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Lookup NU author(s): Dr David Bourn, Dr Richard Fisher, Alexander Henderson, Dr Miranda Splitt, Professor Volker StraubORCiD, Dr Simon Zwolinski
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© 2020, The Author(s), under exclusive licence to Springer Nature Limited.De novo mutations in protein-coding genes are a well-established cause of developmental disorders1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.
Author(s): Kaplanis J, Samocha KE, Wiel L, Zhang Z, Arvai KJ, Eberhardt RY, Gallone G, Lelieveld SH, Martin HC, McRae JF, Short PJ, Torene RI, de Boer E, Danecek P, Gardner EJ, Huang N, Lord J, Martincorena I, Pfundt R, Reijnders MRF, Yeung A, Yntema HG, Borras S, Clark C, Dean J, Miedzybrodzka Z, Ross A, Tennant S, Dabir T, Donnelly D, Humphreys M, Magee A, McConnell V, McKee S, McNerlan S, Morrison PJ, Rea G, Stewart F, Cole T, Cooper N, Cooper-Charles L, Cox H, Islam L, Jarvis J, Keelagher R, Lim D, McMullan D, Morton J, Naik S, O'Driscoll M, Ong K-R, Osio D, Ragge N, Turton S, Vogt J, Williams D, Bodek S, Donaldson A, Hills A, Low K, Newbury-Ecob R, Norman AM, Roberts E, Scurr I, Smithson S, Tooley M, Abbs S, Armstrong R, Dunn C, Holden S, Park S-M, Paterson J, Raymond L, Reid E, Sandford R, Simonic I, Tischkowitz M, Woods G, Bradley L, Comerford J, Green A, Lynch S, McQuaid S, Mullaney B, Berg J, Goudie D, Mavrak E, McLean J, McWilliam C, Reavey E, Azam T, Cleary E, Jackson A, Lam W, Lampe A, Moore D, Porteous M, Baple E, Baptista J, Brewer C, Castle B, Kivuva E, Owens M, Rankin J, Shaw-Smith C, Turner C, Turnpenny P, Tysoe C, Bradley T, Davidson R, Gardiner C, Joss S, Kinning E, Longman C, McGowan R, Murday V, Pilz D, Tobias E, Whiteford M, Williams N, Barnicoat A, Clement E, Faravelli F, Hurst J, Jenkins L, Jones W, Kumar VKA, Lees M, Loughlin S, Male A, Morrogh D, Rosser E, Scott R, Wilson L, Beleza A, Deshpande C, Flinter F, Holder M, Irving M, Izatt L, Josifova D, Mohammed S, Molenda A, Robert L, Roworth W, Ruddy D, Ryten M, Yau S, Bennett C, Blyth M, Campbell J, Coates A, Dobbie A, Hewitt S, Hobson E, Jackson E, Jewell R, Kraus A, Prescott K, Sheridan E, Thomson J, Bradshaw K, Dixit A, Eason J, Haines R, Harrison R, Mutch S, Sarkar A, Searle C, Shannon N, Sharif A, Suri M, Vasudevan P, Canham N, Ellis I, Greenhalgh L, Howard E, Stinton V, Swale A, Weber A, Banka S, Breen C, Briggs T, Burkitt-Wright E, Chandler K, Clayton-Smith J, Donnai D, Douzgou S, Gaunt L, Jones E, Kerr B, Langley C, Metcalfe K, Smith A, Wright R, Bourn D, Burn J, Fisher R, Hellens S, Henderson A, Montgomery T, Splitt M, Straub V, Wright M, Zwolinski S, Allen Z, Bernhard B, Brady A, Brooks C, Busby L, Clowes V, Ghali N, Holder S, Ibitoye R, Wakeling E, Blair E, Carmichael J, Cilliers D, Clasper S, Gibbons R, Kini U, Lester T, Nemeth A, Poulton J, Price S, Shears D, Stewart H, Wilkie A, Albaba S, Baker D, Balasubramanian M, Johnson D, Parker M, Quarrell O, Stewart A, Willoughby J, Crosby C, Elmslie F, Homfray T, Jin H, Lahiri N, Mansour S, Marks K, McEntagart M, Saggar A, Tatton-Brown K, Butler R, Clarke A, Corrin S, Fry A, Kamath A, McCann E, Mugalaasi H, Pottinger C, Procter A, Sampson J, Sansbury F, Varghese V, Baralle D, Callaway A, Cassidy EJ, Daniels S, Douglas A, Foulds N, Hunt D, Kharbanda M, Lachlan K, Mercer C, Side L, Temple IK, Wellesley D, Vissers LELM, Juusola J, Wright CF, Brunner HG, Firth HV, FitzPatrick DR, Barrett JC, Hurles ME, Gilissen C, Retterer K
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2020
Volume: 586
Issue: 7831
Pages: 757-762
Print publication date: 29/10/2020
Online publication date: 14/10/2020
Acceptance date: 17/04/2020
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Research
URL: https://doi.org/10.1038/s41586-020-2832-5
DOI: 10.1038/s41586-020-2832-5
PubMed id: 33057194
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