The performance evaluation of NIPT for fetal chromosome microdeletion/microduplication detection: a retrospective analysis of 68,588 Chinese cases

<b>Background: </b>Chromosomal abnormalities are the main cause of birth defects in newborns. Since the inception of noninvasive prenatal testing (NIPT) technology, it has primarily been applied to the detection of common trisomy (T21, T18, T13). However, the application of NIPT in microdeletion and microduplication detection is still controversial.<b>Methods:</b> This study retrospectively analyzed the data of 68,588 cases that underwent NIPT at Ganzhou Maternal and Child Health Hospital in China. These data were used to evaluate the performance of NIPT in fetal chromosome microdeletion/microduplication detection and to investigate the key factors affecting the NIPT performance.<b>Results:</b> A total of 281 cases (0.41%) had positive NIPT results with copy number variants (CNVs), of which 161 were validated by karyotyping and chromosome microarray analysis (CMA). Among the 161 cases, 92 were confirmed as true positives through karyotyping or CMA, including 61 microdeletion cases and 31 microduplication cases, resulting in a positive predictive value (PPV) of 57.14 %. Improvements in library construction methods increased the fraction of cell-free fetal DNA (cffDNA) from 13.76% to 18.44%, leading to a significant improvement in the detection rate (0.47% vs 0.15%) and PPV (59.86% vs 28.57%) of NIPT for CNVs.<b>Conclusions: </b>This study proved the robust performance of NIPT for fetal chromosome microdeletion/microduplication detection. In addition, the cffDNA fraction is a key factor influencing NIPT, with increased cffDNA fraction improving the performance of NIPT.

**背景：** 染色体异常是新生儿出生缺陷的主要致病原因。自无创产前基因检测（noninvasive prenatal testing, NIPT）技术诞生以来，其主要应用方向为常见三体（T21、T18、T13）的筛查。不过，无创产前基因检测在染色体微缺失与微重复检测中的应用仍颇具争议。
**方法：** 本研究回顾性分析了中国赣州市妇幼保健院68588例行无创产前基因检测的病例数据，用以评估无创产前基因检测在胎儿染色体微缺失/微重复检测中的应用效能，并探究影响其检测效能的关键因素。
**结果：** 共计281例（占比0.41%）无创产前基因检测结果呈拷贝数变异（copy number variants, CNVs）阳性，其中161例经核型分析及染色体微阵列分析（chromosome microarray analysis, CMA）完成验证。在上述161例中，92例经核型分析或染色体微阵列分析证实为真阳性，包含61例染色体微缺失病例与31例染色体微重复病例，阳性预测值（positive predictive value, PPV）达57.14%。文库构建方法的优化使游离胎儿DNA（cell-free fetal DNA, cffDNA）占比从13.76%提升至18.44%，进而使无创产前基因检测对拷贝数变异的检出率（0.47% vs 0.15%）与阳性预测值（59.86% vs 28.57%）均得到显著提升。
**结论：** 本研究证实无创产前基因检测在胎儿染色体微缺失/微重复检测中具备可靠的应用性能。此外，游离胎儿DNA占比是影响无创产前基因检测效能的关键因素，提升其占比可有效改善无创产前基因检测的整体表现。