Applying National Whole-genome Sequencing Findings for Rare Diseases in Clinical Practice: The Imperative of a...

As nationwide government-led whole-genome sequencing (WGS) projects progress, optimizing the clinical integration of large-scale WGS results is crucial. We explored how the initial analysis from Korea's First WGS Pilot Study for Rare Diseases was applied in clinical practice, and then we reanalyzed the data comprehensively at Samsung Medical Center (SMC) Seoul, Korea.

A prospective cohort study designed to collect WGS data under a Korean national initiative was conducted from August 2020 to December 2021. We focused on patients with rare diseases recruited from 16 university hospitals. The participants included 5,000 individuals (2,200 probands and 2,800 family members). The initial WGS data and diagnostic reference reports (from 682 probands and 484 family members), generated based on the First Korean WGS Pilot Study for Rare Diseases, were subsequently reanalyzed by SMC.

The initial analysis of the First Korean WGS Pilot Study data revealed a diagnostic rate of 17%. Upon receiving these results, the SMC conducted two rounds of reanalysis, increasing the diagnostic rate from 15% in the first analysis, to 18% in the second, and finally to 24% in the third (P =1.6×10^-5). Key factors in improving the genetic diagnosis included increased detection of novel (likely) pathogenic variants (P =1.0×10^-4), improved diagnostic rates with larger family recruitment (P =0.004), and refined clinical information for more precise genotype-phenotype correlation analysis (40%).

Although national WGS projects lay a foundation for rare disease diagnosis, hospital-level reanalysis and multidisciplinary collaborations are crucial for optimizing diagnostic outcomes.