The importance and clinical utility of reanalysis of exome and genome sequencing data

Exome sequencing (ES) and genome sequencing (GS) are essential for diagnosing rare genetic disorders, yet a significant number of patients remain without a definitive diagnosis after the initial analysis. Reanalysis of existing ES and GS data has emerged as a clinically indispensable practice, offering the potential to solve previously unresolved cases by leveraging rapid advances in genomic knowledge and technology. This review comprehensively addresses the growing importance, clinical utility, methodologies, and challenges of ES and GS data reanalysis. The increase in diagnostic yield from reanalysis is driven by several key factors: the continuous discovery of new gene-disease associations, ongoing updates to clinical and population genetic databases like ClinVar and gnomAD, the refinement of bioinformatic pipelines, and the application of advanced analytical techniques. Reanalysis has been shown to provide an additional diagnostic yield ranging from 3% to 15% across various disease cohorts, including neurodevelopmental, renal, and cardiovascular disorders. A significant portion of these new diagnoses stems from the reclassification of variants of uncertain significance, which often leads to direct and meaningful changes in clinical management, including targeted surveillance and tailored therapies. The reanalysis of ES and GS data is no longer a supplementary activity but a fundamental component of modern genomic medicine, transforming genomic testing from a one-time event into a continuous diagnostic process. To fully realize its potential, the development of standardized guidelines is crucial to address financial, logistical, and ethical barriers and to facilitate the equitable integration of reanalysis into routine clinical care.