Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta‐analysis

OBJECTIVES: We conducted a systematic review and meta‐analysis to determine the diagnostic yield of exome sequencing (ES) for prenatal diagnosis of fetal structural anomalies, where karyotype/chromosomal microarray (CMA) is normal. METHODS: Following electronic searches of four databases, we included studies with ≥10 structurally abnormal fetuses undergoing ES or whole genome sequencing. The incremental diagnostic yield of ES over CMA/karyotype was calculated and pooled in a meta‐analysis. Sub‐group analyses investigated effects of case selection and fetal phenotype on diagnostic yield. RESULTS: We identified 72 reports from 66 studies, representing 4350 fetuses. The pooled incremental yield of ES was 31% (95% confidence interval (CI) 26%–36%, p < 0.0001). Diagnostic yield was significantly higher for cases pre‐selected for likelihood of monogenic aetiology compared to unselected cases (42% vs. 15%, p < 0.0001). Diagnostic yield differed significantly between phenotypic sub‐groups, ranging from 53% (95% CI 42%–63%, p < 0.0001) for isolated skeletal abnormalities, to 2% (95% CI 0%–5%, p = 0.04) for isolated increased nuchal translucency. CONCLUSION: Prenatal ES provides a diagnosis in an additional 31% of structurally abnormal fetuses when CMA/karyotype is non‐diagnostic. The expected diagnostic yield depends on the body system(s) affected and can be optimised by pre‐selection of cases following multi‐disciplinary review to determine that a monogenic cause is likely.