Exome sequencing as a tool for Mendelian disease gene discovery

Key Points The development of methods that couple targeted capture and massively parallel DNA sequencing —termed exomesequencing — has made it possible to determine cost-effectively nearly all of the coding variation in an individual human genome. Exome sequencing is a powerful and cost-effective new tool for dissecting the genetic basis of Mendelian diseases or traits that have proven intractable to conventional gene-discovery strategies. Most Mendelian disorders that have been solved to date by exome sequencing have relied on comparison of variants found in a small number of unrelated or closely related affected individuals to identify shared novel or rare alleles of the same gene. An alternative to this discrete-filtering approach is to apply tests of association. Exome sequencing of parent–child trios is a highly effective approach for identifying de novo coding mutations, as multiple de novo events occurring within a specific gene (or within a gene family or pathway) is an extremely unlikely event. Solving the remaining several thousand Mendelian disorders by exome or whole-genome sequencing is possible and should be an imperative for the human and medical genetics community. The widespread, useful, convenient and cost-effective use of exome sequencing and eventually whole-genome sequencing for clinical diagnosis and screening will necessitate overcoming a number of major challenges that currently limit its broad applicability. Exome sequencing is a powerful approach for accelerating the discovery of the genes underlying Mendelian disorders and, increasingly, of genes underlying complex traits. This Review describes the experimental and analytical options for applying exome sequencing and the key challenges in using this approach. 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 clini