Prevalence, phenotype and architecture of developmental disorders caused byde novomutation: The Deciphering Developmental Disorders Study
Authors: McRae Jeremy F , Clayton Stephen , Fitzgerald Tomas W , Kaplanis Joanna , Prigmore Elena , Rajan Diana , Sifrim AlejandroW , 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 AndrewW , 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 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 , Newbury-Ecob Ruth , 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 , Price Sue , Pridham Abigail , Procter Annie , Purnell Hellen , Quarrell Oliver , Ragge Nicola , Rahbari Raheleh , Randall Josh , Rankin Julia , 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 , Nellaker Chris , Parker Michael J , Firth Helen V , Wright Caroline F , FitzPatrick David R , Barrett Jeffrey C , Hurles Matthew E 
Published: April 2016

Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damagingde novomutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield ofde novomutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damagingde novomutation at genome-wide significance (P < 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age.

Abbreviations

PTV

Protein-Truncating Variant

DNM

De NovoMutation

DD

Developmental Disorder

DDD

Deciphering Developmental Disorders study