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 and exome sequencing (GS and ES; genome-wide sequencing [GWS]) in pediatric patients with rare and undiagnosed genetic diseases.

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

Results: We identified 108 studies including a total of 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% (13.1, 24.6; I2: 89%) for non-GWS, with 2.4-times odds of diagnosis (1.40, 4.04; p<0.05). The pooled diagnostic yield among within-cohort studies (N=3) for GS was 30.6% (18.6, 45.9; I2: 79%) vs. 23.2% (18.5, 28.7; I2: 58%) for ES, with 1.7-times odds of diagnosis (95% CI: 0.94, 2.92; p=0.13). In 1st-line testing, diagnostic yield trended higher for GS vs. ES across clinical subgroups. The pooled clinical utility among patients with positive diagnoses was 58.7% (47.3, 69.2%; I 2: 81%) for GS and 54.5% (40.7, 67.6%; I 2: 87%) for ES.

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