Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.
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We would like to express our gratitude to the many families with members with mental retardation or learning disability who agreed to participate in these studies performed by the IGOLD consortium. We would also like to thank many clinicians and researchers, including J.T. den Dunnen, L. Holloway, M. May, B. Kerr, J. Erikson, R. Smith, E. Fraser, P. Hodgins, I. Wilkinson, A.J. Gardener, D. Amor, D. Anderson, M. Edwards, V.J. Ajith, A. Barnicoat, P. Beales, K. Becker, A. Brady, C. Brewer, J. Christodoulou, J. Clayton-Smith, T. Cole, A. Collins, J. Cook, J. Craig, S. Davies, H. Dawkins, M. Delatycki, D. Donnai, M. Edwards, F. Essop, D. Fitzpatrick, F. Flinter, B. Franco, A. Fryer, T. Homfray, S. Garcia, C. Gardiner, R. Gardner, C. Garrett, R. Gibbons, A. Green, P. Guilbert, D. Halliday, B. Hamel, P. Harper, E. Hobson, S. Holder, E. Holinski-Feder, H. Hughes, J. Hurst, F. Kavalier, B. Kerr, U. Kini, T. Kleefstra, F. Kooy, K. Lachlan, W. Lam, M. Lees, S. Lindsay, C. Longman, S. Lynch, S. Mansour, C. Mercel, J. McGaughran, V. Murday, J. Nelson, G. Neri, R. Newbury-Ecob, C. Owens, M. Patton, M. Porteous, S. Price, A. Proctor, O. Quarrell, N. Rahman, W. Reardon, E. Rosser, F. Stewart, H. Stewart, S. Tompkins, D. Trump, B. de Vries, T. Webb, D. Wellesley, D. Williams, L. Wilson, R. Winter, N. Wood, and J. Yates, who referred families for research, and N. Rahman for comments on the manuscript. The work was supported by the European Community's Seventh Framework Programme-the GEN2PHEN Project, the New South Wales Department of Health, the Australian NHMRC, the SMILE foundation, the WCH Foundation, D. Harwood, EU grant QLG3-CT- 2002-01810 (EURO-MRX), US National Institutes of Health (HD26202) to C.E.S., the South Carolina Department of Disabilities and Special Needs (SCDDSN), Action Medical Research and the Wellcome Trust.
Supplementary Note, Supplementary Tables 1–8 and Supplementary Figures 1 and 2
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Dysregulations of sonic hedgehog signaling in MED12 ‐related X‐linked intellectual disability disorders
Molecular Genetics & Genomic Medicine (2019)