Molecular diagnostic yield of exome sequencing and genome sequencing in critical ill neonates and infants: A systematic review and meta-analysis.

Abstract

To systematically evaluate the diagnostic yield of exome sequencing (ES) and genome sequencing (GS) for investigating suspected genetic disorders in critically ill neonates and infants. In this review, we retrieved relevant literature published before December 2024 from PubMed, Embase, and Web of Science. We included eligible cohort studies and case series (≥4 patients) adopting ES/GS as primary diagnostic tools. Random-effects proportional meta-analysis, subgroup analysis, and meta-regression were performed to synthesize the overall diagnostic yield, compare various sequencing modalities, and explore the correlation between diagnostic yield and publication year. This study was registered on the International Prospective Register of Systematic Reviews(CRD42025631436). The meta-analysis included 26 ES cohorts (2205 individuals) and 22 GS cohorts (2101 individuals). The overall diagnostic yield was 39.4% for ES (95% CI: 32.8%-46.3%) and 39.4% for GS (95% CI: 34.7%-44.1%). Subgroup analyses revealed trends toward higher yields with trio-based sequencing than with nontrio approaches and with rapid GS than with rapid ES, although these differences were not statistically significant. The meta-regression did not find a significant change in diagnostic yield over time. The results of this systematic review and meta-analysis indicate the substantial diagnostic utility of both ES and GS in critically ill neonates and infants, providing a molecular diagnosis in nearly two-fifths of the cases. These findings support the use of next-generation sequencing to improve diagnostic outcomes in this vulnerable patient population.