拷贝数变异的遗传起源分析在无创产前检测中的应用

Application of Genetic Origin Analysis of Copy Number Variations in Non-Invasive Prenatal Testing.

作者信息

Wang Jing, Zhu Qing-Wen, Cui Ai-Ming, Lin Meng-Si, Lou Hai-Qin

机构信息

Prenatal Diagnosis Center, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, China.

Department of Obstetrics, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, China.

出版信息

Prenat Diagn. 2025 Jan;45(1):44-56. doi: 10.1002/pd.6688. Epub 2024 Oct 19.

DOI:10.1002/pd.6688

PMID:39425690

Abstract

OBJECTIVE

This study aimed to assess the application of origin analysis of copy number variations (CNVs) in non-invasive prenatal testing (NIPT) and provide a basis for expanding the clinical application of NIPT.

METHOD

We enrolled 35,317 patients who underwent NIPT between January 2019 and March 2023. Genome sequencing of copy number variation (CNV-Seq) analysis was performed using the CNV calling pipeline to identify subchromosomal abnormalities in maternal plasma. Genetic origin was determined by comparing the chimaerism ratio of CNV and the concentration of cell-free foetal DNA (cffDNA). All pregnant women with a high risk of CNV, as indicated by the NIPT, were informed of their genetic origins. Amniocentesis was recommended for detecting the CNVs in foetal chromosomes, and pregnancy outcomes were tracked.

RESULTS

A total of 109 pregnancies showed clinically significant positive results for CNV after NIPT, including 65 cases of maternal/foetal (M/F)-CNVs and 44 cases of F-CNVs. The occurrence of M/F-CNVs was independent of age, screening (serological or ultrasound) indications for abnormalities, and mode of pregnancy. The incidence of pathogenic/likely pathogenic (P/LP)-F-CNVs was high in cases where serological screening indicated intermediate, high-risk, or abnormal US findings (p < 0.05). In the M/F-CNV group, most of the P/LP-CNVs were small fragments with low penetrance; 55 (84.62%) were less than 5 Mb in size, and nine (13.85%) were between 5 and 10 Mb. In the F-CNV group, foetal P/LP-CNV was detected in 36 of 42 cases undergoing prenatal diagnosis, and no significant bias was noted in the size distribution of P/LP-F-CNV fragments. The prenatal diagnostic rate and positive predictive value in the F-CNV group were 95.45% and 85.71%, respectively, which were significantly different from those in the M/F group (26.15% and 52.95%), respectively (p < 0.05).

CONCLUSIONS

Genetic origin analysis of CNV can effectively improve adherence to prenatal diagnosis in pregnant women and the accuracy of prenatal diagnosis.

摘要

目的

本研究旨在评估拷贝数变异（CNV）起源分析在无创产前检测（NIPT）中的应用，为扩大NIPT的临床应用提供依据。

方法

我们纳入了2019年1月至2023年3月期间接受NIPT的35317例患者。使用CNV检测流程对拷贝数变异（CNV-Seq）进行基因组测序分析，以识别母血中的亚染色体异常。通过比较CNV的嵌合率和游离胎儿DNA（cffDNA）的浓度来确定遗传起源。所有NIPT提示CNV高风险的孕妇均被告知其遗传起源。建议进行羊膜腔穿刺术检测胎儿染色体中的CNV，并跟踪妊娠结局。

结果

共有109例妊娠在NIPT后显示CNV临床显著阳性结果，包括65例母胎（M/F）-CNV和44例胎儿（F）-CNV。M/F-CNV的发生与年龄、筛查（血清学或超声）异常指征及妊娠方式无关。血清学筛查显示中度、高风险或超声检查结果异常的病例中，致病性/可能致病性（P/LP）-F-CNV的发生率较高（p<0.05）。在M/F-CNV组中，大多数P/LP-CNV是低外显率的小片段；55个（84.62%）大小小于5 Mb，9个（13.85%）在5至10 Mb之间。在F-CNV组中，42例接受产前诊断的病例中有36例检测到胎儿P/LP-CNV，P/LP-F-CNV片段的大小分布无明显偏差。F-CNV组的产前诊断率和阳性预测值分别为95.45%和85.71%，与M/F组（分别为26.15%和52.95%）有显著差异（p<0.05）。