RT Journal Article
SR Electronic
T1 Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation
JF bioRxiv
FD Cold Spring Harbor Laboratory Press
SP 049056
DO 10.1101/049056
A1 McRae, Jeremy F
A1 Clayton, Stephen
A1 Fitzgerald, Tomas W
A1 Kaplanis, Joanna
A1 Prigmore, Elena
A1 Rajan, Diana
A1 Sifrim, Alejandro
A1 Aitken, Stuart
A1 Akawi, Nadia
A1 Alvi, Mohsan
A1 Ambridge, Kirsty
A1 Barrett, Daniel M
A1 Bayzetinova, Tanya
A1 Jones, Philip
A1 Jones, Wendy D
A1 King, Daniel
A1 Krishnappa, Netravathi
A1 Mason, Laura E
A1 Singh, Tarjinder
A1 Tivey, Adrian R
A1 Ahmed, Munaza
A1 Anjum, Uruj
A1 Archer, Hayley
A1 Armstrong, Ruth
A1 Awada, Jana
A1 Balasubramanian, Meena
A1 Banka, Siddharth
A1 Baralle, Diana
A1 Barnicoat, Angela
A1 Batstone, Paul
A1 Baty, David
A1 Bennett, Chris
A1 Berg, Jonathan
A1 Bernhard, Birgitta
A1 Bevan, A Paul
A1 Bitner-Glindzicz, Maria
A1 Blair, Edward
A1 Blyth, Moira
A1 Bohanna, David
A1 Bourdon, Louise
A1 Bourn, David
A1 Bradley, Lisa
A1 Brady, Angela
A1 Brent, Simon
A1 Brewer, Carole
A1 Brunstrom, Kate
A1 Bunyan, David J
A1 Burn, John
A1 Canham, Natalie
A1 Castle, Bruce
A1 Chandler, Kate
A1 Chatzimichali, Elena
A1 Cilliers, Deirdre
A1 Clarke, Angus
A1 Clasper, Susan
A1 Clayton-Smith, Jill
A1 Clowes, Virginia
A1 Coates, Andrea
A1 Cole, Trevor
A1 Colgiu, Irina
A1 Collins, Amanda
A1 Collinson, Morag N
A1 Connell, Fiona
A1 Cooper, Nicola
A1 Cox, Helen
A1 Cresswell, Lara
A1 Cross, Gareth
A1 Crow, Yanick
A1 D'Alessandro, Mariella
A1 Dabir, Tabib
A1 Davidson, Rosemarie
A1 Davies, Sally
A1 de Vries, Dylan
A1 Dean, John
A1 Deshpande, Charu
A1 Devlin, Gemma
A1 Dixit, Abhijit
A1 Dobbie, Angus
A1 Donaldson, Alan
A1 Donnai, Dian
A1 Donnelly, Deirdre
A1 Donnelly, Carina
A1 Douglas, Angela
A1 Douzgou, Sofia
A1 Duncan, Alexis
A1 Eason, Jacqueline
A1 Ellard, Sian
A1 Ellis, Ian
A1 Elmslie, Frances
A1 Evans, Karenza
A1 Everest, Sarah
A1 Fendick, Tina
A1 Fisher, Richard
A1 Flinter, Frances
A1 Foulds, Nicola
A1 Fry, Andrew
A1 Fryer, Alan
A1 Gardiner, Carol
A1 Gaunt, Lorraine
A1 Ghali, Neeti
A1 Gibbons, Richard
A1 Gill, Harinder
A1 Goodship, Judith
A1 Goudie, David
A1 Gray, Emma
A1 Green, Andrew
A1 Greene, Philip
A1 Greenhalgh, Lynn
A1 Gribble, Susan
A1 Harrison, Rachel
A1 Harrison, Lucy
A1 Harrison, Victoria
A1 Hawkins, Rose
A1 He, Liu
A1 Hellens, Stephen
A1 Henderson, Alex
A1 Hewitt, Sarah
A1 Hildyard, Lucy
A1 Hobson, Emma
A1 Holden, Simon
A1 Holder, Muriel
A1 Holder, Susan
A1 Hollingsworth, Georgina
A1 Homfray, Tessa
A1 Humphreys, Mervyn
A1 Hurst, Jane
A1 Hutton, Ben
A1 Ingram, Stuart
A1 Irving, Melita
A1 Islam, Lily
A1 Jackson, Andrew
A1 Jarvis, Joanna
A1 Jenkins, Lucy
A1 Johnson, Diana
A1 Jones, Elizabeth
A1 Josifova, Dragana
A1 Joss, Shelagh
A1 Kaemba, Beckie
A1 Kazembe, Sandra
A1 Kelsell, Rosemary
A1 Kerr, Bronwyn
A1 Kingston, Helen
A1 Kini, Usha
A1 Kinning, Esther
A1 Kirby, Gail
A1 Kirk, Claire
A1 Kivuva, Emma
A1 Kraus, Alison
A1 Kumar, Dhavendra
A1 Kumar, V.K Ajith
A1 Lachlan, Katherine
A1 Lam, Wayne
A1 Lampe, Anne
A1 Langman, Caroline
A1 Lees, Melissa
A1 Lim, Derek
A1 Longman, Cheryl
A1 Lowther, Gordon
