A meta-analysis of diagnostic yield and clinical utility of genome and exome sequencing in pediatric rare and undiagnosed genetic diseases

Abstract

Purpose

To systematically evaluate the diagnostic yield and clinical utility of genome sequencing (GS) and exome sequencing (ES; genome-wide sequencing [GWS]) in pediatric patients with rare and undiagnosed genetic diseases.

Methods

We conducted a meta-analysis of studies published between 2011 and 2023. To address study heterogeneity, comparative analyses included within-cohort studies using random-effects models.

Results

We identified 108 studies including 24,631 probands with diverse clinical indications. The pooled diagnostic yield among within-cohort studies (N = 13) for GWS was 34.2% (95% CI: 27.6-41.5; I²: 86%) vs 18.1% (95% CI: 13.1-24.6; I²: 89%) for non-GWS, with 2.4-times odds of diagnosis (95% CI: 1.40-4.04; P < .05). The pooled diagnostic yield among within-cohort studies (N = 3) for GS was 30.6% (95% CI: 18.6-45.9; I²: 79%) vs 23.2% (95% CI: 18.5-28.7; I²: 58%) for ES, with 1.7-times the odds of diagnosis (95% CI: 0.94-2.92; P = .13). In first-line testing, the diagnostic yield tended to be higher for GS than for ES across clinical subgroups. The pooled clinical utility among patients with a positive diagnosis was 58.7% (95% CI: 47.3-69.2; I²: 81%) for GS and 54.5% (95% CI: 40.7-67.6; I ²: 87%) for ES.

Conclusion

GS appears to have a higher diagnostic yield than ES, with similar clinical utility per positive diagnosis.