Abstract
The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.
Original language | English |
---|---|
Pages (from-to) | 433-438 |
Number of pages | 6 |
Journal | Nature |
Volume | 542 |
Issue number | 7642 |
Early online date | 25 Jan 2017 |
DOIs | |
Publication status | Published - 23 Feb 2017 |
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In: Nature, Vol. 542, No. 7642, 23.02.2017, p. 433-438.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Prevalence and architecture of de novo mutations in developmental disorders
AU - Deciphering Developmental Disorders Study
AU - McRae, Jeremy
AU - Clayton, Stephen
AU - Fitzgerald, Tomas W.
AU - Kaplanis, Joanna
AU - Prigmore, Elena
AU - Rajan, Diana
AU - Sifrim, Alejandro
AU - Aitken, Stuart
AU - Akawi, Nadia
AU - Alvi, Mohsan
AU - Ambridge, Kirsty
AU - Barrett, Daniel M.
AU - Bayzetinova, Tanya
AU - Jones, Philip
AU - Jones, Wendy D
AU - King, Daniel
AU - Krishnappa, Netravathi
AU - Mason, Laura
AU - Singh, Tarjinder
AU - Tivey, Adrian
AU - Ahmed, Munaza
AU - Anjum, Uruj
AU - Archer, Hayley
AU - Armstrong, Ruth
AU - Awada, Jana
AU - Balasubramanian, Meena
AU - Banka, Siddharth
AU - Baralle, Diana
AU - Barnicoat, Angela J
AU - Batstone, Paul
AU - Baty, David
AU - Bennett, Chris
AU - Berg, Jonathan
AU - Bernhard, Birgitta
AU - Bevan, A. Paul
AU - Bitner-Glindzicz, Maria A.K.
AU - Blair, Edward
AU - Blyth, Moira
AU - Bohanna, David
AU - Bourdon, Louise
AU - Bourn, David
AU - Bradley, Lisa
AU - Brady, Angela
AU - Brent, Simon
AU - Brewer, Carole
AU - Brunstrom, Kate
AU - Bunyan, David J
AU - Burn, John
AU - Canham, Natalie
AU - Castle, Bruce
AU - Chandler, Kate
AU - Chatzimichali, EA
AU - Cilliers, Deirdre
AU - Clarke, Angus
AU - Clasper, Susan
AU - Clayton-Smith, Jill
AU - Clowes, Virginia
AU - Coates, A.
AU - Cole, Trevor
AU - Colgiu, Irina-Gabriela
AU - Collins, Amanda
AU - Collinson, Morag N.
AU - Connell, Fiona C.
AU - Cooper, Nicola
AU - Cox, Helen
AU - Cresswell, Lara
AU - Cross, Gareth
AU - Crow, Yanick
AU - D'Alessandro, Mariella
AU - Dabir, Tabib
AU - Davidson, Rosemarie
AU - Davies, Sally
AU - de Vries, Dylan
AU - Dean, John
AU - Deshpande, Charulata
AU - Devlin, Gemma
AU - Dixit, Abhijit
AU - Dobbie, Angus
AU - Donaldson, Alan
AU - Donnai, Dian
AU - Donnelly, Deirdre
AU - Donnelly, C.
AU - Douglas, Angela
AU - Douzgou, Sofia
AU - Duncan, Alexis
AU - Eason, Jacqueline
AU - Ellard, Sian
AU - Ellis, Ian
AU - Elmslie, Frances
AU - Evans, Karenza
AU - Everest, Sarah
AU - Fendick, Tina
AU - Fisher, Richard
AU - Flinter, Frances
AU - Foulds, Nicola
AU - Fry, Andrew E.
AU - Fryer, Alan
AU - Gardiner, Carol
AU - Gaunt, Lorraine
AU - Ghali, Neeti
AU - Gibbons, Richard
AU - Gill, Harinder
AU - Goodship, Judith
AU - Goudie, David R.
AU - Gray, Emma
AU - Green, Andrew
AU - Greene, Philip
AU - Greenhalgh, Lynn
AU - Gribble, Susan
AU - Harrison, Rachel
AU - Harrison, Lucy
AU - Harrison, Victoria
AU - Hawkins, Rose
AU - He, Liu
AU - Hellens, Stephen
AU - Henderson, Alex
AU - Hewitt, Sarah
AU - Hildyard, Lucy
AU - Hobson, Emma
AU - Holden, Simon
AU - Holder, Muriel
AU - Holder, Susan
AU - Hollingsworth, Georgina
AU - Homfray, Tessa
AU - Humphreys, Mervyn
AU - Hurst, Jane
AU - Hutton, Ben
AU - Ingram, Stuart
AU - Irving, Melita
AU - Irving, Melita
AU - Jackson, Andrew
AU - Jarvis, Joanna
AU - Jenkins, Lucy
AU - Johnson, Diana
AU - Jones, Elizabeth
AU - Josifova, Dragana
AU - Joss, Shelagh
AU - Kaemba, Beckie
AU - Kazembe, Sandra
AU - Kelsell, Rosemary
AU - Kerr, Bronwyn
AU - Kingston, Helen
AU - Kini, Usha
AU - Kinning, Esther
AU - Kirby, Gail
AU - Kirk, Claire
AU - Kivuva, Emma
AU - Kraus, Alison
AU - Kumar, Dhavendra
AU - Kumar, V. K. Ajith
AU - Lachlan, Katherine
AU - Lam, Wayne
AU - Lampe, Anne K.
