Using Whole Exome Sequencing to Walk From Clinical Practice to Research and Back Again

Whole exome sequencing (WES) is currently used to identify the genetic causes of many diseases, especially monogenic disorders. Ng et al,1 in 2009, completed the first proof-of-principle study demonstrating the feasibility of using exome sequencing to identify causal variants for diseases, specifically Freeman-Sheldon syndrome. Within 2 years, there was a marked increase in publications presenting WES data, and the pace continues to accelerate (Figure). In 2010, WES began to be used for clinical diagnoses, particularly for mendelian disorders. In early 2011, Worthey et al2 used exome sequencing to facilitate clinical diagnosis and modify treatment in a single case. Despite many of the successes resulting from exome sequencing, more than half of the approximately 7000 known or suspected mendelian disorders have not yet been discovered,3 which highlights the need for more genetic, mechanistic, and clinical studies, particularly if the data are to be used clinically. Moreover, as our knowledge of the genome increases, examples of some of the complexities associated with genotypic-phenotypic relationships further substantiate the need for both additional genomic annotation and many more sequenced genomes with phenotypic information. Some of these complexities include the following: (1) Variants in the same genes may lead to different clinical manifestations or phenotypes; (2) what appear to be similar phenotypic observations may result from different causal disease variants operating through distinct pathophysiological mechanisms; and (3) the recent ENCODE (Encyclopedia of DNA Elements) papers, which suggest that up to 80% of the human genome is functional.4Figure. Number of exome sequencing publications by year. “Human exome sequencing” and “human patient exome sequencing” were searched in PubMed. Reviews, perspectives, and methodology papers were excluded.Article see p 1009In this issue of Circulation , Crotti and colleagues5 use a …