Diagnostic yield of exome reanalysis over time: Contribution of reevaluation type, timing, and patient phenotype.

Abstract

Exome reanalysis increases diagnostic yield; yet, the optimal cadence remains unclear. We evaluated factors influencing molecular diagnosis (MolDx) during routine 6 month reanalyses. Exome data were reanalyzed biannually for 3 years after initial analysis. For each updated report, the timing, reason for update, and diagnostic results were examined. For clarity on clinical indications, we performed a cluster analysis using human phenotype ontology terms to define patient phenotypic clusters. Logistic regression was performed on factors influencing MolDx. The overall MolDx rate increased from 18.3% to 20.4% by the end of the study. Diagnostic rate from reanalysis was 2.6% for nondiagnostic reports with the highest rate occurring approximately 2 years after the initial report. The 21 patient clusters demonstrated significant differences in mean age at testing and MolDx rates. Initial and reanalysis MolDx rates ranged from 3.9% to 37.7% and 0% to 7.3%, respectively. No one factor drove the increase in MolDx. Cluster analysis offered refined guidance on the diagnostic utility of reanalysis based on clinical indication and age, with pediatric clusters having higher MolDx rates at initial analysis and upon reanalysis than adults. Automated processes and tools enable more frequent reanalyses, reducing the wait time for patients to receive a MolDx.