Evaluating the clinical utility and strategy of whole exome sequencing testing for fetuses with increased nuchal translucency

The routine recommendation for detecting monogenic disease in fetuses with increased nuchal translucency remains controversial. This study aimed to evaluate the clinical significance and optimal strategy of whole-exome sequencing in fetuses with increased nuchal translucency. This retrospective study included pregnancies that underwent amniocentesis due to advanced maternal age, positive screening results, or abnormal ultrasound findings between January 2018 and December 2019. Chromosomal abnormalities were diagnosed using chromosome microarray analysis. Whole-exome sequencing testing was sequentially performed in fetuses with nuchal translucency≥3.5 mm. Newborns were followed up regularly until they reached 48 to 60 months of age. Of the 11,774 pregnancies undergoing amniocentesis, 607 fetuses (5.16%) had nuchal translucency≥3 mm. Chromosomal abnormalities were detected in 23.56% (143/607), including aneuploidy (13.18%, 80/607) and chromosome deletion or duplication or regions of homozygosity (10.38%, 63/607). The diagnostic yield of chromosome microarray analysis for aneuploidies and pathogenic or likely pathogenic chromosome abnormalities was 17.63% (107/607), after excluding 36 cases with variants of uncertain significance. Among the 464 fetuses with nuchal translucency≥3 mm and negative chromosome microarray analysis results, 240 cases had fetal nuchal translucency≥3.5 mm, of which 96 cases underwent whole-exome sequencing testing. Whole-exome sequencing identified diagnostic variants in genes associated with an increased nuchal translucency phenotype in 10.42% (10/96) of cases. These variants involved genes of DEAD-box helicase 3 X-linked (DDX3X), Ras like without CAAX 1 (RIT1), NIPBL cohesin loading factor (NIPBL), ankyrin repeat domain containing 11 (ANKRD11), piezo type mechanosensitive ion channel component 2 (PIEZO2), Neurofibromin 1 (NF1), ASXL transcriptional regulator 1 (ASXL1), coiled-coil domain-containing protein 22 (CCDC22), and tubulin, beta-3 (TUBB3), which are inherited in either an X-linked or autosomal dominant pattern. Adverse outcomes were observed in 80% (8/10) of these cases, including 4 induced abortions, 3 cases of developmental delay, and 1 neonatal death. A total of 86 fetuses (14.17%, 86/607) had additional ultrasound findings. Fetuses with nuchal translucency≥3.5 mm and additional ultrasound findings identified during the second trimester exhibited a significantly higher rate of chromosomal abnormalities compared to those without additional findings (44.62% vs 19.00%, P=.00). Among fetuses with nuchal translucency≥3 mm and negative chromosome microarray analysis or whole-exome sequencing testing results, 90.39% (395/437, after excluding 27 pregnancies lost to follow-up) were healthy during follow-up. The remaining approximately 10% (42 cases) experienced miscarriage, induced abortion, intrauterine fetal death, or developmental delay. Chromosome microarray analysis identified chromosomal abnormalities in 17.63% of fetuses with nuchal translucency≥3 mm. Fetuses with increased nuchal translucency and additional ultrasound findings exhibited a markedly higher rate of chromosomal abnormalities. Whole-exome sequencing provided an additional diagnostic yield of 10.42% for monogenic disorders in fetuses with nuchal translucency≥3.5 mm. Whole-exome sequencing testing, combined with data reanalysis based on subsequent prenatal or postnatal phenotypes, offers an optimal strategy for diagnosing monogenic diseases in fetuses with increased nuchal translucency.