期刊
NATURE GENETICS
卷 42, 期 1, 页码 30-U41出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.499
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资金
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute
- National Institute of Child Health and Human Development of the US National Institutes of Health
- Life Sciences Discovery Fund
- Washington Research Foundation
- Agency for Science Technology and Research, Singapore
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL094976] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R21HG004749] Funding Source: NIH RePORTER
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 40x and sufficient depth to call variants at similar to 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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