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 etiologies of many diseases, especially monogenic disorders. Ng et al., 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.(1) Within two years, there was a marked increase in publications presenting WES data and the pace continues to accelerate (Figure 1). In 2010, WES began to be used for clinical diagnoses, particularly for Mendelian disorders. In early 2011, Worthey et al(2) 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 7,000 known or suspected Mendelian disorders have not yet been discovered,(3) highlighting 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: 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 papers which suggest that up to 80% of the human genome is functional.(4).