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Lancet. 2015 Apr 4;385(9975):1305-14. doi: 10.1016/S0140-6736(14)61705-0. Epub 2014 Dec 17.

Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.

Collaborators (274)

Barrett JC, Carter NP, Firth HV, FitzPatrick DR, Hurles ME, Parker M, Wright CF, Ambridge K, Barrett DM, Bayzetinova T, Gribble S, Krishnappa N, Mason LE, Prigmore E, Rajan D, Coomber EL, Gerety SS, Clayton S, Fitzgerald TW, Jones P, Miller R, Tivey AR, Akawi N, Al-Turki S, Barrett JC, Fitzgerald TW, Hurles ME, Jones WD, King D, van Kogelenberg M, McRae J, Morley KI, Parthiban V, Sifrim A, Middleton A, Parker M, Wright CF, Bevan A, Bragin E, Swaminathan G, Andrews R, Burton J, Bumpstead SJ, Edkins S, Ellis P, Gray E, Jones D, Scott C, Simpkin D, Walker D, Widaa S, Banerjee R, Fu B, Pereira SL, Yang F, Dominiczak A, Morris A, Porteous D, Smith B, Dean J, McGowan R, Ross A, D'Alessandro M, Batstone P, Samant S, Belfast SS, Dabir T, Donnelly D, Magee A, McConnell V, McKee S, Stewart F, Kirk C, Humphreys M, McNerlan S, Brueton L, Cole T, Cooper N, Cox H, Jarvis J, Lim D, Morton J, Norman A, Patel C, Ragge N, Sharif S, Tein M, Vogt J, Williams D, Kirby G, Bohanna D, McKay K, McMullan DJ, Newbury-Ecob R, Smithson S, Hawkins R, Roberts E, Wragg C, Armstrong R, Firth H, Holden S, Mehta S, Park SM, Paterson J, Raymond L, Sandford R, Woods G, Roberts J, Wilcox S, Simonic I, Treacy B, Archer H, Davies S, Kumar D, McCann E, Pilz DT, Procter A, Evans K, Morgan S, Mugalaasi H, Lynch SA, O'Shea R, Berg J, Goudie D, Schweiger S, Rice D, Baty D, Pratt N, FitzPatrick DR, Lam W, Lampe A, Greene P, Maher E, Moore D, Brewer C, Castle B, Kivuva E, Rankin J, Shaw-Smith C, Turner C, Turnpenny P, Devlin G, Everest S, Ellard S, Tysoe C, Davidson R, Gardiner C, Joss S, Kinning E, Murday V, Tolmie J, Whiteford M, Duncan A, Lowther G, Williams N, Bennett C, Blyth M, Hobson E, Kraus A, Prescott K, Smith A, Thomson J, Squires M, Coates A, Hewitt S, Roberts P, Vasudevan P, Kaemba B, Kazembe S, Cresswell L, Weber A, Fryer A, Greenhalgh L, Sweeney E, Roberts G, Sutton V, Douglas A, Maye U, Bernhard B, Brady A, Canham N, Ghali N, Holder S, Wakeling AV, Sequeira C, Singzon R, Bourdon L, Payne S, Hurst J, Lees M, Rosser E, Scott R, Brunstrom K, Hollingsworth G, Jenkins L, Waters J, Connell F, Deshpande C, Flinter F, Irving M, Josifova D, Mohammed S, Robert L, Fendick T, Langman C, Ogilvie C, Yau M, Elmslie F, Homfray T, Mansour S, McEntagart M, Saggar A, Tatton-Brown K, Anjum U, Marks K, Taylor R, Chandler K, Clayton-Smith J, Crow Y, Jones E, Kerr B, Metcalfe K, Donnelly C, Skitt Z, Gaunt L, Miles E, Burn J, Fisher R, Goodship J, Henderson A, Montgomery T, Splitt M, Wright M, Sneddon L, Bourn D, Hellens S, Dixit A, Eason J, Sarkar A, Shannon N, Suri M, Selby A, Cross G, Martin K, Blair E, Gibbons R, Kini U, Price S, Shears D, Stewart H, Phipps J, Pridham A, Purnell H, Clasper S, Seller A, Balasubramanian M, Johnson D, Parker M, Nevitt L, Ingram S, Taylor C, Shearing E, Smith K, Ahmed M, Baralle D, Collins A, Foulds N, Lachlan K, Temple I, Wellesley D, Harrison L, Torokwa A, Bunyan DJ, Collinson MN.

Author information

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK. Electronic address:
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK; Institute of Psychiatry, King's College London, London, UK; Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
The Ethox Centre, Nuffield Department of Population Health University of Oxford, Old Road Campus, Oxford, UK.
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, WGH, Edinburgh, UK.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK; Cambridge University Hospitals Foundation Trust, Addenbrooke's Hospital, Cambridge, UK.



Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount.


The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team.


Around 80,000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation.


Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene-phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial.


Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.

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