The contribution of X-linked coding variation to severe developmental disorders

著者: Hilary C. Martin, Eugene J. Gardner, Kaitlin E. Samocha, Joanna Kaplanis, Nadia Akawi, Alejandro Sifrim, Ruth Y. Eberhardt, Ana Lisa Taylor Tavares, Matthew D. C. Neville, Mari Niemi, Giuseppe Gallone, Jeremy F. McRae, Deciphering Developmental Disorders Study, Sílvia Borràs, Caroline Clark, John Dean, Zosia Miedzybrodzka, Alison Ross, Stephen Tennant, Tabib Dabir, Deirdre Donnelly, Mervyn Humphreys, Alex Magee, Vivienne McConnell, Shane McKee, Susan McNerlan, Patrick J. Morrison, Gillian Rea, Fiona Stewart, Trevor Cole, Nicola Cooper, Lisa Cooper‐Charles, Helen Cox, Lily Islam, Joanna Jarvis, Rebecca Keelagher, Derek Lim, Dominic McMullan, Jenny Morton, Swati Naik, Mary O’Driscoll, Kai‐Ren Ong, Deborah Osio, Nicola Ragge, Sarah Turton, Julie Vogt, Denise Williams, Simon Bodek, Alan Donaldson, Alison Hills, Karen Low, Ruth Newbury‐Ecob, Andrew Norman, Eileen Roberts, Ingrid Scurr, Sarah Smithson, Madeleine Tooley, Steve Abbs, Ruth Armstrong, Carolyn Dunn, Simon Holden, Soo‐Mi Park, Joan Paterson, Lucy Raymond, Evan Reid, Richard Sandford, Ingrid Simonic, Marc Tischkowitz, Geoff Woods, Lisa Bradley, Joanne Comerford, Andrew Green, Sally Ann Lynch, Shirley McQuaid, Brendan Mullaney, Jonathan Berg, David Goudie, Eleni Mavrak, Joanne McLean, Catherine McWilliam, Eleanor Reavey, Tara Azam, Elaine Cleary, Andrew P. Jackson, Wayne Lam, Anne Lampe, David Moore, Mary Porteous, Emma L. Baple, Júlia Baptista, Carole Brewer, Bruce Castle, Emma Kivuva, Martina Owens, Julia Rankin, Charles Shaw‐Smith, Claire Turner, Peter D. Turnpenny, Carolyn Tysoe, Therese Bradley, Rosemarie Davidson, Carol Gardiner, Shelagh Joss, Esther Kinning, Cheryl Longman, Ruth McGowan, Victoria Murday, Daniela T. Pilz, Edward S. Tobias, Margo Whiteford, Nicola Williams, Angela Barnicoat, Emma Clement, Francesca Faravelli, Jane A. Hurst, Lucy Jenkins, Wendy D. Jones, Vikrant Kumar, Melissa Lees, Sam Loughlin, Alison Male, Deborah Morrogh, Elisabeth Rosser, Richard H. Scott, Louise C. Wilson, Ana Beleza‐Meireles, Charu Deshpande, Frances Flinter, Muriel Holder, Melita Irving, Louise Izatt, Dragana Josifova, Shehla Mohammed, Aneta Molenda, Leema Robert, Wendy Wassyng Roworth, Deborah Ruddy, Mina Ryten, Shu Yau, Christopher Bennett, Moira Blyth, Jennifer Campbell, Andrea Coates, Angus Dobbie, Sarah Hewitt, Emma Hobson, Eilidh Jackson, Rosalyn Jewell, Alison Kraus, Katrina Prescott, Eamonn Sheridan, Jenny Thomson, Kirsty Bradshaw, Abhijit Dixit, Jacqueline Eason, Rebecca L. Haines, Rachel Harrison, Stacey Mutch, Ajoy Sarkar, Claire Searle, Nora Shannon, Abid Sharif, Mohnish Suri, Pradeep Vasudevan, Natalie Canham, Ian O. Ellis, Lynn Greenhalgh, Emma Howard, Victoria Stinton, Andrew Swale, Astrid Weber, Siddharth Banka, Catherine Breen, Tracy A. Briggs, Emma Burkitt‐Wright, Kate Chandler, Jill Clayton‐Smith, Dian Donnai, Sofia Douzgou, Lorraine Gaunt, Elizabeth Jones, Bronwyn Kerr, Claire Langley, Kay Metcalfe, Audrey Smith, Ronnie Wright, David Bourn, John Burn, Richard Fisher, Steve Hellens, Alex Henderson, Tara Montgomery, Miranda Splitt, Volker Straub, Michael Wright, Simon Zwolinski, Zoe Allen, Birgitta Bernhard, Angela Brady, Claire Brooks, Louise Busby, Virginia Clowes, Neeti Ghali, Susan Holder, Rita Ibitoye, Emma Wakeling, Edward Blair, Jenny Carmichael, Deirdre Cilliers, Susan Clasper, Richard J. Gibbons, Usha Kini, Tracy Lester, Andrea H. Németh, Joanna Poulton, Sue Price, Debbie Shears, Helen Stewart, Andrew O.M. Wilkie, Shadi Albaba, Duncan Baker, Meena Balasubramanian, Diana Johnson, Michael Parker, Oliver Quarrell, A. Stewart, Josh Willoughby, Charlene Crosby, Frances Elmslie, Tessa Homfray, Huilin Jin, Nayana Lahiri, Sahar Mansour, Karen Marks, Meriel McEntagart, Anand Saggar, Kate Tatton‐Brown, Rachel Butler, Angus Clarke, Sian Corrin, Andrew E. Fry, Arveen Kamath, Emma McCann, Hood Mugalaasi, Caroline Pottinger, Annie Procter, Julian R. Sampson, Francis H. Sansbury, Vinod Varghese, Diana Baralle, Alison Callaway, Emma J. Cassidy, Stacey Daniels, Andrew G. L. Douglas, Nicola Foulds, David Hunt, Mira Kharbanda, Katherine Lachlan, Catherine Mercer, Lucy Side, I. Karen Temple, Diana Wellesley, Caroline F. Wright, David Fitzpatrick, Helen V. Firth, Matthew E. Hurles - Nature Communications 2021 被引用: 65

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.