Genetic Examination for Fetuses with Increased Fetal Nuchal Translucency by Genomic Technology

Abstract

This study aims to investigate the value of chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in fetuses with increased nuchal translucency (defined as NT above the 95th centile for the crown-rump length). A total of 374 singleton pregnancies with gestational ages ranging from 11 to 13 + 6 weeks were investigated. Ultrasound displayed increased NT and no detectable structural malformations in these fetuses. Pregnancies were divided into 4 groups according to the NT values: 95th centile-3.4 mm (114 cases); 3.5-4.4 mm (150 cases); 4.5-5.4 mm (55 cases); and ≥5.5 mm (55 cases). The possible chromosomal anomalies were all analyzed by CMA first. Furthermore, 24 cases with increased NT but negative CMA results were investigated by WES, and the outcomes were followed up. Among all the 374 cases, causative genetic defects were detected in 100/374 (26.7%) of the cases along with 9 variants of unknown significance (VOUS) by CMA. CMA testing yielded 30 pathogenic variants (30/55), accounting for a detection rate of 54.5%, and 1 VOUS in the group of NT ≥5.5 mm, indicating the highest detection rate in the 4 groups. The 24 cases of the CMA negative sub-cohort with WES analysis further yielded 2 VOUS and 3 likely pathogenic variants, including 2 dominant de novo mutations in SOS1 and ECE1 and 1 recessive inherited compound heterozygous mutation in PIGN, which are associated with cardiac defects. All 3 cases opted for termination of pregnancy (TOP). In addition, 2 cases with increased NT were negative by both CMA and WES analysis, and fetal demise occurred. In conclusion, for the investigation of fetuses with increased NT exome sequencing is suggested to be considered in cases with negative CMA findings. However, appropriate genetic counseling should be given to optimizing its utilization in prenatal diagnosis.

Diagnostic yield of next‐generation sequencing in fetuses with isolated increased nuchal translucency: systematic review and meta‐analysis

“…During the iterative review, 90 series of structurally abnormal fetuses that included fetuses with increased NT were identified (Figure 1). Among the 101 abstracts identified, 17 full-text articles were reviewed and 10 were deemed eligible and included in the study [17][18][19][20][21][22][23][24][25][26] . In addition, our own series, which was presented previously as an abstract at an international conference, was included 27 .…”

“…Among the 11 studies, three included only cases of increased NT (of which two included isolated increased NT only 23,24 and one included both isolated cases and cases with an associated abnormality 22 ), one study included a fetus with signs of hydrops 25 , while the remaining seven studies included fetuses with various structural anomalies (Table 1). Only cases with isolated increased NT at the time of genetic testing were selected for this systematic review and meta-analysis.…”

Isolated Increased Nuchal Translucency in First Trimester Ultrasound Scan: Diagnostic Yield of Prenatal Microarray and Outcome of Pregnancy

“…The first studies on prenatal WES suggested a 10-25% increase in diagnostic yield in fetuses with various sonographic abnormalities (42)(43)(44). Approximately six studies on prenatal WES have included fetuses with an isolated increased NT and normal microarray results (16,42,(45)(46)(47)(48). The diagnostic yield of prenatal WES in these studies varies from 0 to 13% with an average of 5%.…”

“…Many studies have reported data on the use of prenatal microarray in fetuses with (isolated) increased NT, with the first report starting as early as 2003 (13) and approximately five English studies in the years 2020 and 2021 (14)(15)(16)(17)(18). These studies show a relatively wide range (0-20%) of additional genetic findings in fetuses with increased NT with regard to prenatal microarray when compared to standard karyotyping.…”

Increased nuchal translucency after low‐risk noninvasive prenatal testing: What should we tell prospective parents?

“…Since then, larger cohorts of fetuses with isolated and non‐isolated increased NT have been studied with sequencing after normal microarray (Table 5). 42–48 Yang et al. performed trio exome sequencing on 73 fetuses with isolated first trimester increased NT ≥3.5 mm and normal CMA 45 .…”