A1 Lynch, Sally A
A1 Magee, Alex
A1 Maher, Eddy
A1 Male, Alison
A1 Mansour, Sahar
A1 Marks, Karen
A1 Martin, Katherine
A1 Maye, Una
A1 McCann, Emma
A1 McConnell, Vivienne
A1 McEntagart, Meriel
A1 McGowan, Ruth
A1 McKay, Kirsten
A1 McKee, Shane
A1 McMullan, Dominic J
A1 McNerlan, Susan
A1 McWilliam, Catherine
A1 Mehta, Sarju
A1 Metcalfe, Kay
A1 Middleton, Anna
A1 Miedzybrodzka, Zosia
A1 Miles, Emma
A1 Mohammed, Shehla
A1 Montgomery, Tara
A1 Moore, David
A1 Morgan, Sian
A1 Morton, Jenny
A1 Mugalaasi, Hood
A1 Murday, Victoria
A1 Murphy, Helen
A1 Naik, Swati
A1 Nemeth, Andrea
A1 Nevitt, Louise
A1 Newbury-Ecob, Ruth
A1 Norman, Andrew
A1 O'Shea, Rosie
A1 Ogilvie, Caroline
A1 Ong, Kai-Ren
A1 Park, Soo-Mi
A1 Parker, Michael J
A1 Patel, Chirag
A1 Paterson, Joan
A1 Payne, Stewart
A1 Perrett, Daniel
A1 Phipps, Julie
A1 Pilz, Daniela T
A1 Pollard, Martin
A1 Pottinger, Caroline
A1 Poulton, Joanna
A1 Pratt, Norman
A1 Prescott, Katrina
A1 Price, Sue
A1 Pridham, Abigail
A1 Procter, Annie
A1 Purnell, Hellen
A1 Quarrell, Oliver
A1 Ragge, Nicola
A1 Rahbari, Raheleh
A1 Randall, Josh
A1 Rankin, Julia
A1 Raymond, Lucy
A1 Rice, Debbie
A1 Robert, Leema
A1 Roberts, Eileen
A1 Roberts, Jonathan
A1 Roberts, Paul
A1 Roberts, Gillian
A1 Ross, Alison
A1 Rosser, Elisabeth
A1 Saggar, Anand
A1 Samant, Shalaka
A1 Sampson, Julian
A1 Sandford, Richard
A1 Sarkar, Ajoy
A1 Schweiger, Susann
A1 Scott, Richard
A1 Scurr, Ingrid
A1 Selby, Ann
A1 Seller, Anneke
A1 Sequeira, Cheryl
A1 Shannon, Nora
A1 Sharif, Saba
A1 Shaw-Smith, Charles
A1 Shearing, Emma
A1 Shears, Debbie
A1 Sheridan, Eamonn
A1 Simonic, Ingrid
A1 Singzon, Roldan
A1 Skitt, Zara
A1 Smith, Audrey
A1 Smith, Kath
A1 Smithson, Sarah
A1 Sneddon, Linda
A1 Splitt, Miranda
A1 Squires, Miranda
A1 Stewart, Fiona
A1 Stewart, Helen
A1 Straub, Volker
A1 Suri, Mohnish
A1 Sutton, Vivienne
A1 Swaminathan, Ganesh Jawahar
A1 Sweeney, Elizabeth
A1 Tatton-Brown, Kate
A1 Taylor, Cat
A1 Taylor, Rohan
A1 Tein, Mark
A1 Temple, I Karen
A1 Thomson, Jenny
A1 Tischkowitz, Marc
A1 Tomkins, Susan
A1 Torokwa, Audrey
A1 Treacy, Becky
A1 Turner, Claire
A1 Turnpenny, Peter
A1 Tysoe, Carolyn
A1 Vandersteen, Anthony
A1 Varghese, Vinod
A1 Vasudevan, Pradeep
A1 Vijayarangakannan, Parthiban
A1 Vogt, Julie
A1 Wakeling, Emma
A1 Wallwark, Sarah
A1 Waters, Jonathon
A1 Weber, Astrid
A1 Wellesley, Diana
A1 Whiteford, Margo
A1 Widaa, Sara
A1 Wilcox, Sarah
A1 Wilkinson, Emily
A1 Williams, Denise
A1 Williams, Nicola
A1 Wilson, Louise
A1 Woods, Geoff
A1 Wragg, Christopher
A1 Wright, Michael
A1 Yates, Laura
A1 Yau, Michael
A1 Nellaker, Chris
A1 Parker, Michael J
A1 Firth, Helen V
A1 Wright, Caroline F
A1 FitzPatrick, David R
A1 Barrett, Jeffrey C
A1 Hurles, Matthew E
YR 2016
UL http://biorxiv.org/content/early/2016/04/20/049056.abstract
AB Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (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 of de novo mutations 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 damaging de novo mutation at genome-wide significance (P < 7 x 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.