CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
Authors: Snijders Blok Lot , Rousseau Justine , Twist Joanna , Ehresmann Sophie , Takaku Motoki , Venselaar Hanka , Rodan Lance H. , Nowak Catherine B. , Douglas Jessica , Swoboda Kathryn J. , Steeves Marcie A. , Sahai Inderneel , Stumpel Connie T. R. M. , Stegmann Alexander P. A. , Wheeler Patricia , Willing Marcia , Fiala Elise , Kochhar Aaina , Gibson William T. , Cohen Ana S. A. , Agbahovbe Ruky , Innes A. Micheil , Au P. Y. Billie , Rankin Julia , Anderson Ilse J. , Skinner Steven A. , Louie Raymond J. , Warren Hannah E. , Afenjar Alexandra , Keren Boris , Nava Caroline , Buratti Julien , Isapof Arnaud , Rodriguez Diana , Lewandowski Raymond , Propst Jennifer , van Essen Ton , Choi Murim , Lee Sangmoon , Chae Jong H. , Price Susan , Schnur Rhonda E. , Douglas Ganka , Wentzensen Ingrid M. , Zweier Christiane , Reis André , Bialer Martin G. , Moore Christine , Koopmans Marije , Brilstra Eva H. , Monroe Glen R. , van Gassen Koen L. I. , van Binsbergen Ellen , Newbury-Ecob Ruth , Bownass Lucy , Bader Ingrid , Mayr Johannes A. , Wortmann Saskia B. , Jakielski Kathy J. , Strand Edythe A. , Kloth Katja , Bierhals Tatjana ,   The DDD study, McRae Jeremy F. , Clayton Stephen , Fitzgerald Tomas W. , Kaplanis Joanna , Prigmore Elena , Rajan Diana , Sifrim Alejandro , Aitken Stuart , Akawi Nadia , Alvi Mohsan , Ambridge Kirsty , Barrett Daniel M. , Bayzetinova Tanya , Jones Philip , Jones Wendy D. , King Daniel , Krishnappa Netravathi , Mason Laura E. , Singh Tarjinder , Tivey Adrian R. , Ahmed Munaza , Anjum Uruj , Archer Hayley , Armstrong Ruth , Awada Jana , Balasubramanian Meena , Banka Siddharth , Baralle Diana , Barnicoat Angela , Batstone Paul , Baty David , Bennett Chris , Berg Jonathan , Bernhard Birgitta , Bevan A. Paul , Bitner-Glindzicz Maria , Blair Edward , Blyth Moira , Bohanna David , Bourdon Louise , Bourn David , Bradley Lisa , Brady Angela , Brent Simon , Brewer Carole , Brunstrom Kate , Bunyan David J. , Burn John , Canham Natalie , Castle Bruce , Chandler Kate , Chatzimichali Elena , Cilliers Deirdre , Clarke Angus , Clasper Susan , Clayton-Smith Jill , Clowes Virginia , Coates Andrea , Cole Trevor , Colgiu Irina , Collins Amanda , Collinson Morag N. , Connell Fiona , Cooper Nicola , Cox Helen , Cresswell Lara , Cross Gareth , Crow Yanick , D’Alessandro Mariella , Dabir Tabib , Davidson Rosemarie , Davies Sally , de Vries Dylan , Dean John , Deshpande Charu , Devlin Gemma , Dixit Abhijit , Dobbie Angus , Donaldson Alan , Donnai Dian , Donnelly Deirdre , Donnelly Carina , Douglas Angela , Douzgou Sofia , Duncan Alexis , Eason Jacqueline , Ellard Sian , Ellis Ian , Elmslie Frances , Evans Karenza , Everest Sarah , Fendick Tina , Fisher Richard , Flinter Frances , Foulds Nicola , Fry Andrew , Fryer Alan , Gardiner Carol , Gaunt Lorraine , Ghali Neeti , Gibbons Richard , Gill Harinder , Goodship Judith , Goudie David , Gray Emma , Green Andrew , Greene Philip , Greenhalgh Lynn , Gribble Susan , Harrison Rachel , Harrison Lucy , Harrison Victoria , Hawkins Rose , He Liu , Hellens Stephen , Henderson Alex , Hewitt Sarah , Hildyard Lucy , Hobson Emma , Holden Simon , Holder Muriel , Holder Susan , Hollingsworth Georgina , Homfray Tessa , Humphreys Mervyn , Hurst Jane , Hutton Ben , Ingram Stuart , Irving Melita , Islam Lily , Jackson Andrew , Jarvis Joanna , Jenkins Lucy , Johnson Diana , Jones Elizabeth , Josifova Dragana , Joss Shelagh , Kaemba Beckie , Kazembe Sandra , Kelsell Rosemary , Kerr Bronwyn , Kingston Helen , Kini Usha , Kinning Esther , Kirby Gail , Kirk Claire , Kivuva Emma , Kraus Alison , Kumar Dhavendra , Kumar V. K. Ajith , Lachlan Katherine , Lam Wayne , Lampe Anne , Langman Caroline , Lees Melissa , Lim Derek , Longman Cheryl , Lowther Gordon , Lynch Sally A. , Magee Alex , Maher Eddy , Male Alison , Mansour Sahar , Marks Karen , Martin Katherine , Maye Una , McCann Emma , McConnell Vivienne , McEntagart Meriel , McGowan Ruth , McKay Kirsten , McKee Shane , McMullan Dominic J. , McNerlan Susan , McWilliam Catherine , Mehta Sarju , Metcalfe Kay , Middleton Anna , Miedzybrodzka Zosia , Miles Emma , Mohammed Shehla , Montgomery Tara , Moore David , Morgan Sian , Morton Jenny , Mugalaasi Hood , Murday Victoria , Murphy Helen , Naik Swati , Nemeth Andrea , Nevitt Louise , Norman Andrew , O’Shea Rosie , Ogilvie Caroline , Ong Kai-Ren , Park Soo-Mi , Parker Michael J. , Patel Chirag , Paterson Joan , Payne Stewart , Perrett Daniel , Phipps Julie , Pilz Daniela T. , Pollard Martin , Pottinger Caroline , Poulton Joanna , Pratt Norman , Prescott Katrina , Pridham Abigail , Procter Annie , Purnell Hellen , Quarrell Oliver , Ragge Nicola , Rahbari Raheleh , Randall Josh , Raymond Lucy , Rice Debbie , Robert Leema , Roberts Eileen , Roberts Jonathan , Roberts Paul , Roberts Gillian , Ross Alison , Rosser Elisabeth , Saggar Anand , Samant Shalaka , Sampson Julian , Sandford Richard , Sarkar Ajoy , Schweiger Susann , Scott Richard , Scurr Ingrid , Selby Ann , Seller Anneke , Sequeira Cheryl , Shannon Nora , Sharif Saba , Shaw-Smith Charles , Shearing Emma , Shears Debbie , Sheridan Eamonn , Simonic Ingrid , Singzon Roldan , Skitt Zara , Smith Audrey , Smith Kath , Smithson Sarah , Sneddon Linda , Splitt Miranda , Squires Miranda , Stewart Fiona , Stewart Helen , Straub Volker , Suri Mohnish , Sutton Vivienne , Swaminathan Ganesh Jawahar , Sweeney Elizabeth , Tatton-Brown Kate , Taylor Cat , Taylor Rohan , Tein Mark , Temple I. Karen , Thomson Jenny , Tischkowitz Marc , Tomkins Susan , Torokwa Audrey , Treacy Becky , Turner Claire , Turnpenny Peter , Tysoe Carolyn , Vandersteen Anthony , Varghese Vinod , Vasudevan Pradeep , Vijayarangakannan Parthiban , Vogt Julie , Wakeling Emma , Wallwark Sarah , Waters Jonathon , Weber Astrid , Wellesley Diana , Whiteford Margo , Widaa Sara , Wilcox Sarah , Wilkinson Emily , Williams Denise , Williams Nicola , Wilson Louise , Woods Geoff , Wragg Christopher , Wright Michael , Yates Laura , Yau Michael , Nellåker Chris , Parker Michael , Firth Helen V. , Wright Caroline F. , FitzPatrick David R. , Barrett Jeffrey C. , Hurles Matthew E. , Roberts John D. , Petrovich Robert M. , Machida Shinichi , Kurumizaka Hitoshi , Lelieveld Stefan , Pfundt Rolph , Jansen Sandra , Deriziotis Pelagia , Faivre Laurence , Thevenon Julien , Assoum Mirna , Shriberg Lawrence , Kleefstra Tjitske , Brunner Han G. , Wade Paul A. , Fisher Simon E. , Campeau Philippe M. 
Published: October 2018

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.