Genet Med. 2025 Feb 25:101398. doi: 10.1016/j.gim.2025.101398. Online ahead of print.
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.
PMID:40022598 | DOI:10.1016/j.gim.2025.101398
