Clinical interpretation and implications of whole-genome sequencing.

Abstract

As technical barriers to human DNA sequencing decrease and the cost of whole-genome sequencing (WGS) approaches $1000, WGS and protein-coding genome sequencing (whole-exome sequencing [WES]) are increasingly used in clinical medicine. Both WGS/WES can successfully aid clinical diagnosis,^1-3 reveal the genetic basis of rare familial diseases,^4-6 and explicate novel disease biology.^7,8 Regardless of context, even in apparently healthy individuals, WGS/WES are expected to uncover genetic findings of potential clinical importance.^9-11 However, comprehensive clinical interpretation and reporting of clinically significant findings are seldom performed. As WGS/WES are applied more broadly, questions have been raised about the duty for discovery, interpretation, and reporting of clinical findings. Recently published recommendations define genetic variant types in a minimum list of inherited disease genes that are suggested to be subject to discovery, reporting, and clinical follow-up regardless of the primary indication for sequencing, patient preference, or patient age.¹² Despite this, the technical sensitivity and reproducibility of clinical genetic findings using WGS and the clinical opportunities and costs associated with discovery and reporting of these and other clinical findings in WGS data remain undefined.