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; I²: 87%) for ES.

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

Keywords: Clinical utility; Diagnostic yield; Exome sequencing; Genetic testing; Genome sequencing.