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- Title
Exome sequencing identifies the cause of a mendelian disorder.
- Authors
Ng, Sarah B; Buckingham, Kati J; Lee, Choli; Bigham, Abigail W; Tabor, Holly K; Dent, Karin M; Huff, Chad D; Shannon, Paul T; Jabs, Ethylin Wang; Nickerson, Deborah A; Shendure, Jay; Bamshad, Michael J
- 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 40x and sufficient depth to call variants at approximately 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.
- Publication
Nature genetics, 2010, Vol 42, Issue 1, p30
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.499