Diagnostic Yield of Sequencing for Prenatal Diagnosis of Fetal Structural Anomalies: An Updated Systematic Review

The clinical utility of sequencing in prenatal diagnosis is known, but diagnostic yield varies widely depending on clinical indication. Here we update an earlier systematic review reporting the diagnostic yield of prenatal sequencing in structurally abnormal fetuses, with particular focus on factors affecting diagnostic yield. The search strategy outlined in the previous review (2018-2022) was repeated to include reports published between October 2021 and January 2025. Combining these records with those from the earlier review, an overall incremental diagnostic yield of sequencing compared to chromosomal microarray analysis (CMA) was calculated and pooled in a meta-analysis. Subgroup analyses were performed on selected, unselected, and exploratory cohorts, as well as individual phenotypic subgroups. 155 records were reviewed (89 from the current and 66 from the earlier publication). The overall pooled diagnostic yield of sequencing above CMA across all indications was 27% (95% CI 24%-30%, p < 0.0001). Subgroup analysis showed that the diagnostic yield was 40%, 20%, and 17% in selected, unselected, and exploratory subgroups, respectively. Concurrent CNV analysis of sequencing data provided nine additional diagnoses over sequential sequencing after a non-diagnostic CMA. Prenatal sequencing provides an additional yield of 27% following a non-diagnostic CMA across a range of fetal structural anomalies, and this increases to 40% with careful case-selection. Sequencing continues to be a powerful diagnostic tool when performed for well-evidenced indications.