De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures
Yoko Itō(University of Ottawa), Keren Carss(Cambridge University Hospitals NHS Foundation Trust), Sofia Duarte(University of Ottawa), Taila Hartley(University of Ottawa), Boris Keren(Sorbonne Université), Manju A. Kurian(Sorbonne Université), Isabelle Marey(Assistance Publique – Hôpitaux de Paris), Perinne Charles(Sorbonne Université), Carla Mendonça(Radboud University Nijmegen), Caroline Nava(Radboud University Nijmegen), Rolph Pfundt(University Medical Center Groningen), Alba Sanchis‐Juan(University Medical Center Groningen), Hans van Bokhoven(Radboud University Nijmegen), Anthony van Essen(Dalhousie University), Conny M.A. van Ravenswaaij‐Arts(University Medical Center Groningen), Timothy J. Aitman, David Bennett, Mark J. Caulfield, Patrick F. Chinnery, Daniel P. Gale, Ania Koziell, Taco W. Kuijpers, Michael Laffan, Eamonn R. Maher, Hugh S. Markus, Nicholas W. Morrell, Willem H. Ouwehand, David J. Perry(University of Cambridge), F. Lucy Raymond(Cambridge University Hospitals NHS Foundation Trust), Irene Roberts, Kenneth G. C. Smith, Adrian J. Thrasher, Hugh Watkins, Catherine Williamson, Geoffrey Woods, Sofie Ashford, John R. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Christopher J. Penkett, Kathleen Stirrups, Marijke Veltman, Tim Young, Matthew A. Brown, Emma Clement, John Davis, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin(Unidade Local de Saúde de São José), Sofia Papadia, Karola Rehnström, Hannah Stark, David Allsup, Steve Austin, Tamam Bakchoul, Tadbir K. Bariana, Paula Bolton‐Maggs, Elizabeth Chalmers, Janine Collins, Peter Collins, Wendy N. Erber, Tamara Everington, Rémi Favier, Kathleen Freson, Bruce Furie, Michael Gattens, Johanna Gebhart, Keith Gomez, Daniel Greene, Andreas Greinacher, Paolo Gresele(University of Ottawa), Daniel Hart, Johan W. M. Heemskerk, Yvonne Henskens, Rashid Kazmi, David Keeling, Anne M. Kelly, Michele P. Lambert, Claire Lentaigne(University of Ottawa), Ri Liesner, Mike Makris(Dalhousie University), Sarah Mangles, Mary Mathias, Carolyn M. Millar, Andrew Mumford, Paquita Nurden, Jeanette Payne, John Pasi, Kathelijne Peerlinck, Shoshana Revel‐Vilk, Michael Richards, Matthew T. Rondina, Catherine Roughley, Sol Schulman, Harald Schulze, Marie Scully, Suthesh Sivapalaratnam, Matthew Stubbs, R. Campbell Tait, Kate Talks, Jecko Thachil, Cheng‐Hock Toh, Ernest Turro, Chris Van Geet, Minka De Vries, Timothy Q. Warner, Henry G. Watson(Dalhousie University), Sarah K. Westbury, Abigail Furnell, Rutendo Mapeta, Paula Rayner-Matthews, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Christopher D. Watt, Deborah Whitehorn, Antony Attwood, Louise C. Daugherty, Sri V. V. Deevi, Csaba Halmagyi, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Mégy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ping Yu, Julie von Ziegenweldt, William J. Astle, Marta Bleda(University of Cambridge), Keren Carss(Cambridge University Hospitals NHS Foundation Trust), Stefan Gräf, Matthias Haimel, Hana Lango Allen, Sylvia Richardson, Paul Calleja, Stuart Rankin, Wojciech Turek, Julie Anderson, Christine Bryson, Jenny Carmichael, Coleen McJannet, Sophie Stock, Louise Allen, Gautum Ambegaonkar, Ruth Armstrong, Gavin Arno, Maria Bitner‐Glindzicz, Angie Brady, Natalie Canham, Manali Chitre, Emma Clement, Virginia Clowes, Patrick Deegan, Charu Deshpande, Rainer Döffinger, Helen V. Firth, Frances Flinter, Courtney E. French, Alice Gardham, Neeti Ghali, Paul Gissen, Detelina Grozeva, Robert Henderson, Anke Hensiek, Simon Holden, Muriel Holder, Susan Holder, Jane A. Hurst, Dragana Josifova, Deepa Krishnakumar(University