Prenatal Whole-Genome Sequencing for Fetal Anomalies: Diagnostic Performance, Challenges, and Clinical Implications.

Prenatal whole-genome sequencing (WGS) is a comprehensive genetic test for fetal anomalies, enabling simultaneous detection of aneuploidies, copy number variants (CNVs), single-nucleotide variants (SNVs), small insertions/deletions, structural variants, and regions of absence of heterozygosity. However, its clinical performance, optimal sequencing strategies, and implementation challenges remain incompletely defined. We conducted a narrative review of PubMed-indexed studies (1966-December 2025) evaluating prenatal WGS in fetuses with structural anomalies. Across 29 studies, diagnostic yield ranged from approximately 20% to 40%, influenced by phenotype complexity, sequencing depth, and study design. Low-coverage WGS (≤5×) reliably detected large chromosomal abnormalities with a performance comparable to chromosomal microarray analysis. Moderate-coverage WGS (20-40×) additionally enabled detection of SNVs and structural variants, providing up to 30% incremental diagnostic yield after uninformative standard testing. Turnaround times were typically 14-21 days. Higher sequencing depth increases detection of variants of uncertain significance (0.6% to 35.7%) and secondary/incidental findings (1.6-30.8%). Prenatal WGS offers meaningful diagnostic value but requires careful patient selection, multidisciplinary expertise, and structured pre- and post-test genetic counseling to ensure responsible integration into routine clinical practice, with careful consideration of clinical benefit and economic feasibility.