Reanalysis of whole exome sequencing in patients with rare disease

초록

＞Introduction/b＞ Ongoing discoveries of new disease-associated genes , advances in technology, changing phenotypes have led to a growing recognition of the need for reanalysis in patients with undiagnosed rare diseases. Reanalysis of whole exome sequencing can increase the diagnostic yield by 10-13% without additional genetic testing. b＞Methods/b＞We retrospectively reanalyzed genetic variants in 89 patients who underwent whole-exome sequencing (WES) at a single tertiary hospital between 2020 and 2024. Variant interpretation and reclassification were conducted according to the 2015 ACMG/AMP guidelines, incorporating updated evidence from public databases, recent literature, and clinical data. Systematic reanalysis was applied for undiagnosed cases, and the final evaluation was completed in August 2025. b＞Result/b＞ A total of 17 cases (19.1%) showed changes in results upon reanalysis. Of these, 10 cases were newly diagnosis through reanalysis, which increased the overall diagnostic yield from 31.5% (n=28) to 42.6% (n=38). Among the newly diagnosed cases, three were reclassified based on updated literature , three were attributed to improved bioinformatics pipelines, and four were established through comprehensive clinical reevaluation with phenotype-genotype correlation supported by updated variant database. Three cases changed the result from negative to inconclusive and two cases changed from inconclusive to negative. In addition, two secondary finding were removed from the report due to variant were reclassified from likely pathogenic to VUS. b＞Conclusion/b＞Rapid advances in knowledge of genetic disorders and sequencing technologies highlights the importance of reanalysis genetic testing. Nonetheless, practical challenges remain, and further research is required to establish effective strategies. Keywords: Reanalysis , Exome Sequencing,