Comprehensive prenatal diagnostics: Exome versus genome sequencing

Objective This study aimed to assess the diagnostic yield of prenatal genetic testing using trio whole exome sequencing (WES) and trio whole genome sequencing (WGS) in pregnancies with fetal anomalies by comparing the results with conventional chromosomal microarray (CMA) analysis. Methods A total of 40 pregnancies with fetal anomalies or increased nuchal translucency (NT ≥ 5 mm) were included between the 12th and 21st week of gestation. Trio WES/WGS and CMA were performed in all cases. Results The trio WES/WGS analysis increased the diagnostic yield by 25% in cases with negative CMA results. Furthermore, all six chromosomal aberrations identified by CMA were independently detected by WES/WGS analysis. In total, 16 out of 40 cases obtained a genetic sequence variant, copy number variant, or aneuploidy explaining the phenotype, resulting in an overall WES/WGS diagnostic yield of 40%. WES analysis provided a more reliable identification of mosaic sequence variants than WGS because of its higher sequencing depth. Conclusions Prenatal WES/WGS proved to be powerful diagnostic tools for fetal anomalies, surpassing the diagnostic yield of CMA. They have the potential to serve as standalone methods for prenatal diagnosis. The study highlighted the limitations of WGS in accurately detecting mosaic variants, which is particularly relevant when analyzing chorionic villus samples. Key points What's already known about this topic? Whole exome or genome sequencing (WES/WGS) increases the diagnostic yield compared to chromosomal microarray (CMA) alone. Confined placental mosaicism (CPM) is observed at the sequence level, which may provide ambiguous results in CVS WES/WGS analysis. What does this study add? WES/WGS can be a stand‐alone prenatal test detecting both sequence variants and CNVs as well as chromosomal aneuploidies. WES outperforms WGS in identifying mosaic sequence variants prenatally with high accuracy due to higher sequencing depth. The study highlights the limitations of WGS in detecting mosaic variants compared with WES.