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.

Exome sequencing - the targeted sequencing of the subset of the human genome that is protein coding - is a powerful and cost-effective new tool for dissecting the genetic basis of diseases and traits that have proved to be intractable to conventional gene-discovery strategies. Over the past 2 years, experimental and analytical approaches relating to exome sequencing have established a rich framework for discovering the genes underlying unsolved Mendelian disorders. Additionally, exome sequencing is being adapted to explore the extent to which rare alleles explain the heritability of complex diseases and health-related traits. These advances also set the stage for applying exome and whole-genome sequencing to facilitate clinical diagnosis and personalized disease-risk profiling.