Chromosomal microarray analysis versus noninvasive prenatal testing in fetuses with increased nuchal translucency

Abstract

Objective To evaluate if the NT value of 2.5 mm ≤ NT < 3.0 mm is an appropriate indication for CMA tests among fetuses with isolated increased NT and NIPT is more suitable instead. Methods A total of 442 fetuses with NT ≥ 2.5 mm were included, in which 241 fetuses underwent karyotype. CMA tests were then carried out when cytogenic analysis showed normal chromosomes and CNV status was compared between 2.5 mm ≤ NT < 3.0 mm and ≥3.0 mm subgroups. For the NIPT evaluation, 201 of 442 fetuses with smaller increased NT (2.5 mm ≤ NT < 3.0 mm) was examined by either NIPT or karyotype. Results Of the 241 fetuses with NT ≥ 2.5 mm, 47(19.50%) were identified by karyotype with chromosomal abnormalities. Among 194 cases with normal karyotype, CMA unraveled additional CNVs in 16(8.25%) cases, including 3(1.55%) pathogenic CNVs, 2(1.03%) likely pathogenic CNVs and 11(5.67%) VOUS. After the subgroup analysis, however, only one case (1.16%) of likely pathogenic was identified by CMA among 86 fetuses with NT between 2.5 mm and 3.0 mm, whereas the rest of 15 CNV cases were all presented in fetuses with NT ≥ 3.0 mm. For the NIPT evaluation, the detection rate of 201 fetuses with isolated increased NT between 2.5 and 3.0 mm was 3.98%, which was indifferent to karyotype with the rate of 5%. In comparison with fetuses with 2.5–3.0 mm combined with other risks, the detection rate of karyotype was 26.92%. Conclusion While no pathogenic CNVs were detected in fetuses, chromosomal aneuploidies and genomic imbalance were found to be the major type of abnormalities when NT was 2.5–3.0 mm. Therefore, our data suggested that CMA should not be recommended when fetuses with an NT value less than 3.0 mm. Instead, NIPT with similar rate of detection as karyotype was recommended for fetuses with isolated increased NT between 2.5 and 3.0 mm.

When NIPT meets WES, prenatal diagnosticians face the dilemma: genetic etiological analysis of 2,328 cases of NT thickening and follow-up of pregnancy outcomes

“…The detection rates of aneuploidy and CNVs in fetuses with NT 95th percentile-2.99 mm were high, while the incremental yield of monogenic disorders was 0%. Therefore, we suggest, as most of the literature (Wang et al, 2022;Xie et al, 2022;Yin et al, 2022) To assess the risk of chromosomal abnormalities in fetuses with NT of 3.0-3.49 mm and to determine whether invasive prenatal testing is necessary, our results showed an 11.7% risk of chromosomal abnormalities (including aneuploidy and pCNVs). The study by Petersen et al (2020) performed a meta-analysis of literature cases with NT of 3.0-3.49 mm and a retrospective study of two groups of pregnant women with invasive testing and CMA, which showed 13.5% of 522 fetuses were diagnosed with chromosomal aberrations, similar to the results of our study.…”

“…Moreover, in 259 fetuses with a NT 95th percentile-2.99 mm, CMA detected 13 CNVs that were not detectable by conventional karyotyping, including only three pCNVs (1.16%). In the previous studies, Wang et al (2022) found that chromosomal aneuploidy and genomic imbalance were the primary fetal abnormalities when NT was 2.5-3.0 mm and that for fetuses with increased isolated NT between 2.5 and 3.0 mm, NIPT (3.98%) had a similar rate of karyotype detection (5%) in a study of 201 fetuses with examined by NIPT and karyotype. Xie et al (2022) applied NIPT-Plus to 72 fetuses with increased NT and achieved a sensitivity and specificity of 95.2% and 100% for common chromosomal aneuploidy, respectively.…”

“…Chromosomal microarray analysis can not only detect chromosome aneuploidy but also large fragment deletions or duplications and submicroscopic copy number variant (CNV) abnormalities, showing advantages over conventional karyotyping in prenatal diagnosis. Previous studies have shown different detection rates for pCNVs in euploidy fetuses with increased NT varying from 2% to 15% (Grande et al, 2015;Lund et al, 2015;Pan et al, 2016;Srebniak et al, 2016;Egloff et al, 2018;Su et al, 2019;Zhang et al, 2019;Zhao et al, 2020;Wang et al, 2022). Grande et al (2015) concluded that, compared with karyotyping, the incremental yield of CMA was 4% (95% CI, 2%-7%) in a recent meta-analysis of 17 studies.…”

A rapid PCR-free next-generation sequencing method for comprehensive diagnosis of chromosome disease syndromes in prenatal samples

“…The incidence also exceeds 6% in fetuses with structural abnormalities by ultrasound test but normal chromosome karyotypes. [9][10][11] During early pregnancy screening, invasive amniocentesis or chorionic villus sampling (CVS) is used after biochemical and ultrasound studies show potential abnormal fetal development to obtain prenatal samples for chromosome karyotype analysis and chromosome microarray analysis (CMA), which is the gold standard of prenatal diagnosis. [12,13] Karyotype analysis can detect structural abnormalities such as an abnormal number of chromosomes as well as deletions, duplications, inversions, and translocations larger than 10 Mb (at least 5 Mb).…”

“…The incidence also exceeds 6% in fetuses with structural abnormalities by ultrasound test but normal chromosome karyotypes. [ 9 – 11 ]…”