Deep sequencing of patient genomes for disease diagnosis: when will it become routine?

Abstract

Next-generation sequencing technologies have greatly lowered the cost of whole-genome sequencing (WGS) and related approaches. Thus, comprehensive sequencing for diagnostic purposes may clear this financial hurdle in the near future. The report by Bainbridge and colleagues in this issue of Science Translational Medicine illustrates the diagnostic power of WGS. In this Perspective, we discuss whether and how genome sequencing might become routine for clinical diagnosis.

Fig. 1. Contrasting technologies

Frequency of sequences is plotted versus depth of sequence coverage to show, for comparison purposes, the patterns of distribution of sequence coverage afforded by research-grade WGS (blue line) and exome-seq/targeted NGS (red line). The genome coverage achieved by WGS is symmetric about the mean, which at this time is typically 30-fold coverage. Approximately 5% of the genome has insufficient coverage to allow variants to be detected (dotted white line). In contrast, the genome coverage achieved by exome-seq and targeted NGS is right-skewed. Thus, approximately 100-fold average coverage is necessary to achieve a sensitivity of variant detection similar to WGS.

Fig. 2. Fast forward?

Shown are the major similarities and differences in refinements needed for diagnostic use (DX) of WGS, exome-seq, and targeted NGS. The average depth of coverage differs in each approach. Reflex confirmatory testing of all clinically relevant results is necessary for WGS and exome-seq but probably not for targeted NGS; this is because it is possible to obtain a large number of independent observations of each sequence variant. All three methods require pathological interpretation and reporting by a certified laboratory director.