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Clinical utility of rapid whole-genome sequencing for prenatal diagnosis of fetal structural anomalies: a prospective multicenter cohort study in China

Year: 2026

Type: article

Abstract: Fetal structural anomalies occur in up to 2–3% of pregnancies and are a leading indication for prenatal genetic testing. In this setting, clinical utility depends critically on turnaround time (TAT) because management decisions must be made within a narrow gestational window. Although previous prenatal genome sequencing studies have focused largely on diagnostic yield and analytic validation, evidence on real-world implementation and effects on management remains limited. This prospective multicenter study evaluated the clinical utility, TAT, and management impact of rapid whole-genome sequencing (rWGS) in prenatal diagnosis. Among 176 fetuses evaluated across seven centers in China, trio rWGS was implemented as a first-tier diagnostic platform, yielding a cumulative molecular diagnostic rate of 29.0% (51/176), including chromosomal aneuploidies, copy-number variants (CNVs), structural variants (SVs), monogenic single-nucleotide variants, and insertions/deletions (SNVs/indels). Median TAT was 10 days (range, 7–12), significantly faster than prenatal exome sequencing (median, 17 days; n = 94; P < 0.001). rWGS results informed perinatal management in 139 cases (79.0%), including pregnancy decisions, actionable postnatal management implications from positive findings, and the reassurance that negative results may provide. Notably, pregnancy was continued in 52 of 104 families with negative results; ten newborns subsequently underwent successful surgical correction. Among 39 third-trimester cases with late-manifesting or progressive phenotypes—28 (71.8%) with entirely normal midtrimester ultrasound findings and 11 (28.2%) with subtle early findings that progressed—rWGS achieved a diagnostic yield of 28.2%, comparable to the 29.0% yield in the overall cohort. In this multicenter setting, rWGS provided timely, comprehensive genomic diagnoses and captured evolving, late-manifesting fetal phenotypes. These findings highlight the dynamic nature of fetal genetic disorders and support serial surveillance rather than reliance on a single ultrasound examination. Supported by a 10-day TAT and clinically informative positive and negative results, rWGS facilitates timely decision-making, perinatal management, and reproductive planning.

Source: Human Genomics

DOI: 10.1186/s40246-026-01065-z