Genetic Analysis of Isolated Fetal Growth Restriction

Background: Fetal Growth Restriction (FGR) is an important obstetric condition associat-ed with perinatal morbidity and long-term developmental risks. This study aimed to evaluate the genetic etiology of isolated FGR using karyotyping, chromosomal microarray analysis (CMA), and trio-based whole exome sequencing (WES). Methods: A retrospective cohort of 153 fetuses with isolated FGR (diagnosed by ultrasound, from February 2018 to July 2024) underwent karyotyping and CMA. Negative cases (n=50) were further analyzed by trio-WES. Results: Karyotyping identified chromosomal abnormalities in 3 cases (2.0%), while CMA detected pathogenic/likely pathogenic CNVs or UPD in 12 cases (7.8%), in-cluding the 3 with chromosomal abnormalities and 9 cases with normal karyotypes (6.0%), CMA increased diagnostic yield by 5.9%, detecting CNVs/UPD missed by karyo-typing. Trio-WES in 50 cases with normal karyotypes and CMA findings identified 14 pathogenic or likely pathogenic variants in 12 cases (24%), with 7 cases (14%) having var-iants directly related to FGR, including one case of uniparental disomy (UPD) that was missed by CMA. Additionally, WES identified 1 case of FGR caused by maternal hyper-phenylalaninemia and 7 pathogenic variants not directly related to FGR, highlighting the need for comprehensive genetic counseling. These findings underscore the potential of WES to uncover maternal genetic disorders that may impact fetal growth and develop-ment. Conclusions: Integration of CMA and WES into prenatal protocols improved diag-nostic yield in isolated FGR. WES allows the detection of UPD, which can be missed by CMA alone, thus enhancing genetic evaluation of FGR. Moreover, WES has the potential to identify maternal genetic conditions that may affect fetal growth, providing valuable in-sights for genetic counseling and multidisciplinary management.