Impact of Laboratory-Driven Proactive Reanalysis: Reclassification to Positive in 5% of Initially Negative or Uncertain Exome Sequencing Cases

Reanalysis of exome sequencing (ES) data increases diagnostic utility; however, there is no consensus on when and under what circumstances reanalysis should occur. Requesting and performing ES reanalysis burdens both clinical and laboratory workflows. Maximizing the potential for reclassification is essential. Here, we describe the impact of a laboratory-driven proactive reanalysis process that triggers reanalysis when new evidence is identified. We reviewed reanalysis outcomes of an ES cohort. Reanalysis events were categorized based on initiating factors (laboratory-driven proactive, family studies, and clinician-initiated). Laboratory-driven proactive reclassifications are prompted by systematic review of new scientific data. Outcomes were evaluated by initiating factors, reclassification types, evidence used, and time since original report. Overall, 23% of cases underwent at least one reanalysis, with 35% of reanalyses resulting in reclassification. There was a 4% increase in diagnostic yield, including 5% of initially unsolved ES receiving diagnostic reports. Diagnostic reclassifications rates were significantly higher for laboratory-driven proactive reanalyses (54%; p<0.0001) than family studies (18%) and clinician-initiated reanalyses (4%). New gene-disease relationships were the most efficacious evidence source. Laboratory-driven proactive reclassifications occurred steadily over time. Laboratory-driven proactive reanalysis effectively provides more diagnostic reclassifications compared to clinician-initiated reanalysis. Laboratories should curate and integrate emerging evidence into ES reanalysis.