Whole-exome sequencing increases variant detection compared to karyotyping and CMA in an unselected FGR cohort

This study aims to systematically evaluate the diagnostic yields of karyotyping, chromosomal microarray analysis (CMA), and whole-exome sequencing (WES) in an unselected cohort of fetuses with fetal growth restriction (FGR). A total of 129 FGR fetuses were included, of which 64 underwent all three genetic tests, enabling a head-to-head comparison. Among these 64 cases, WES detected genetic variants in 25.0% (16/64), compared to 9.4% (6/64) for CMA and 3.1% (2/64) for karyotyping. Notably, in cases negative by both karyotyping and CMA, WES provided an additional diagnostic yield of 15.6%. Even in isolated FGR, WES identified variants in 23.6% (13/55) of cases. Follow-up data at one year of age revealed that infants born after FGR had an increased risk of postnatal growth retardation (16.1%) and delayed language development (9.7%). This study demonstrates that in a real-world, phenotypically unselected FGR cohort, WES substantially increases variant detection, particularly in cases where conventional testing is negative.