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。无创产前检测（noninvasive prenatal testing, NIPT）技术问世以来，主要用于常见三体综合征（T21、T18、T13）的筛查。不过，该技术在染色体微缺失/微重复检测中的应用仍存在争议。方法：本研究回顾性分析了中国赣州市妇幼保健院68588例行无创产前检测的病例数据，旨在评估NIPT在胎儿染色体微缺失/微重复检测中的效能，并探究影响NIPT检测效能的关键因素。结果：本研究中共计281例（0.41%）NIPT结果呈拷贝数变异（copy number variants, CNVs）阳性，其中161例通过核型分析与染色体微阵列分析（chromosome microarray analysis, CMA）得到验证。在这161例中，92例经核型分析或CMA确诊为真阳性，包括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）为57.14%。随着文库构建方法的优化，胎儿游离DNA（cell-free fetal DNA, cffDNA）占比从13.76%提升至18.44%，NIPT针对CNVs的检出率（0.47% vs 0.15%）与PPV（59.86% vs 28.57%）均得到显著改善。结论：本研究证实了NIPT在胎儿染色体微缺失/微重复检测中具有可靠的检测效能。此外，胎儿游离DNA占比是影响NIPT检测效能的关键因素，提升该占比可有效改善NIPT的检测性能。