Diagnostic Yield of Genome Sequencing Versus Exome Sequencing in Pediatric Patients With Rare Phenotypes: A...

Rare diseases affect 6% of Western societies and are a leading cause of pediatric mortality. The popularization of Next Generation Sequencing technologies, especially exome sequencing (ES), revolutionized the diagnosis of children with rare disease. Still, most patients face extensive diagnostic odysseys and remain undiagnosed. Recently, genome sequencing (GS) emerged in hope that its broader coverage could improve diagnostic yield compared to ES. This study aims to systematically review and meta-analyze the diagnostic power of ES versus GS in pediatric populations with rare diseases. A systematic review of PubMed, Cochrane, and Embase databases was performed on December 11, 2024, for nonrandomized studies comparing GS diagnostic yield with ES or ES reanalysis in pediatric populations with rare disease. Statistical analyses were performed in R software version 4.4.2, and the study was registered on PROSPERO (CRD42024619640). In a cohort of 1684 patients from 11 studies, GS-specific diagnostic yield was 7.0% (95% CI: 5.1%-9.5%; p < 0.0001). Subgroup analysis revealed that ES reanalysis and GS provided statistically similar diagnostic yields in patients with prior negative ES due to overlapping confidence intervals. The diagnostic rate of ES reanalysis was 14.2% (8.9%-21.8%; p < 0.0001), while total GS diagnostic yield in the same cohort was 24.1% (17.6%-31.9%; p < 0.0239). This meta-analysis showed that GS could establish molecular diagnoses in 7.0% more patients after negative ES. However, similar diagnostic yields from ES reanalysis and GS emphasize the importance of periodic reanalysis and variant reinterpretation in diagnostic workflows.