Exome sequencing as a tool for Mendelian disease gene discovery

Abstract

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.