., Bialer, M. G., Moore, C., Koopmans, M., Brilstra, E. H., DDD Study, Fisher, S. E. & Campeau, P. M., 15 Feb 2019, In: Nature Communications. 10, p. 1-4 4 p., 883.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

Open Access
Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
Snijders Blok, L., Rousseau, J., Twist, J., Ehresmann, S., Takaku, M., Venselaar, H., Rodan, L. H., Nowak, C. B., Douglas, J., Swoboda, K. J., Steeves, M. A., Sahai, I., Stumpel, C. T. R. M., Stegmann, A. P. A., Wheeler, P., Willing, M., Fiala, E., Kochhar, A., Gibson, W. T., Cohen, A. S. A., & 33 othersAgbahovbe, R., Innes, A. M., Au, P. Y. B., Rankin, J., Anderson, I. J., Skinner, S. A., Louie, R. J., Warren, H. E., Afenjar, A., Keren, B., Nava, C., Buratti, J., Isapof, A., Rodriguez, D., Lewandowski, R., Propst, J., van Essen, T., Choi, M., Lee, S., Chae, J. H., Price, S., Schnur, R. E., Douglas, G., Wentzensen, I. M., Zweier, C., Reis, A., Bialer, M. G., Moore, C., Jansen, S., Brunner, H. G., DDD Study, Fisher, S. E. & Campeau, P. M., 2 May 2019, In: Nature Communications. 10, 4 p., 2079.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

Open Access

Cite this

Blok, L. S., Rousseau, J., Twist, J., Ehresmann, S., Takaku, M., Venselaar, H., Rodan, L. H., Nowak, C. B., Douglas, J., Swoboda, K. J., Steeves, M. A., Sahai, I., Stumpel, C. T. R. M., Stegmann, A. P. A., Wheeler, P., Willing, M., Fiala, E., Kochhar, A., Gibson, W. T., ... Fisher, S. E. (2018). CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. Nature Communications, 9(1), Article 4619. https://doi.org/10.1038/s41467-018-06014-6

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title = "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.",

keywords = "DE-NOVO MUTATIONS, CHROMATIN REMODELING COMPLEX, INTELLECTUAL DISABILITY, DEACETYLASE COMPLEX, EXOME, DISORDER, FAMILY, GENE, NURD, DIAGNOSIS",

author = "Blok, {Lot Snijders} and Justine Rousseau and Joanna Twist and Sophie Ehresmann and Motoki Takaku and Hanka Venselaar and Rodan, {Lance H.} and Nowak, {Catherine B.} and Jessica Douglas and Swoboda, {Kathryn J.} and Steeves, {Marcie A.} and Inderneel Sahai and Stumpel, {Connie T. R. M.} and Stegmann, {Alexander P. A.} and Patricia Wheeler and Marcia Willing and Elise Fiala and Aaina Kochhar and Gibson, {William T.} and Cohen, {Ana S. A.} and Ruky Agbahovbe and Innes, {A. Micheil} and Au, {P. Y. Billie} and Julia Rankin and Anderson, {Ilse J.} and Skinner, {Steven A.} and Louie, {Raymond J.} and Warren, {Hannah E.} and Alexandra Afenjar and Boris Keren and Caroline Nava and Julien Buratti and Arnaud Isapof and Diana Rodriguez and Raymond Lewandowski and Jennifer Propst and {van Essen}, Ton and Murim Choi and Sangmoon Lee and Chae, {Jong H.} and Susan Price and Schnur, {Rhonda E.} and Ganka Douglas and Wentzensen, {Ingrid M.} and Christiane Zweier and Andre Reis and Bialer, {Martin G.} and Christine Moore and Sandra Jansen and Brunner, {Han G.} and {DDD Study} and Campeau, {Philippe M.} and Fisher, {Simon E.}",

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doi = "10.1038/s41467-018-06014-6",

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issn = "2041-1723",

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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, Jansen, S, Brunner, HG, DDD Study, Campeau, PM & Fisher, SE 2018, 'CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language', Nature Communications, vol. 9, no. 1, 4619. https://doi.org/10.1038/s41467-018-06014-6

TY - JOUR

T1 - CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

AU - Blok, Lot Snijders

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, Andre

AU - Bialer, Martin G.

AU - Moore, Christine

AU - Jansen, Sandra

AU - Brunner, Han G.

AU - DDD Study

AU - Campeau, Philippe M.

AU - Fisher, Simon E.

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 - DE-NOVO MUTATIONS

KW - CHROMATIN REMODELING COMPLEX

KW - INTELLECTUAL DISABILITY

KW - DEACETYLASE COMPLEX

KW - EXOME

KW - DISORDER

KW - FAMILY

KW - GENE

KW - NURD

KW - DIAGNOSIS

U2 - 10.1038/s41467-018-06014-6

DO - 10.1038/s41467-018-06014-6

M3 - Article

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4619

ER -

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

Abstract

Keywords

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Research output

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

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

Cite this