Large-scale discovery of novel genetic causes of developmental disorders

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

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832 Citations (Scopus)


Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.

Original languageEnglish
Pages (from-to)223-228
Number of pages6
Issue number7542
Publication statusPublished - Mar 12 2015
Externally publishedYes

ASJC Scopus subject areas

  • General


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