母体性染色体异常对无创产前检测胎儿性染色体非整倍性的影响

Influence of maternal sex chromosomal abnormalities on non-invasive prenatal testing for fetal sex chromosome aneuploidies

目的探讨母体性染色体异常对孕妇外周血胎儿游离DNA(cell-free fetal DNA,cffDNA)无创产前检测(non-invasive prenatal testing,NIPT)筛查胎儿性染色体非整倍性(sex chromosome aneuploidies,SCAs)结果的影响。方法以36例NIPT提示为SCAs高风险、但经羊水诊断证实为假阳性的孕妇为研究对象,对其进行母体外周血染色体核型分析或母体白细胞全基因组高通量低深度测序。结果共发现8例孕妇存在性染色体异常,异常率达22.22%,其中3例为非整倍体异常,4例为性染色体嵌合体,1例为染色体结构异常。NIPT重分析测序结果与母体染色体拷贝数变异(copy number variants,CNVs)检测的结果基本一致。当cffDNA(ChrX)/cffDNA的比值>2时,6/8的孕妇存在母体性染色体异常,胎儿核型为正常;而当其比值<2时,36例孕妇中仅2例存在母体性染色体异常,10例胎儿被证实为SCAs。结论母体性染色体异常会显著干扰NIPT的检测结果,这可能是NIPT检出胎儿SCAs假阳性的重要原因。当NIPT提示胎儿SCAs时,有必要检查母体的性染色体。cffDNA(ChrX)/cffDNA的比值可能有助于判断异常信号的来源。

Objective To study the influence of maternal sex chromosomal abnormalities on the prediction of fetal sex chromosome abnormalities(SCAs)by non-invasive prenatal testing(NIPT).Methods Thirty-six pregnant women with a prediction for fetal SCAs by NIPT were verified as false positive after prenatal diagnosis using amniotic fluid samples.With informed consent,these women were subjected to chromosomal karyotyping or copy number variations(CNVs)analysis through high-throughput sequencing.Results Sex chromosomal abnormalities were found in 8 women,which yielded an abnormal rate of 22.22%(8/36).Among these,3 had sex chromosome aneuploidies(47,XXX),4 had sex chromosome mosaicisms,and 1 carried structural chromosomal abnormalities.Reanalysis of the results of NIPT were consistent with the maternal CNVs by large.With the ratio of cffDNA(ChrX)/cffDNA was>2,6 of the eight women were found to harbor sex chromosome abnormalities,and the fetal karyotype was normal.However,with a ratio of<2,only 2 of the 38 pregnant women had sex chromosome abnormalities,and 10 of the fetuses were confirmed as positive.Conclusion The presence of maternal sex chromosomal abnormalities can greatly influence the result of NIPT,which may also be an important reason for false prediction for fetal SCAs by NIPT.When NIPT indicates abnormal SCAs,it is necessary to analyze maternal sex chromosomes.The ratio of cffDNA(ChrX)/cffDNA may help to determine the source of abnormal signals.