Authors
Yi-Lee Ting, Trevor J Williams, Hillery Metz, Megan Li, Molly Stetler, Amy E Knight Johnson, Brandon D Bunker, Daniel E Pineda-Alvarez, Robert D Daber
Published in
Genetics in medicine : official journal of the American College of Medical Genetics. Pages 102549. Mar 04, 2026. Epub Mar 04, 2026.
Abstract
Exome reanalysis increases diagnostic yield, yet the optimal cadence remains unclear. We evaluated factors influencing molecular diagnosis (MolDx) during routine six month reanalyses.
Exome data were reanalyzed biannually for three years following 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 (HPO) 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 non-diagnostic reports with the highest rate occurring approximately two 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.
PMID:
41795598
Bibliographic data and abstract were imported from PubMed on 09 Mar 2026.
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