Prenatal Chromosomal Microarray Analysis and Whole-Exome Sequencing in Fetuses with Thickened Nuchal Translucency

Abstract

Background: Fetal chromosomal abnormalities predispose the fetus to developmental malformations, which can reduce the quality of newborn births. This study aimed to investigate the clinical utility of chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in fetuses with thickened nuchal translucency (NT). Methods: A total of 62 singleton pregnant women were enrolled in this study. Ultrasonography showed increased fetal NT (≥3.0 mm) with or without structural malformations. The subjects were divided into four groups based on the NT value: 3.0–3.4 mm (33 cases), 3.5–4.4 mm (21 cases), 4.5–5.4 mm (3 cases), and 5.5 mm (5 cases). Chromosomal abnormalities were initially analyzed using CMA, followed by trio familial whole-exome sequencing (Trio-WES) in 15 subjects with CMA-negative results. All the subjects were monitored for pregnancy outcomes. Results: Out of 62 cases, CMA identified 12 cases of aneuploidy, 1 case of pathogenic copy number variation (CNV-P), and 5 cases of unknown copy number variation (CNV-VOUS). The detection rate of fetal chromosomal abnormality was 21.0% (13/62). Fifteen CMA-negative fetuses without structural deformities were analyzed by Trio-WES, which produced six VOUS results with two loci each in SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1) and collagen type II alpha 1 chain (COL2A1) and one locus each in leucine-zipper-like transcription regulator 1 (LZTR1) and B-Raf proto-oncogene, serine/threonine kinase (BRAF). Conclusions: This study supports the application of CMA in prenatal diagnosis. It suggests that the positive detection rate of WES may be low in CMA-negative cases with increased NT without structural malformation. Therefore, appropriate genetic counseling should be provided to optimize the use of CMA and WES in prenatal diagnosis.