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. 2009 May;41(5):535-43.
doi: 10.1038/ng.367. Epub 2009 Apr 19.

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

Patrick S Tarpey  1 , Raffaella Smith, Erin Pleasance, Annabel Whibley, Sarah Edkins, Claire Hardy, Sarah O'Meara, Calli Latimer, Ed Dicks, Andrew Menzies, Phil Stephens, Matt Blow, Chris Greenman, Yali Xue, Chris Tyler-Smith, Deborah Thompson, 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, M Isabel Tejada, Francisco Martinez, Gemma Carvill, Rene Goliath, Arjan P M de Brouwer, Hans van Bokhoven, Hilde Van Esch, Jamel Chelly, Martine Raynaud, Hans-Hilger Ropers, Fatima E Abidi, Anand K Srivastava, James Cox, Ying Luo, Uma Mallya, Jenny Moon, Josef Parnau, Shehla Mohammed, John L Tolmie, Cheryl Shoubridge, Mark Corbett, Alison Gardner, Eric Haan, Sinitdhorn Rujirabanjerd, Marie Shaw, Lucianne Vandeleur, Tod Fullston, Douglas F Easton, Jackie Boyle, Michael Partington, Anna Hackett, Michael Field, Cindy Skinner, Roger E Stevenson, Martin Bobrow, Gillian Turner, Charles E Schwartz, Jozef Gecz, F Lucy Raymond, P Andrew Futreal, Michael R Stratton
Affiliations

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

Patrick S Tarpey et al. Nat Genet. 2009 May.

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.

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Figure 1
Figure 1
Pedigrees of families with likely deleterious variants in the SYP, ZNF711 and CASK genes. Shaded symbols indicate individuals with mental retardation and open symbols indicate individuals who are unaffected. Symbols containing a red square indicate individuals with both mental retardation and nystagmus. An asterisk indicates the presence of the variant allele and ‘wt’ indicates the presence of the wild-type allele. lod scores are shown in parentheses. (a) SYP. In family MRFU-470, additional individuals were unavailable to genotype. (b) ZNF711. In family 208 the maternal grandfather of the proband (I.1) is thought likely to have mild mental retardation, though this individual was unavailable to enable a detailed clinical assessment. (c) CASK. In family 74, individual III.4 was considered to have milder mental retardation compared to the other affected males and did not present with nystagmus. A lod score of −0.3 was generated when individual III.4 was considered as affected with mental retardation, and a lod score of 1.1 was obtained when his disease status was considered unknown.
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