Detection of chromosomal and gene abnormality with karyotyping, chromosomal microarray analysis and trio-based whole exome sequencing in pregnancies with fetal growth restriction: implications for precise prenatal diagnosis

Abstract Background Although extensively investigated, the genetic etiology of fetal growth restriction (FGR) has not been fully understood. Previous studies have shown the potential of karyotyping, chromosomal microarray analysis (CMA) and trio-based WES (trio-WES) in prenatal diagnosis, however, there is little knowledge on the comparative effectiveness of these three prenatal genetic tools. The present study aimed to evaluate and compare the effectiveness of karyotyping, CMA and trio-WES for prenatal diagnosis and prognostic evaluation of FGR, in order to identify the optimal genetic diagnostic testing of FGR. Methods All clinical data were retrospectively collected from 388 pregnant women that received invasive prenatal diagnosis due to FGR in Wenzhou Central Hospital and Fujian Maternity and Child Health Hospital during the period from April 2015 to August 2024. All fetuses received karyotyping and CMA, and additional trio-WES was performed among 26 pregnancies negative for karyotyping and CMA. The effectiveness of karyotyping, CMA, and trio-WES alone and in combinations was evaluated for diagnosis of chromosomal abnormality in pregnancies with FGR, and the pregnancy outcomes were followed up. Results Karyotyping detected a 4.38% (17/388) chromosomal abnormality rate and CMA detected a 13.4% (52/388) chromosomal abnormality rate, which resulted in a 9.28% (36/388)incremental yield above karyotyping. The diagnostic yield of Karyotyping combined with CMA was 13.66% (53/388). The common microdeletion and microduplication syndromes included 4p16.3.3 microdeletion syndrome, 1q21.2 microduplication syndrome, 16p13.3 microdeletion syndrome and 22q11.21 microduplication syndrome. Trio-WES revealed a high detection rate (30.77%,8/26) for diagnosis of P/LP variants, and the growth- and development-related genes included IGF1R, GNAS, COL9A3, FGD1, FLNB, PORCN, EVC, OTX2 and GH1. Of all pregnancies with FGR, the proportions of live births, induced labors, natural abortion, perinatal mortality, and percentage of loss to follow-up were 70.62% (274/388), 19.84% (77/388), 0.52% (2/388), 1.80% (7/388) and 7.22% (28/388), respectively. Conclusions Karyotyping combined with CMA remains the first-tier tool for prenatal genetic diagnosis of pregnancies with FGR, and additional trio-WES may increase the detection of chromosomal abnormality. IGF1R, GNAS, COL9A3 and FGD1 may be candidate genes causing FGR.