A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation
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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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Half of X-linked mental retardation cases can be ascribed to rare protein-coding mutations found by sequencing X-chromosomal exons.
“the demonstration that half of the cases of X-linked mental retardation can be ascribed to rare protein-coding mutations, which were discovered by comprehensive sequencing of X-chromosomal exons43.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [43]
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- Authors
- Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., Greenman, C., Xue, Y., Tyler-Smith, C., Thompson, D., Gray, K., Andrews, J., Barthorpe, S., Buck, G., Cole, J., Dunmore, R., Jones, D., Maddison, M., Mironenko, T., Turner, R., Turrell, K., Varian, J., West, S., Widaa, S., Wray, P., Teague, J., Butler, A., Jenkinson, A., Jia, M., Richardson, D., Shepherd, R., Wooster, R., Tejada, M. I., Martinez, F., Carvill, G., Goliath, R., de Brouwer, A. P. M., van Bokhoven, H., Van Esch, H., Chelly, J., Raynaud, M., Ropers, H.-H., Abidi, F. E., Srivastava, A. K., Cox, J., Luo, Y., Mallya, U., Moon, J., Parnau, J., Mohammed, S., Tolmie, J. L., Shoubridge, C., Corbett, M., Gardner, A., Haan, E., Rujirabanjerd, S., Shaw, M., Vandeleur, L., Fullston, T., Easton, D. F., Boyle, J., Partington, M., Hackett, A., Field, M., Skinner, C., Stevenson, R. E., Bobrow, M., Turner, G., Schwartz, C. E., Gecz, J., Raymond, F. L., Futreal, P. A., & Stratton, M. R.
- Affiliations
- Wellcome Sanger Institute (GB)
- University of Cambridge (GB)
- Cancer Research UK (GB)
- Hospital de Cruces (ES)
- University of Cape Town (ZA)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Max Planck Institute for Molecular Genetics (DE)
- Greenwood Genetic Center (US)
- Guy's Hospital (GB)
- South Australia Pathology (AU)
- Hunter Genetics (AU)
- Institute of Cancer Research (GB)
- Corresponding author
- Futreal, P Andrew
- Stratton, Michael R
- ORCID
- Tarpey, Patrick S
- Pleasance, Erin
- Whibley, Annabel
- Edkins, Sarah
- Latimer, Calli
- Dicks, Ed
- Menzies, Andrew
- Stephens, Phil
- Greenman, Chris
- Xue, Yali
- Thompson, Deborah
- Gray, Kristian
- Barthorpe, Syd
- Buck, Gemma
- Jones, David
- Mironenko, Tatiana
- Widaa, Sara
- Teague, Jon
- Jia, Mingming
- Richardson, David
- Shepherd, Rebecca
- Tejada, M Isabel
- Carvill, Gemma
- Chelly, Jamel
- Raynaud, Martine
- Ropers, Hans-Hilger
- Srivastava, Anand K
- Cox, James
- Luo, Ying
- Mohammed, Shehla
- Shoubridge, Cheryl
- Corbett, Mark
- Gardner, Alison
- Haan, Eric
- Fullston, Tod
- Easton, Douglas F
- Boyle, Jackie
- Hackett, Anna
- Skinner, Cindy
- Turner, Gillian
- Schwartz, Charles E
- Raymond, F Lucy
- Futreal, P Andrew
- Stratton, Michael R
- Venue
- Nature Genetics
- Published
- 2009-04-19
- Volume
- 41
- Issue
- 5
- Pages
- 535-543
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2872007
- OpenAlex
- W2152231606
- Cited by
- 603
- References
- 43
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 15 · 2023: 20 · 2022: 26 · 2021: 35 · 2020: 31 · 2019: 29 · 2018: 25 · 2017: 30 · 2016: 40 · 2015: 36 · 2014: 50 · 2013: 40 · 2012: 51
- FWCI
- 38.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Wellcome Trust (077012)
- Cancer Research UK (10118, 11022)
- National Institutes of Health (5r01hd026202-15)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD026202, HD 26202)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- X-linked intellectual disability, X chromosome, coding exons, pathogenic variants, synaptophysin, CASK, X-linked genes, loss of function, rare variants
- MeSH terms
- Chromosome Mapping, Exons, Female, Humans, Male, Pedigree, Genetic Variation, Sequence Analysis, DNA, X-Linked Intellectual Disability, Chromosomes, Human, X
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