College London), Manju A. Kurian(University College London), Melissa Lees, Robert E. MacLaren, Anna Maw, Sarju Mehta, Michel Michaelides(University Medical Center Groningen), Anthony T. Moore, Elaine Murphy, Soo‐Mi Park, Alasdair Parker, C. Patch, Joan Paterson, Julia Rankin, Evan Reid, Elisabeth Rosser(University of Cambridge), Alba Sanchis‐Juan(Cambridge University Hospitals NHS Foundation Trust), Richard Sandford, Saikat Santra, Richard H. Scott, Aman Sohal, Penelope E. Stein, Ellen Thomas, Dorothy Thompson, Marc Tischkowitz, Julie Vogt, Emma Wakeling, Evangeline Wassmer, Andrew R. Webster, Sonia Ali, Souad Ali, Harm Boggard, Colin Church, Gerry Coghlan, Victoria Cookson, Paul A. Corris, Amanda Creaser-Myers, Rosa DaCosta, Natalie Dormand, Mélanie Eyries, Henning Gall, Pavandeep Ghataorhe, Stefano Ghio, Ardi Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Alan Greenhalgh, Charaka Hadinnapola, Arjan C. Houweling, Marc Humbert, Anna Huis in’t Veld, Fiona Kennedy, David G. Kiely, Gábor Kovács, Allan Lawrie, Rob V. Mackenzie Ross, Rajiv D. Machado, Larahmie Masati, Sharon Meehan, Shahin Moledina, David Montani, Shokri Othman, Andrew J. Peacock, Joanna Pepke‐Żaba, Val Pollock, Gary Polwarth, Lavanya Ranganathan, Christopher J. Rhodes, Kévin Rue-Albrecht, Gwen Schotte, Debbie Shipley(Unité de recherche sur les maladies cardiovasculaires et métaboliques), Florent Soubrier, Laura Southgate, Laura Scelsi, Jay Suntharalingam, Yvonne Tan, Mark Toshner, Carmen Treacy, Richard C. Trembath, Anton Vonk Noordegraaf(Dalhousie University), Sara E. Walker, Ivy Wanjiku, John Wharton, Martin R. Wilkins, Stephen J. Wort, Katherine Yates, Hana Alachkar, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Claire Booth, Michael J. Browning, Siobhan O. Burns, Anita Chandra, Nichola Cooper, Sophie Davies, Lisa Devlin, Elizabeth Drewe, David Edgar, William Egner, Rohit Ghurye, Kimberley Gilmour(Dalhousie University), Sarah Goddard, Pavel Gordins(Unidade Local de Saúde de São José), Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Stephen Jolles, Peter Kelleher, Dinakantha Kumararatne(Dalhousie University), Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Sai Murng, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith L. Seneviratne, Carrock Sewell, Emily Staples(Radboud University Nijmegen), Hans J. Stauss, James Thaventhiran, Moira Thomas, Steve Welch, Lisa Willcocks, Nigel Yeatman, Patrick Yong, Phil Ancliff, Christian Babbs, Mark Layton, Eleni Louka, Simon J. McGowan, Adam J. Mead, Noémi Roy, Jenny Chambers, Peter Dixon, Cecelia Estiu, Bill Hague, Hanns–Ulrich Marschall, Michael A. Simpson, Sam Chong, Ingrid Emmerson, Lionel Ginsberg, David Gosal, Robert D. M. Hadden, Rita Horváth, Mohamed Mahdi-Rogers, Adnan Manzur, Andrew Marshall, Emma Matthews, Mark I. McCarthy, Mary Reilly, Tara Renton, Andrew J. Rice, Andreas C. Themistocleous, Tom Vale, Natalie Van Zuydam, Suellen M. Walker, Elizabeth Ormondroyd, Gavin Hudson, Wei Wei, Patrick Yu Wai Man, James W. Whitworth, Maryam Afzal, Elizabeth Colby, Moin A. Saleem, Omid S. Alavijeh, H. Terry Cook, Sally Johnson, Adam P. Levine, Edwin Wong, Rhea Tan(University of Ottawa), Kym M. Boycott(Children's Hospital of Eastern Ontario), Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis E. Bulman, David A. Dyment, Kym M. Boycott(Children's Hospital of Eastern Ontario), Kristin D. Kernohan(University of Ottawa), Sarah Dyack(Dalhousie University), F. Lucy Raymond(Cambridge University Hospitals NHS Foundation Trust)
Cited by 47Open Access
Abstract
Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.
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