Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study
Open accessAbstract
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 × 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 Novo Mutation DD Developmental Disorder DDD Deciphering Developmental Disorders study
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The dURV elevation was concentrated in X-linked intellectual disability genes (OR=1.88; 95% CI=1.34-2.64; P=9.5e-4) and developmental disorder genes (OR=1.67; 95% CI=1.31-2.13; P=1.6e-4).
“We did observe the dURV elevation to be concentrated in X-linked intellectual disability (XLID) genes41,42 (OR=1.88; 95% CI=1.34–2.64; P = 9.5 × 10−4) and in developmental disorder (DD) genes43 (OR=1.67; 95% CI=1.31-2.13; P = 1.6 × 10−4) (Online Methods).”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [43]
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Akbari, A. (2025) · Springer eBooks · doi:10.1007/978-3-319-66816-1_1232-1
- Authors
- McRae, J. F., Clayton, S., Fitzgerald, T. W., Kaplanis, J., Prigmore, E., Rajan, D., Sifrim, A., Aitken, S., Akawi, N., Alvi, M., Ambridge, K., Barrett, D. M., Bayzetinova, T., Jones, P., Jones, W. D., King, D., Krishnappa, N., Mason, L. E., Singh, T., Tivey, A. R., Ahmed, M., Anjum, U., Archer, H., Armstrong, R., Awada, J., Balasubramanian, M., Banka, S., Baralle, D., Barnicoat, A., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A. P., Bitner-Glindzicz, M., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Bradley, L., Brady, A., Brent, S., Brewer, C., Brunstrom, K., Bunyan, D. J., Burn, J., Canham, N., Castle, B., Chandler, K., Chatzimichali, E., Cilliers, D., Clarke, A., Clasper, S., Clayton-Smith, J., Clowes, V., Coates, A., Cole, T., Colgiu, I., Collins, A., Collinson, M. N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., D'Alessandro, M., Dabir, T., Davidson, R., Davies, S., de Vries, D., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dobbie, A., Donaldson, A., Donnai, D., Donnelly, D., Donnelly, C., Douglas, A., Douzgou, S., Duncan, A., Eason, J., Ellard, S., Ellis, I., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fry, A., Fryer, A., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Gill, H., Goodship, J., Goudie, D., Gray, E., Green, A., Greene, P., Greenhalgh, L., Gribble, S., Harrison, L., Harrison, V., Hawkins, R., He, L., Hellens, S., Henderson, A., Hewitt, S., Hildyard, L., Hobson, E., Holden, S., Holder, M., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Hutton, B., Ingram, S., Irving, M., Islam, L., Jackson, A., Jarvis, J., Jenkins, L., Johnson, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kelsell, R., Kerr, B., Kingston, H., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Kumar, V. K. A., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Longman, C., Lowther, G., Lynch, S. A., Magee, A., Maher, E., Male, A., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D. J., McNerlan, S., McWilliam, C., Mehta, S., Metcalfe, K., Middleton, A., Miedzybrodzka, Z., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morton, J., Mugalaasi, H., Murday, V., Murphy, H., Naik, S., Nemeth, A., Nevitt, L., Newbury-Ecob, R., Norman, A., O'Shea, R., Ogilvie, C., Ong, K.-R., Park, S.-M., Parker, M. J., Patel, C., Paterson, J., Payne, S., Perrett, D., Phipps, J., Pilz, D. T., Pollard, M., Pottinger, C., Poulton, J., Pratt, N., Prescott, K., Price, S., Pridham, A., Procter, A., Purnell, H., Quarrell, O., Ragge, N., Rahbari, R., Randall, J., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, J., Roberts, P., Roberts, G., Ross, A., Rosser, E., Saggar, A., Samant, S., Sampson, J., Sandford, R., Sarkar, A., Schweiger, S., Scott, R., Scurr, I., Selby, A., Seller, A., Sequeira, C., Shannon, N., Sharif, S., Shaw-Smith, C., Shearing, E., Shears, D., Sheridan, E., Simonic, I., Singzon, R., Skitt, Z., Smith, A., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Straub, V., Suri, M., Sutton, V., Swaminathan, G. J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I. K., Thomson, J., Tischkowitz, M., Tomkins, S., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Varghese, V., Vasudevan, P., Vijayarangakannan, P., Vogt, J., Wakeling, E., Wallwark, S., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Wilkinson, E., Williams, D., Williams, N., Wilson, L., Woods, G., Wragg, C., Wright, M., Yates, L., Yau, M., Nellaker, C., Parker, M. J., Firth, H. V., Wright, C. F., FitzPatrick, D. R., Barrett, J. C., & Hurles, M. E.
