AUTOMATED VERSUS MANUAL REANALYSIS IN RARE DISEASE GENOMICS

Abstract

PurposePeriodic 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. MethodsWe 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. ResultsManual 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 an output of approximately three variants per case. ConclusionReanalysis at 1.8 years yields modest but clinically meaningful gain. Automated reanalysis closely approximates manual performance while reducing hands-on effort, supporting scalable reanalysis in routine genomic care.