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

Xueqi Ji; Qiongmei Li; Yiming Qi; Xingwang Wang; Hongke Ding; Jian Lu; Yan Zhang; Aihua Yin

doi:10.3389/fgene.2023.1227724

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

Front Genet. 2023 Aug 2:14:1227724. doi: 10.3389/fgene.2023.1227724. eCollection 2023.

Authors

Xueqi Ji^{1

2}, Qiongmei Li^{1

2}, Yiming Qi^{1

2

3}, Xingwang Wang^{1

2

3}, Hongke Ding^{1

2

3}, Jian Lu^{1

2

3}, Yan Zhang^{1

2

3}, Aihua Yin^{1

2

3}

Affiliations

¹ Guangzhou Medical University, Guangzhou, Guangdong, China.
² Prenatal Diagnosis Centre, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China.
³ Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China.

Abstract

Objective: To assess the performance of diverse prenatal diagnostic approaches for nuchal translucency (NT) thickening and to investigate the optimal prenatal screening or diagnostic action with a NT thickening of 95th percentile-3.50 mm. Methods: A retrospective analysis of 2,328 pregnancies with NT ≥ 95th percentile through ultrasound-guided transabdominal chorionic villus sampling (CVS), amniocentesis, or cordocentesis obtained clinical samples (chorionic villi, amniotic fluid, and cord blood), and real-time quantitative fluorescent PCR (QF-PCR), chromosome karyotyping (CS), chromosome microarray analysis (CMA), or whole exome sequencing (WES) were provided to identify genetic etiologies. Results: In this study, the incidence of chromosomal defects increased with NT thickness. When NT ≥ 6.5 mm, 71.43% were attributed to genetic abnormalities. The 994 gravidas with fetal NT thickening underwent short tandem repeat (STR), CS, and CMA. In 804 fetuses with normal karyotypes, CMA detected 16 (1.99%) extra pathogenic or likely pathogenic copy number variations (CNVs). The incremental yield of CMA was only 1.16% (3/229) and 3.37% (10/297) in the group with NT 95th percentile-2.99 mm and NT 3.0-3.49 mm, separately. Among the 525 gravidas with fetal NT thickening who underwent STR, CMA, and WES, the incremental yield of WES was 4.09% (21/513). In the group of NT 95th percentile-2.99 mm, there were no additional single-nucleotide variations (SNVs) detected in WES, while in 143 cases with NT of 3.0-3.49 mm, the incremental yield of WES was 5.59% (8/143). Conclusion: In the group of NT 95th percentile-3.0 mm, since chromosomal aneuploidy and chromosomal copy number variation were the primary causes and the additional contribution of CMA and WES was not significant, we recommend NIPT-Plus for pregnant women with a NT thickening of 95th percentile-3.0 mm first. In addition, comprehensive prenatal genetic testing involving CMA and WES can benefit pregnancies with NT thickening of 3.0-3.49 mm.

Keywords: CMA; NIPT; NT thickening; WES; prenatal diagnosis.

Grants and funding

The study was financially supported by the National Nature Science Foundation of China (grant 81771598 to AY), the Guangzhou Science and Technology Planning Project (grant 202103000047), Guangdong Medical Research Foundation (A2021094) and the Guangdong Medical Research Foundation (B2022082).