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  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., et al. (2018). CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. Nature Communications, 9: 4619. doi:10.1038/s41467-018-06014-6.

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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 Creators:
Snijders Blok, Lot1, 2, 3, Author           
Rousseau, Justine4, Author
Twist, Joanna5, Author
Ehresmann, Sophie4, Author
Takaku, Motoki5, Author
Venselaar, Hanka6, Author
Rodan, Lance H.7, Author
Nowak, Catherine B.7, Author
Douglas, Jessica7, Author
Swoboda, Kathryn J.8, Author
Steeves, Marcie A.9, Author
Sahai, Inderneel9, Author
Stumpel, Connie T. R. M.10, Author
Stegmann, Alexander P. A.10, Author
Wheeler, Patricia11, Author
Willing, Marcia12, Author
Fiala, Elise12, Author
Kochhar, Aaina13, Author
Gibson, William T.14, 15, Author
Cohen, Ana S. A.14, 15, Author
Agbahovbe, Ruky14, 15, AuthorInnes, A. Micheil16, AuthorAu, P. Y. Billie16, AuthorRankin, Julia17, AuthorAnderson, Ilse J.18, AuthorSkinner, Steven A.19, AuthorLouie, Raymond J.19, AuthorWarren, Hannah E.19, AuthorAfenjar, Alexandra20, AuthorKeren, Boris21, 22, AuthorNava, Caroline21, 23, 24, AuthorBuratti, Julien21, AuthorIsapof, Arnaud25, AuthorRodriguez, Diana22, AuthorLewandowski, Raymond26, AuthorPropst, Jennifer26, AuthorVan Essen, Ton27, AuthorChoi, Murim28, AuthorLee, Sangmoon28, AuthorChae, Jong H.29, AuthorPrice, Susan30, AuthorSchnur, Rhonda E.31, AuthorDouglas, Ganka31, AuthorWentzensen, Ingrid M.31, AuthorZweier, Christiane32, AuthorReis, André32, AuthorBialer, Martin G.33, AuthorMoore, Christine33, AuthorKoopmans, Marije34, AuthorBrilstra, Eva H.34, AuthorMonroe, Glen R.34, AuthorVan Gassen, Koen L. I.34, AuthorVan Binsbergen, Ellen34, AuthorNewbury-Ecob, Ruth35, AuthorBownass, Lucy35, AuthorBader, Ingrid36, AuthorMayr, Johannes A.37, AuthorWortmann, Saskia B.37, 38, 39, AuthorJakielski, Kathy J.40, AuthorStrand, Edythe A.41, AuthorKloth, Katja42, AuthorBierhals, Tatjana42, AuthorThe DDD study, Author              Roberts, John D.5, AuthorPetrovich, Robert M.5, AuthorMachida, Shinichi43, AuthorKurumizaka, Hitoshi43, AuthorLelieveld, Stefan2, AuthorPfundt, Rolph2, AuthorJansen, Sandra2, 3, AuthorDerizioti, Pelagia1, Author           Faivre, Laurence44, 45, AuthorThevenon, Julien44, 45, AuthorAssoum, Mirna44, 45, AuthorShriberg, Lawrence46, AuthorKleefstra, Tjitske2, 3, AuthorBrunner, Han G.2, 3, 10, AuthorWade, Paul A.5, AuthorFisher, Simon E.1, 3, Author           Campeau, Philippe M.4, 47, Author more..
Affiliations:
1Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society, ou_792549              
2Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands, ou_persistent22              
3Donders Institute for Brain, Cognition and Behaviour, External Organizations, ou_55236              
4CHU Sainte-Justine Research Center, Montreal, Canada, ou_persistent22              
5National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA, ou_persistent22              
6Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands, ou_persistent22              
7Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA , ou_persistent22              
8Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, ou_persistent22              
9Department of Medical Genetics, Massachusetts General Hospital, Boston, MA, USA, ou_persistent22              
10Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands, ou_persistent22              
11Nemours Childrens Clinic, Orlando, FL, USA, ou_persistent22              
12Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA, ou_persistent22              
13Valley Children’s Hospital, Madera, CA, USA, ou_persistent22              
14British Columbia Children’s Hospital Research Institute, Vancouver, Canada, ou_persistent22              
15Department of Medical Genetics, University of British Columbia, Vancouver, Canada, ou_persistent22              
16Department of Medical Genetics and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada, ou_persistent22              
17Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust (Heavitree),, Exeter, UK, ou_persistent22              
18Division of Genetics, Department of Medicine, University of Tennessee Medical Center, Knoxville, TN, USA, ou_persistent22              
19Greenwood Genetic Center, Greenwood, SC, USA, ou_persistent22              
20GRC ConCer-LD, Sorbonne Universités, UPMC Univ Paris ; Department of Medical Genetics and Centre de Référence Malformations et maladies congénitales du cervelet et déficiences intellectuelles de causes rares, Armand Trousseau Hospital, GHUEP,, Paris, France, ou_persistent22              
21AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, France, ou_persistent22              
22GRC ConCer-LD, Sorbonne Universités, UPMC Univ Paris 06; Department of Child Neurology and National Reference Center for Neurogenetic Disorders, Armand Trousseau Hospital, Paris, France, ou_persistent22              
23Groupe de Recherche Clinique (GRC) ‘déficience intellectuelle et autisme’, Paris, France, ou_persistent22              
24INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris, Paris, France, ou_persistent22              
25GRC ConCer-LD, Sorbonne Universités, UPMC Univ Paris 06; Department Child Neurology and Reference Center for Neuromuscular Diseases “Nord/Est/Ile-de-France”, FILNEMUS, Armand Trousseau Hospital, Paris, France, ou_persistent22              
26Clinical Genetics Division, Virginia Commonwealth University Health System, Richmond, VA, USA, ou_persistent22              
27Clinical Genetics Department, University Medical Center Groningen, Groningen, The Netherlands, ou_persistent22              
28Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea, ou_persistent22              
29Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children’s Hospital, Seoul, Republic of Korea, ou_persistent22              
30Oxford University Hospitals NHS Foundation Trust, Oxford, UK , ou_persistent22              
31GeneDx, Gaithersburg, MD, USA, ou_persistent22              
32Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, ou_persistent22              
33Northwell Health, Division of Medical Genetics and Genomics, Great Neck, NY, USA, ou_persistent22              
34Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands, ou_persistent22              
35University Hospitals Bristol, Department of Clinical Genetics, St Michael’s Hospital, Bristol, UK, ou_persistent22              
36Department of Clinical Genetics, University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria, ou_persistent22              
37Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria, ou_persistent22              
38Institute of Human Genetics, Technische Universität München, Munich, Germany, ou_persistent22              
39Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany, ou_persistent22              
40Communication Sciences and Disorders, Augustana College, Rock Island, IL, USA, ou_persistent22              
41Department of Neurology, Mayo Clinic, Rochester, MN, USA, ou_persistent22              
42Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, ou_persistent22              
43Waseda University, Tokyo, Japan, ou_persistent22              
44Equipe Génétique des Anomalies du Développement, Université de Bourgogne- Franche Comté, Dijon, France, ou_persistent22              
45Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d’Enfants, CHU Dijon et Université de Bourgogne, Dijon, France, ou_persistent22              
46Waisman Center, Phonology Project, Madison, WI, USA, ou_persistent22              
47Sainte-Justine Hospital, University of Montreal, Montreal, Canada, ou_persistent22              

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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.

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Language(s): eng - English
 Dates: 2018-11-05
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-018-06014-6
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 9 Sequence Number: 4619 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723