Article abstract
Nature Genetics 41, 535 - 543 (2009)
Published online: 19 April 2009 | doi:10.1038/ng.367
A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation
Patrick S Tarpey1, Raffaella Smith1, Erin Pleasance1, Annabel Whibley2, Sarah Edkins1, Claire Hardy1, Sarah O'Meara1, Calli Latimer1, Ed Dicks1, Andrew Menzies1, Phil Stephens1, Matt Blow1, Chris Greenman1, Yali Xue1, Chris Tyler-Smith1, Deborah Thompson3, Kristian Gray1, Jenny Andrews1, Syd Barthorpe1, Gemma Buck1, Jennifer Cole1, Rebecca Dunmore1, David Jones1, Mark Maddison1, Tatiana Mironenko1, Rachel Turner1, Kelly Turrell1, Jennifer Varian1, Sofie West1, Sara Widaa1, Paul Wray1, Jon Teague1, Adam Butler1, Andrew Jenkinson1, Mingming Jia1, David Richardson1, Rebecca Shepherd1, Richard Wooster1, M Isabel Tejada4, Francisco Martinez5, Gemma Carvill6, Rene Goliath6, Arjan P M de Brouwer7, Hans van Bokhoven7, Hilde Van Esch8, Jamel Chelly9, Martine Raynaud10, Hans-Hilger Ropers11, Fatima E Abidi12, Anand K Srivastava12, James Cox2, Ying Luo2, Uma Mallya2, Jenny Moon2, Josef Parnau2, Shehla Mohammed13, John L Tolmie14, Cheryl Shoubridge15, Mark Corbett15, Alison Gardner15, Eric Haan15, Sinitdhorn Rujirabanjerd15, Marie Shaw15, Lucianne Vandeleur15, Tod Fullston15, Douglas F Easton3, Jackie Boyle16, Michael Partington16, Anna Hackett16, Michael Field16, Cindy Skinner12, Roger E Stevenson12, Martin Bobrow2, Gillian Turner16, Charles E Schwartz12, Jozef Gecz15,17, F Lucy Raymond2, P Andrew Futreal1 & Michael R Stratton1,18
Abstract
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.
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
- Cambridge Institute of Medical Research, Cambridge, UK.
- Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratory, Cambridge, UK.
- Molecular Genetics Laboratory, Hospital de Cruces, Bizkaia, Spain.
- Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario La Fe, Av/Campanar, Valencia, Spain.
- MRC Human Genetics Research Unit, Faculty of Health Sciences, University of Cape Town, South Africa.
- Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
- Center for Human Genetics, University Hospital Leuven, Leuven, Belgium.
- Université Paris Descartes; Institut Cochin; INSERM Unité 567; CNRS UMR 8104, Paris, France.
- INSERM, U930; Centre Hospitalier Régional Universitaire de Tours, Service de Génétique, Tours, France.
- Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin-Dahlem, Germany.
- JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, USA.
- Guy's Hospital, Great Maze Pond, London, UK.
- Institute of Medical Genetics, Yorkhill Hospital, Glasgow, UK.
- SA Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
- GOLD Service, Hunter Genetics, Waratah, New South, Wales, Australia.
- The University of Adelaide, Adelaide, SA, Australia.
- Institute of Cancer Research, Surrey, UK.
Correspondence to: Michael R Stratton1,18 e-mail: mrs@sanger.ac.uk
Correspondence to: P Andrew Futreal1 e-mail: paf@sanger.ac.uk
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