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A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation

Nature Genetics volume 41, pages 535543 (2009) | Download Citation


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.

Author information


  1. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Patrick S Tarpey
    • , Raffaella Smith
    • , Erin Pleasance
    • , Sarah Edkins
    • , Claire Hardy
    • , Sarah O'Meara
    • , Calli Latimer
    • , Ed Dicks
    • , Andrew Menzies
    • , Phil Stephens
    • , Matt Blow
    • , Chris Greenman
    • , Yali Xue
    • , Chris Tyler-Smith
    • , Kristian Gray
    • , Jenny Andrews
    • , Syd Barthorpe
    • , Gemma Buck
    • , Jennifer Cole
    • , Rebecca Dunmore
    • , David Jones
    • , Mark Maddison
    • , Tatiana Mironenko
    • , Rachel Turner
    • , Kelly Turrell
    • , Jennifer Varian
    • , Sofie West
    • , Sara Widaa
    • , Paul Wray
    • , Jon Teague
    • , Adam Butler
    • , Andrew Jenkinson
    • , Mingming Jia
    • , David Richardson
    • , Rebecca Shepherd
    • , Richard Wooster
    • , P Andrew Futreal
    •  & Michael R Stratton
  2. Cambridge Institute of Medical Research, Cambridge, UK.

    • Annabel Whibley
    • , James Cox
    • , Ying Luo
    • , Uma Mallya
    • , Jenny Moon
    • , Josef Parnau
    • , Martin Bobrow
    •  & F Lucy Raymond
  3. Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratory, Cambridge, UK.

    • Deborah Thompson
    •  & Douglas F Easton
  4. Molecular Genetics Laboratory, Hospital de Cruces, Bizkaia, Spain.

    • M Isabel Tejada
  5. Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario La Fe, Av/Campanar, Valencia, Spain.

    • Francisco Martinez
  6. MRC Human Genetics Research Unit, Faculty of Health Sciences, University of Cape Town, South Africa.

    • Gemma Carvill
    •  & Rene Goliath
  7. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Arjan P M de Brouwer
    •  & Hans van Bokhoven
  8. Center for Human Genetics, University Hospital Leuven, Leuven, Belgium.

    • Hilde Van Esch
  9. Université Paris Descartes; Institut Cochin; INSERM Unité 567; CNRS UMR 8104, Paris, France.

    • Jamel Chelly
  10. INSERM, U930; Centre Hospitalier Régional Universitaire de Tours, Service de Génétique, Tours, France.

    • Martine Raynaud
  11. Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin-Dahlem, Germany.

    • Hans-Hilger Ropers
  12. JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, USA.

    • Fatima E Abidi
    • , Anand K Srivastava
    • , Cindy Skinner
    • , Roger E Stevenson
    •  & Charles E Schwartz
  13. Guy's Hospital, Great Maze Pond, London, UK.

    • Shehla Mohammed
  14. Institute of Medical Genetics, Yorkhill Hospital, Glasgow, UK.

    • John L Tolmie
  15. SA Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia.

    • Cheryl Shoubridge
    • , Mark Corbett
    • , Alison Gardner
    • , Eric Haan
    • , Sinitdhorn Rujirabanjerd
    • , Marie Shaw
    • , Lucianne Vandeleur
    • , Tod Fullston
    •  & Jozef Gecz
  16. GOLD Service, Hunter Genetics, Waratah, New South, Wales, Australia.

    • Jackie Boyle
    • , Michael Partington
    • , Anna Hackett
    • , Michael Field
    •  & Gillian Turner
  17. The University of Adelaide, Adelaide, SA, Australia.

    • Jozef Gecz
  18. Institute of Cancer Research, Surrey, UK.

    • Michael R Stratton


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P.S.T. and R. Smith supervised the X-chromosome sequencing, collation and analysis of data. A.W., S.E., C.H., S.O., C.L., E.D., A.M., P.S., M. Blow, C.G., K.G., J.A., S.B., G.B., J. Cole, R.D., D.J., M.M., T.M., R.T., K.T., J.V., S. West, S. Widaa, P.W., J.T., A.B., A.J., M.J., D.R., R. Shepherd, R.W., A.P.M.d.B., F.E.A., A.K.S., J. Cox, Y.L., U.M., J.M., J.P., C. Shoubridge, M.C., A.G., E.H., S.R., M.S., L.V., T.F. and C. Skinner. performed sequencing, additional molecular analyses and contributed to the data analysis. E.P., D.T., C.T.-S., Y.X., D.F.E. contributed to the analytic design and performed statistical investigations. M.I.T., F.M., G.C., R.G., A.P.M.d.B., H.v.B., H.v.E., J. Chelly, M.R., H.H.R., S.M., J.L.T., M.P., A.H., M.F., R.E.S., G.T., C.E.S., J.G. and F.L.R contributed samples and clinical data from affected individuals. R.E.S., M. Bobrow, G.T., C.E.S., J.G., F.L.R., P.A.F. and M.R.S. conceived, designed and directed the study and wrote the manuscript. All authors contributed to discussion of the results and manuscript preparation. The genetic variants for each individual screened may be obtained from F.L.R. under an agreement not to misuse or further distribute.

Corresponding authors

Correspondence to P Andrew Futreal or Michael R Stratton.

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