Exome sequencing identifies the cause of a mendelian disorder

We demonstrate the first successful application of exome sequencing to discover the gene for a rare, Mendelian disorder of unknown cause, Miller syndrome (OMIM %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 ~97 % of each targeted exome. Filtering against public SNP databases and a small number of HapMap exomes for genes with two novel variants in each of the four cases 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. Rare monogenic diseases are of substantial interest because identification of their genetic basis provides important knowledge about disease mechanisms, biological pathways, and potential therapeutic targets. However, to date, allelic variants underlying fewer than half o