The contribution of X-linked coding variation to severe developmental disorders
Authors: Martin Hilary C. , Gardner Eugene J. , Samocha Kaitlin E. , Kaplanis Joanna , Akawi Nadia , Sifrim Alejandro , Eberhardt Ruth Y. , Tavares Ana Lisa Taylor , Neville Matthew D. C. , Niemi Mari E. K. , Gallone Giuseppe , McRae Jeremy ,   Deciphering Developmental Disorders Study, Borras Silvia , Clark Caroline , Dean John , Miedzybrodzka Zosia , Ross Alison , Tennant Stephen , Dabir Tabib , Donnelly Deirdre , Humphreys Mervyn , Magee Alex , McConnell Vivienne , McKee Shane , McNerlan Susan , Morrison Patrick J. , Rea Gillian , Stewart Fiona , Cole Trevor , Cooper Nicola , Cooper-Charles Lisa , Cox Helen , Islam Lily , Jarvis Joanna , Keelagher Rebecca , Lim Derek , McMullan Dominic , Morton Jenny , Naik Swati , O’Driscoll Mary , Ong Kai-Ren , Osio Deborah , Ragge Nicola , Turton Sarah , Vogt Julie , Williams Denise , Bodek Simon , Donaldson Alan , Hills Alison , Low Karen , Newbury-Ecob Ruth , Norman Andrew M. , Roberts Eileen , Scurr Ingrid , Smithson Sarah , Tooley Madeleine , Abbs Steve , Armstrong Ruth , Dunn Carolyn , Holden Simon , Park Soo-Mi , Paterson Joan , Raymond Lucy , Reid Evan , Sandford Richard , Simonic Ingrid , Tischkowitz Marc , Woods Geoff , Bradley Lisa , Comerford Joanne , Green Andrew , Lynch Sally , McQuaid Shirley , Mullaney Brendan , Berg Jonathan , Goudie David , Mavrak Eleni , McLean Joanne , McWilliam Catherine , Reavey Eleanor , Azam Tara , Cleary Elaine , Jackson Andrew , Lam Wayne , Lampe Anne , Moore David , Porteous Mary , Baple Emma , Baptista Júlia , Brewer Carole , Castle Bruce , Kivuva Emma , Owens Martina , Rankin Julia , Shaw-Smith Charles , Turner Claire , Turnpenny Peter , Tysoe Carolyn , Bradley Therese , Davidson Rosemarie , Gardiner Carol , Joss Shelagh , Kinning Esther , Longman Cheryl , McGowan Ruth , Murday Victoria , Pilz Daniela , Tobias Edward , Whiteford Margo , Williams Nicola , Barnicoat Angela , Clement Emma , Faravelli Francesca , Hurst Jane , Jenkins Lucy , Jones Wendy , Kumar V.K.Ajith , Lees Melissa , Loughlin Sam , Male Alison , Morrogh Deborah , Rosser Elisabeth , Scott Richard , Wilson Louise , Beleza Ana , Deshpande Charu , Flinter Frances , Holder Muriel , Irving Melita , Izatt Louise , Josifova Dragana , Mohammed Shehla , Molenda Aneta , Robert Leema , Roworth Wendy , Ruddy Deborah , Ryten Mina , Yau Shu , Bennett Christopher , Blyth Moira , Campbell Jennifer , Coates Andrea , Dobbie Angus , Hewitt Sarah , Hobson Emma , Jackson Eilidh , Jewell Rosalyn , Kraus Alison , Prescott Katrina , Sheridan Eamonn , Thomson Jenny , Bradshaw Kirsty , Dixit Abhijit , Eason Jacqueline , Haines Rebecca , Harrison Rachel , Mutch Stacey , Sarkar Ajoy , Searle Claire , Shannon Nora , Sharif Abid , Suri Mohnish , Vasudevan Pradeep , Canham Natalie , Ellis Ian , Greenhalgh Lynn , Howard Emma , Stinton Victoria , Swale Andrew , Weber Astrid , Banka Siddharth , Breen Catherine , Briggs Tracy , Burkitt-Wright Emma , Chandler Kate , Clayton-Smith Jill , Donnai Dian , Douzgou Sofia , Gaunt Lorraine , Jones Elizabeth , Kerr Bronwyn , Langley Claire , Metcalfe Kay , Smith Audrey , Wright Ronnie , Bourn David , Burn John , Fisher Richard , Hellens Steve , Henderson Alex , Montgomery Tara , Splitt Miranda , Straub Volker , Wright Michael , Zwolinski Simon , Allen Zoe , Bernhard Birgitta , Brady Angela , Brooks Claire , Busby Louise , Clowes Virginia , Ghali Neeti , Holder Susan , Ibitoye Rita , Wakeling Emma , Blair Edward , Carmichael Jenny , Cilliers Deirdre , Clasper Susan , Gibbons Richard , Kini Usha , Lester Tracy , Nemeth Andrea , Poulton Joanna , Price Sue , Shears Debbie , Stewart Helen , Wilkie Andrew , Albaba Shadi , Baker Duncan , Balasubramanian Meena , Johnson Diana , Parker Michael , Quarrell Oliver , Stewart Alison , Willoughby Josh , Crosby Charlene , Elmslie Frances , Homfray Tessa , Jin Huilin , Lahiri Nayana , Mansour Sahar , Marks Karen , McEntagart Meriel , Saggar Anand , Tatton-Brown Kate , Butler Rachel , Clarke Angus , Corrin Sian , Fry Andrew , Kamath Arveen , McCann Emma , Mugalaasi Hood , Pottinger Caroline , Procter Annie , Sampson Julian , Sansbury Francis , Varghese Vinod , Baralle Diana , Callaway Alison , Cassidy Emma J. , Daniels Stacey , Douglas Andrew , Foulds Nicola , Hunt David , Kharbanda Mira , Lachlan Katherine , Mercer Catherine , Side Lucy , Temple I. Karen , Wellesley Diana , Wright Caroline F. , FitzPatrick David R. , Firth Helen V. , Hurles Matthew E. 
Published: January 2021

AbstractOver 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.