Incremental yield of exome sequencing over standard prenatal testing in structurally normal fetuses: systematic review and meta-analysis

Objective
To critically review the literature and synthesize evidence on the incremental yield of prenatal exome sequencing (PES) in fetuses with an apparently normal phenotype with a normal G-banded karyotype or chromosomal microarray (CMA).

Methods
This systematic review and meta-analysis was conducted using a predetermined protocol and registered with PROSPERO (ID: CRD42024593349). We included observational cohort studies reporting on the incremental yield of PES in fetuses with an apparently normal phenotype and a previously normal G-banded karyotype/CMA. The risk of bias of the included studies was assessed using the Newcastle–Ottawa Scale. The pooled proportion of events was calculated using generalized linear mixed models, using the metaprop function in R version 2.15.1.

Results
Four studies (1916 fetuses) were included in this systematic review and meta-analysis, of which 32 cases had a pathogenic or likely pathogenic variant. The pooled incremental yield of PES in fetuses with an apparently normal phenotype was 1.6% (95% CI, 1.0–2.6%); the majority of variants were de novo within genes associated with autosomal dominant inherited conditions (pooled incremental yield, 0.9% (95% CI, 0.5–1.7%)). Based on the expected severity of the associated disease, the pooled incremental yield was 0.5% (95% CI, 0.1–1.5%) for severe disease and 0.5% (95% CI, 0.2–1.5%) for moderate disease. There were insufficient data to conduct the predefined secondary analyses according to normality of phenotype at birth, variants of uncertain significance and expected age of disease onset.

Conclusion
Pooling data from four studies, we found that 1.6% of phenotypically normal fetuses with a normal G-banded karyotype or CMA may have a pathogenic or likely pathogenic variant identified on PES, most of which occur de novo. The likelihood of a variant being associated with severe disease in such fetuses is 0.5%. However, more research is needed regarding the development of a universal classification of disease severity and the utilization of this evidence in clinical practice.