AU - Langman, Caroline
AU - Lees, Melissa
AU - Lim, Derek
AU - Longman, Cheryl
AU - Lowther, Gordon
AU - Lynch, Sally A.
AU - Magee, Alex
AU - Maher, Eddy
AU - Male, Alison
AU - Mansour, Sahar
AU - Marks, Karen
AU - Martin, Katherine
AU - Maye, Una
AU - Maye, Una
AU - McConnell, Vivienne
AU - McEntagart, Meriel
AU - McKay, Kirsten
AU - McGowan, Ruth
AU - Mckee, Shane
AU - McMullan, Dominic J.
AU - McNerlan, Susan
AU - McWilliam, Catherine
AU - Mehta, Sarju
AU - Metcalfe, Kay
AU - Middleton, Anna
AU - Miedzybrodzka, Zosia
AU - Miles, Emma K
AU - Mohammed, Shehla
AU - Montgomery, Tara
AU - Moore, David
AU - Morgan, Sian
AU - Morton, Jenny E.
AU - Mugalaasi, Hood
AU - Murday, Victoria
AU - Murphy, Helen
AU - Naik, Swati
AU - Nemeth, Andrea M.
AU - Nevitt, Louise
AU - Newbury-Ecob, Ruth
AU - Norman, Andrew
AU - O’Shea, Rosie
AU - Ogilvie, Caroline
AU - Ong, Kai-ren
AU - Park, Soo Mi
AU - Parker, Michael J.
AU - Patel, Chirag
AU - Paterson, Joan
AU - Payne, Stewart J.
AU - Perrett, Daniel
AU - Phipps, Julie
AU - Pilz, Daniela T
AU - Pollard, Martin
AU - Pottinger, Caroline
AU - Poulton, Joanna
AU - Pratt, Norman
AU - Prescott, Katrina
AU - Price, Sue
AU - Pridham, Abigail
AU - Procter, Annie M.
AU - Purnell, Hellen
AU - Quarrell, Oliver
AU - Ragge, Nicola
AU - Rahbari, Raheleh
AU - Randall, Joshua
AU - Rankin, Julia
AU - Raymond, F. Lucy
AU - Rice, Debbie
AU - Robert, Leema
AU - Roberts, Eileen
AU - Roberts, Jonathan
AU - Roberts, Paul
AU - Roberts, Gillian
AU - Ross, Alison
AU - Rosser, Elisabeth
AU - Saggar, Anand K
AU - Samant, Shalaka
AU - Sampson, Julian
AU - Sandford, Richard
AU - Sarkar, Ajoy
AU - Schweiger, Susann
AU - Scott, Richard
AU - Scurr, Ingrid
AU - Selby, Anna
AU - Seller, A.
AU - Sequeira, Cheryl
AU - Shannon, Nora
AU - Sharif, Saba
AU - Shaw-Smith, Charles
AU - Shearing, Emma
AU - Shears, Debbie
AU - Sheridan, Eamonn
AU - Simonic, Ingrid
AU - Singzon, Roldan
AU - Skitt, Zara
AU - Smith, Audrey
AU - Smith, Kath
AU - Smithson, Sarah
AU - Sneddon, Linda
AU - Splitt, Miranda
AU - Squires, M.
AU - Stewart, Fiona
AU - Stewart, Helen
AU - Straub, Volker
AU - Suri, Mohnish
AU - Sutton, Vivienne
AU - Swaminathan, Ganesh Jawahar
AU - Sweeney, Elizabeth
AU - Tatton-Brown, Kate
AU - Taylor, Cat
AU - Taylor, Rohan
AU - Tein, Mark
AU - Temple, I. Karen
AU - Thomson, Jenny
AU - Tischkowitz, Marc
AU - Tomkins, Susan
AU - Torokwa, Audrey
AU - Treacy, Becky
AU - Turner, Claire
AU - Turnpenny, Peter
AU - Tysoe, Carolyn
AU - Vandersteen, Anthony
AU - Varghese, Vinod
AU - Vasudevan, Pradeep
AU - Vijayarangakannan, Parthiban
AU - Vogt, Julie
AU - Wakeling, Emma
AU - Wallwark, Sarah
AU - Waters, Jonathon
AU - Weber, Astrid
AU - Wellesley, Diana
AU - Whiteford, Margo
AU - Widaa, Sara
AU - Wilcox, Sarah
AU - Wilkinson, Emily
AU - Williams, Denise
AU - Williams, Nicola
AU - Wilson, Louise
AU - Woods, Geoff
AU - Wragg, Christopher
AU - Wright, Michael
AU - Yates, Laura
AU - Yau, Michael
AU - Nellåker, Chris
AU - Parker, Michael
AU - Firth, Helen V.
AU - Wright, Caroline F.
AU - FitzPatrickd, David R.
AU - Barrett, Jeffrey C.
AU - Hurles, Matthew E.
PY - 2017/2/23
Y1 - 2017/2/23
N2 - The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.
AB - The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.
UR - https://europepmc.org/articles/PMC6016744
U2 - 10.1038/nature21062
DO - 10.1038/nature21062
M3 - Article
C2 - 28135719
SN - 0028-0836
VL - 542
SP - 433
EP - 438
JO - Nature
JF - Nature
IS - 7642
ER -