- Affiliations
- Wellcome Sanger Institute (GB)
- Western General Hospital (GB)
- University of Oxford (GB)
- Salisbury District Hospital (GB)
- St George's, University of London (GB)
- Glan Clwyd Hospital (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Sheffield Children's Hospital (GB)
- Manchester Academic Health Science Centre (GB)
- Great Ormond Street Hospital (GB)
- NHS Grampian (GB)
- NHS Tayside (GB)
- London North West Healthcare NHS Trust (GB)
- Chapel Allerton Hospital (GB)
- Birmingham Women's Hospital (GB)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Belfast Health and Social Care Trust (GB)
- Royal Devon & Exeter NHS Foundation Trust (GB)
- Guy's Hospital (GB)
- Leicester Royal Infirmary (GB)
- Nottingham University Hospitals NHS Trust (GB)
- NHS Greater Glasgow and Clyde (GB)
- University Hospitals Bristol NHS Foundation Trust (GB)
- Liverpool Womens NHS Foundation Trust (GB)
- Children's Health Ireland at Crumlin (IE)
- ORCID
- McRae, Jeremy F
- Fitzgerald, Tomas W
- Kaplanis, Joanna
- Prigmore, Elena
- Akawi, Nadia
- Jones, Wendy D
- Krishnappa, Netravathi
- Singh, Tarjinder
- Tivey, Adrian R
- Balasubramanian, Meena
- Banka, Siddharth
- Baralle, Diana
- Berg, Jonathan
- Bevan, A Paul
- Bitner-Glindzicz, Maria
- Blyth, Moira
- Bourn, David
- Brent, Simon
- Bunyan, David J
- Burn, John
- Cilliers, Deirdre
- Clarke, Angus
- Clowes, Virginia
- Collins, Amanda
- Cooper, Nicola
- Cox, Helen
- Cross, Gareth
- Crow, Yanick
- Dean, John
- Deshpande, Charu
- Dixit, Abhijit
- Donaldson, Alan
- Douzgou, Sofia
- Eason, Jacqueline
- Ellard, Sian
- Elmslie, Frances
- Foulds, Nicola
- Ghali, Neeti
- Gibbons, Richard
- Gray, Emma
- Green, Andrew
- Greene, Philip
- Hewitt, Sarah
- Holden, Simon
- Homfray, Tessa
- Ingram, Stuart
- Irving, Melita
- Jackson, Andrew
- Johnson, Diana
- Jones, Elizabeth
- Josifova, Dragana
- Joss, Shelagh
- Kerr, Bronwyn
- Kini, Usha
- Kinning, Esther
- Kivuva, Emma
- Kraus, Alison
- Lachlan, Katherine
- Lam, Wayne
- Lees, Melissa
- Lim, Derek
- Lynch, Sally A
- Male, Alison
- Mansour, Sahar
- Martin, Katherine
- McEntagart, Meriel
- McGowan, Ruth
- McKee, Shane
- McMullan, Dominic J
- Mehta, Sarju
- Middleton, Anna
- Miedzybrodzka, Zosia
- Mohammed, Shehla
- Moore, David
- Nemeth, Andrea
- Newbury-Ecob, Ruth
- Ogilvie, Caroline
- Ong, Kai-Ren
- Park, Soo-Mi
- Patel, Chirag
- Perrett, Daniel
- Phipps, Julie
- Pollard, Martin
- Pottinger, Caroline
- Poulton, Joanna
- Quarrell, Oliver
- Ragge, Nicola
- Rahbari, Raheleh
- Roberts, Paul
- Roberts, Gillian
- Samant, Shalaka
- Sampson, Julian
- Sandford, Richard
- Schweiger, Susann
- Scott, Richard
- Shannon, Nora
- Sharif, Saba
- Sheridan, Eamonn
- Smithson, Sarah
- Sneddon, Linda
- Splitt, Miranda
- Stewart, Fiona
- Stewart, Helen
- Straub, Volker
- Suri, Mohnish
- Sutton, Vivienne
- Swaminathan, Ganesh Jawahar
- Temple, I Karen
- Thomson, Jenny
- Tischkowitz, Marc
- Turnpenny, Peter
- Varghese, Vinod
- Vasudevan, Pradeep
- Vogt, Julie
- Wakeling, Emma
- Wellesley, Diana
- Widaa, Sara
- Williams, Nicola
- Wilson, Louise
- Woods, Geoff
- Wragg, Christopher
- Yates, Laura
- Firth, Helen V
- Wright, Caroline F
- FitzPatrick, David R
- Barrett, Jeffrey C
- Hurles, Matthew E
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2016-04-20
- OpenAlex
- W2340547371
- Cited by
- 30
- References
- 43
- Citations by year
- 2025: 2 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 3 · 2017: 6 · 2016: 16
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Wellcome Trust (HICF-1009-003, GEN/284/12, WT 098051, 10/H0305/83)
- University of Edinburgh
- Medical Research Council (WT098051, MR/J010448/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- de novo mutations, developmental disorders, exome sequencing, diagnostic yield, parental age, sex differences, loss-of-function mutations, haploinsufficiency, birth prevalence, gene discovery, genetic architecture, phenotypic diversity
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