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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References
World Health Organization. The ICD-10 classification of mental and behavioural disorders (World Health Organization, Geneva, 1992).
American Psychiatic Association. Diagnostic and statistical manual of mental disorders DSM-IV (American Psychiatric Association, Washington, D.C., 1994).
Polder, J.J., Meerding, W.J., Bonneux, L. & van der Maas, P.J. Healthcare costs of intellectual disability in the Netherlands: a cost-of-illness perspective. J. Intellect. Disabil. Res. 46, 168–178 (2002).
McCandless, S.E., Brunger, J.W. & Cassidy, S.B. The burden of genetic disease on inpatient care in a children's hospital. Am. J. Hum. Genet. 74, 121–127 (2004).
Laxova, R., Ridler, M.A. & Bowen-Bravery, M. An etiological survey of the severely retarded Hertfordshire children who were born between January 1, 1965 and December 31, 1967. Am. J. Med. Genet. 1, 75–86 (1977).
Baird, P.A. & Sadovnick, A.D. Mental retardation in over half-a-million consecutive livebirths: an epidemiological study. Am. J. Ment. Defic. 89, 323–330 (1985).
Chelly, J., Khelfaoui, M., Francis, F., Cherif, B. & Bienvenu, T. Genetics and pathophysiology of mental retardation. Eur. J. Hum. Genet. 14, 701–713 (2006).
Inlow, J.K. & Restifo, L.L. Molecular and comparative genetics of mental retardation. Genetics 166, 835–881 (2004).
Vissers, L.E. et al. Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am. J. Hum. Genet. 73, 1261–1270 (2003).
Schreppers-Tijdink, G.A., Curfs, L.M., Wiegers, A., Kleczkowska, A. & Fryns, J.P. A systematic cytogenetic study of a population of 1170 mentally retarded and/or behaviourly disturbed patients including fragile X-screening. The Hondsberg experience. J. Genet. Hum. 36, 425–446 (1988).
Ravnan, J.B. et al. Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities. J. Med. Genet. 43, 478–489 (2006).
Chiurazzi, P., Schwartz, C.E., Gecz, J. & Neri, G. XLMR genes: update 2007. Eur. J. Hum. Genet. 16, 422–434 (2008).
Ropers, H.H. & Hamel, B.C. X-linked mental retardation. Nat. Rev. Genet. 6, 46–57 (2005).
de Brouwer, A.P. et al. Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium. Hum. Mutat. 28, 207–208 (2007).
Ross, M.T. et al. The DNA sequence of the human X chromosome. Nature 434, 325–337 (2005).
Tarpey, P.S. et al. Mutations in the gene encoding the sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X–linked mental retardation. Am. J. Hum. Genet. 79, 1119–1124 (2006).
Tarpey, P.S. et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am. J. Hum. Genet. 80, 345–352 (2007).
Tarpey, P.S. et al. Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat. Genet. 39, 1127–1133 (2007).
Raymond, F.L. et al. Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X–linked mental retardation associated with a marfanoid habitus. Am. J. Hum. Genet. 80, 982–987 (2007).
Field, M. et al. Mutations in the BRWD3 gene cause X–linked mental retardation associated with macrocephaly. Am. J. Hum. Genet. 81, 367–374 (2007).
Gilfillan, G.D. et al. SLC9A6 Mutations Cause X–Linked Mental Retardation, Microcephaly, Epilepsy, and Ataxia, a Phenotype Mimicking Angelman Syndrome. Am. J. Hum. Genet. 82, 1003–1010 (2008).
Najm, J. et al. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat. Genet. 40, 1065–1067 (2008).
Hsueh, Y.P. The role of the MAGUK protein CASK in neural development and synaptic function. Curr. Med. Chem. 13, 1915–1927 (2006).
McDonald, J.H. & Kreitman, M. Adaptive protein evolution at the Adh locus in Drosophila. Nature 351, 652–654 (1991).
Bustamante, C.D. et al. Natural selection on protein-coding genes in the human genome. Nature 437, 1153–1157 (2005).
Kwiatkowski, D.P. How malaria has affected the human genome and what human genetics can teach us about malaria. Am. J. Hum. Genet. 77, 171–192 (2005).
Reese, M.G., Eeckman, F.H., Kulp, D. & Haussler, D. Improved splice site detection in Genie. J. Comput. Biol. 4, 311–323 (1997).
Huang, H. et al. Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes. Genome Biol. 5, R47 (2004).
Osada, N. Inference of expression-dependent negative selection based on polymorphism and divergence in the human genome. Mol. Biol. Evol. 24, 1622–1626 (2007).
Wang, H.Y. et al. Rate of evolution in brain-expressed genes in humans and other primates. PLoS Biol. 5, e13 (2007).
Adie, E.A., Adams, R.R., Evans, K.L., Porteous, D.J. & Pickard, B.S. Speeding disease gene discovery by sequence based candidate prioritization. BMC Bioinformatics 6, 55 (2005).
Deininger, P.L., Moran, J.V., Batzer, M.A. & Kazazian, H.H. Jr. Mobile elements and mammalian genome evolution. Curr. Opin. Genet. Dev. 13, 651–658 (2003).
Sakharkar, M.K. et al. A report on single exon genes (SEG) in eukaryotes. Front. Biosci. 9, 3262–3267 (2004).
Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).
Dicks, E. et al. AutoCSA, an algorithm for high throughput DNA sequence variant detection in cancer genomes. Bioinformatics 23, 1689–1691 (2007).
Thompson, D., Easton, D.F. & Goldgar, D.E. A full-likelihood method for the evaluation of causality of sequence variants from family data. Am. J. Hum. Genet. 73, 652–655 (2003).
Rozas, J., Sanchez-DelBarrio, J.C., Messeguer, X., Rozas, R. & Dna, S.P. DNA polymorphism analyses by the coalescent and other methods. Bioinformatics 19, 2496–2497 (2003).
Hsiao, L.L. et al. A compendium of gene expression in normal human tissues. Physiol. Genomics 7, 97–104 (2001).
Liang, S., Li, Y., Be, X., Howes, S. & Liu, W. Detecting and profiling tissue-selective genes. Physiol. Genomics 26, 158–162 (2006).
Katoh, K., Kuma, K., Miyata, T. & Toh, H. Improvement in the accuracy of multiple sequence alignment program MAFFT. Genome Inform 16, 22–33 (2005).
Valdar, W.S. Scoring residue conservation. Proteins 48, 227–241 (2002).
Grantham, R. Amino acid difference formula to help explain protein evolution. Science 185, 862–864 (1974).
Acknowledgements
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.
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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.
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Tarpey, P., Smith, R., Pleasance, E. et al. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet 41, 535–543 (2009). https://doi.org/10.1038/ng.367
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DOI: https://doi.org/10.1038/ng.367
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