Abstract
We demonstrate the first successful application of exome sequencing to discover the gene for a rare mendelian disorder of unknown cause, Miller syndrome (MIM%263750). For four affected individuals in three independent kindreds, we captured and sequenced coding regions to a mean coverage of 40× and sufficient depth to call variants at ∼97% of each targeted exome. Filtering against public SNP databases and eight HapMap exomes for genes with two previously unknown variants in each of the four individuals identified a single candidate gene, DHODH, which encodes a key enzyme in the pyrimidine de novo biosynthesis pathway. Sanger sequencing confirmed the presence of DHODH mutations in three additional families with Miller syndrome. Exome sequencing of a small number of unrelated affected individuals is a powerful, efficient strategy for identifying the genes underlying rare mendelian disorders and will likely transform the genetic analysis of monogenic traits.
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Change history
22 November 2009
In the version of this article initially published online, the panels of Figure 1 were incorrectly labeled. The error has been corrected for the print, PDF and HTML versions of this article.
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Acknowledgements
We thank the families for their participation and the Foundation of Nager and Miller Syndrome for their support. We thank M. McMillin for assistance with project coordination. We thank R. Scott, T. Cox, L. Cox, R. Jack, E. Eichler, M. Emond, G. Cooper, J. Kidd, R. Waterston and E. Wijsman for discussions. Our work was supported in part by grants from the National Heart, Lung, and Blood Institute, National Human Genome Research Institute and National Institute of Child Health and Human Development of the US National Institutes of Health, the Life Sciences Discovery Fund and the Washington Research Foundation. S.B.N. is supported by the Agency for Science Technology and Research, Singapore. A.W.B. is supported by a training fellowship from the National Human Genome Research Institute.
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The project was conceived and experiments planned by M.J.B., D.A.N. and J.S. Review of phenotypes and sample collection were performed by E.W.J. and M.J.B. Experiments were performed by S.B.N., K.J.B. and C.L. Genetic counseling and ethical consultation were provided by K.M.D. and H.K.T. Data analysis were performed by S.B.N., K.J.B., A.W.B., C.D.H., P.T.S. and J.S. The manuscript was written by M.J.B., J.S., S.B.N. and K.J.B. All aspects of the study were supervised by M.J.B., D.A.N. and J.S.
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Ng, S., Buckingham, K., Lee, C. et al. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 42, 30–35 (2010). https://doi.org/10.1038/ng.499
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DOI: https://doi.org/10.1038/ng.499
