CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language (vol 9, 4619, 2018)

DDD Study

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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 languageEnglish
Article number4619
Number of pages4
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 5 Nov 2018

Keywords

  • chromatin remodelling
  • clinical epigenetics
  • disease genetics
  • neurodevelopmental disorders

Cite this

@article{e7c10261efc4477a8fed594266de0515,
title = "CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language (vol 9, 4619, 2018)",
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 = "chromatin remodelling, clinical epigenetics, disease genetics, neurodevelopmental disorders",
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 Mariella D'Alessandro and John Dean and Zosia Miedzybrodzka and Alison Ross and {DDD Study}",
note = "An Author Correction to this article was published on 15 February 2019 An Author Correction to this article was published on 02 May 2019 We thank all individuals and families for their contribution. We thank Amaia Carri{\'o}n Castillo and Else Eising for assistance with the WGS analysis of the index individual, and Sarah Graham and Elliot Sollis for cloning the wild-type CHD3 construct for immunofluorescence. This work was supported by the Netherlands Organization for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., S.E.F., and H.G.B.), the Max Planck Society (S.E.F.), the National Institute on Deafness and Other Communication Disorders Grant DC000496 (L.Sh.) and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (Grant U54 HD090256) to L.Sh., the Canadian Institutes of Health Research Grants MOP-119595 and PJT-148830 to W.T.G. Individuals 11, 16, 24, and 28 were part of The DDD Study cohort. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund [Grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [Grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The DDD study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.",
year = "2018",
month = "11",
day = "5",
doi = "10.1038/s41467-019-10161-9",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language (vol 9, 4619, 2018)

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 - D'Alessandro, Mariella

AU - Dean, John

AU - Miedzybrodzka, Zosia

AU - Ross, Alison

AU - DDD Study

N1 - An Author Correction to this article was published on 15 February 2019 An Author Correction to this article was published on 02 May 2019 We thank all individuals and families for their contribution. We thank Amaia Carrión Castillo and Else Eising for assistance with the WGS analysis of the index individual, and Sarah Graham and Elliot Sollis for cloning the wild-type CHD3 construct for immunofluorescence. This work was supported by the Netherlands Organization for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., S.E.F., and H.G.B.), the Max Planck Society (S.E.F.), the National Institute on Deafness and Other Communication Disorders Grant DC000496 (L.Sh.) and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (Grant U54 HD090256) to L.Sh., the Canadian Institutes of Health Research Grants MOP-119595 and PJT-148830 to W.T.G. Individuals 11, 16, 24, and 28 were part of The DDD Study cohort. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund [Grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [Grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The DDD study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

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 - chromatin remodelling

KW - clinical epigenetics

KW - disease genetics

KW - neurodevelopmental disorders

U2 - 10.1038/s41467-019-10161-9

DO - 10.1038/s41467-019-10161-9

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 4619

ER -