Automated Versus Manual Reanalysis In Rare Disease Genomics

Purpose. Periodic reanalysis of genome sequencing data can yield additional diagnoses as knowledge evolves, yet manual reanalysis is labour-intensive. We compared automated and manual reanalysis approaches in rare disease genomics. Methods. We reanalyzed 377 rare disease cases: 158 with pathogenic or likely pathogenic (P/LP) findings, 49 with variants of uncertain significance (VUS) findings, and 170 had no findings. Manual reanalysis used standard diagnostic workflow for all cases without prior P/LP diagnoses (219 cases). An automated pipeline using Talos was benchmarked on the 158 P/LP cases before application to the 219-case reanalysis cohort. The mean reanalysis interval was 660 days. Results. Manual reanalysis identified three additional P/LP cases and two newly classified as VUS, increasing P/LP cases from 158 (41.9%) to 161 (42.7%). Talos recovered all three P/LP findings but only identified one of the two new VUS findings. Benchmarking showed 80.0% singleton concordance and 75.2% (82.8% proband-only) trio concordance, with approximately three variants per case. Conclusion. Reanalysis at 1.8 years yields modest but clinically meaning- ful gain. Automated reanalysis closely approximates manual performance while reducing hands-on effort, supporting scalable reanalysis in routine genomic care. Keywords: rare disease genomics, genome sequencing, automated reanalysis, variant prioritization, Talos, diagnostic yield