Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations

Abstract

<p><strong>Purpose: </strong>This meta-analysis aims to compare the diagnostic and clinical utility of whole-exome sequencing (WES) versus whole-genome sequencing (WGS) in pediatric and adult patients with rare diseases across diverse populations.</p><p><strong>Methods: </strong>A meta-analysis was conducted to identify studies from 2011-2021.</p><p><strong>Results: </strong>One-hundred-and-sixty-one studies across 31 countries/regions were eligible, featuring 50,417 probands of diverse populations. Diagnostic rates of WES (0.38, 95% CI 0.36-0.40) and WGS (0.34, 95% CI 0.30-0.38) were similar (p=0.1). Within-cohort comparison illustrated a 1.2 times odds of diagnosis by WGS over WES (95% CI 0.79-1.83, p=0.38). WGS studies discovered a higher range of novel genes than WES studies, yet the rate of variant of unknown significance (VUS) did not differ (p=0.78). Among high-quality studies, clinical utility of WGS (0.77, 95% CI 0.64-0.90) was higher than WES (0.44, 95% CI 0.30-0.58) (p<0.01).</p><p><strong>Conclusion: </strong>This meta-analysis provides an important update to demonstrate the similar diagnostic rates between WES and WGS and the higher clinical utility of WGS over WES. With the newly published recommendations for clinical interpretation of variants found in non-coding regions of the genome and the trend of decreasing VUS and WGS cost, it is expected that WGS will be more widely used in clinical settings.</p>