Yield of Whole Genome Sequencing for Pathogenic Single Nucleotide Variants in Congenital Heart Disease: A Systematic Review and Meta-Analysis.

Abstract

Objective: This systematic review and meta-analysis aimed to assess the diagnostic yield of pathogenic or likely pathogenic (P/LP) single nucleotide variants (SNVs) using whole genome sequencing (WGS) in congenital heart disease (CHD).

Methods: A systematic search of three databases (2000-2024) was conducted, and two reviewers independently screened studies and extracted data following PRISMA and MOOSE guidelines. Pooled proportions were calculated using a random-effects model, and study quality was assessed using modified STARD criteria.

Results: Fourteen studies were included, comprising 933 CHD cases, of which 165 had P/LP SNVs. The overall diagnostic yield of WGS for P/LP SNVs was 17.83%, with a yield of 9.83% in isolated CHD cases (without other abnormalities) and 22.36% in syndromic cases (with extracardiac anomalies, developmental abnormalities, or distinctive features). Among 105 cases from four studies with negative chromosomal microarray (CMA) results, 20 had subsequently positive findings by WGS, yielding a 20% incremental diagnostic benefit of WGS over CMA.

Conclusions: These findings highlight the utility of WGS in identifying clinically relevant SNVs in CHD and suggest that WGS should be considered in the diagnostic workup of CHD, particularly in syndromic cases, to guide personalized management and multidisciplinary care.

Prospero registration: CRD42025634370.