Soster Erica, Tynan John, Gibbons Clare, Meschino Wendy, Wardrop Jenna, Almasri Eyad, Schwartz Stuart, McLennan Graham
Labcorp®, La Jolla, CA, USA.
PetDx, The Center for Novel Therapeutics, La Jolla, CA, USA.
Mol Cytogenet. 2023 Jun 10;16(1):10. doi: 10.1186/s13039-023-00642-4.
Noninvasive prenatal testing (NIPT) allows for screening of fetal aneuploidy and copy number variants (CNVs) from cell-free DNA (cfDNA) in maternal plasma. Professional societies have not yet embraced NIPT for fetal CNVs, citing a need for additional performance data. A clinically available genome-wide cfDNA test screens for fetal aneuploidy and CNVs larger than 7 megabases (Mb).
This study reviews 701 pregnancies with "high risk" indications for fetal aneuploidy which underwent both genome-wide cfDNA and prenatal microarray. For aneuploidies and CNVs considered 'in-scope' for the cfDNA test (CNVs ≥ 7 Mb and select microdeletions), sensitivity and specificity was 93.8% and 97.3% respectively, with positive and negative predictive values of 63.8% and 99.7% as compared to microarray. When including 'out-of-scope' CNVs on array as false negatives, the sensitivity of cfDNA falls to 48.3%. If only pathogenic out-of-scope CNVs are treated as false negatives, the sensitivity is 63.8%. Of the out-of-scope CNVs identified by array smaller than 7 Mb, 50% were classified as variants of uncertain significance (VUS), with an overall VUS rate in the study of 2.29%.
While microarray provides the most robust assessment of fetal CNVs, this study suggests that genome-wide cfDNA can reliably screen for large CNVs in a high-risk cohort. Informed consent and adequate pretest counseling are essential to ensuring patients understand the benefits and limitations of all prenatal testing and screening options.
无创产前检测（NIPT）可用于从孕妇血浆中的游离DNA（cfDNA）筛查胎儿非整倍体和拷贝数变异（CNV）。专业学会尚未将NIPT用于胎儿CNV检测，理由是需要更多性能数据。一种临床可用全基因组cfDNA检测可筛查胎儿非整倍体和大于7兆碱基（Mb）的CNV。
本研究回顾了701例有胎儿非整倍体“高风险”指征的妊娠病例，这些病例均接受了全基因组cfDNA检测和产前微阵列检测。对于cfDNA检测范围内的非整倍体和CNV（CNV≥7 Mb和特定微缺失），与微阵列相比，敏感性和特异性分别为93.8%和97.3%，阳性预测值和阴性预测值分别为63.8%和99.7%。当将阵列上超出范围的CNV作为假阴性纳入时，cfDNA的敏感性降至48.3%。如果仅将致病性超出范围的CNV视为假阴性，则敏感性为63.8%。在阵列检测出的小于7 Mb的超出范围的CNV中，50%被分类为意义未明的变异（VUS），本研究中的总体VUS率为2.29%。
虽然微阵列对胎儿CNV提供了最可靠的评估，但本研究表明，全基因组cfDNA能够在高风险队列中可靠地筛查大的CNV。知情同意和充分的检测前咨询对于确保患者了解所有产前检测和筛查选项的益处和局限性至关重要。
