基于二代测序技术的基因组拷贝数变异检测在产前诊断中的应用

Application of copy number variation sequencing for prenatal diagnosis

目的探讨拷贝数变异测序(copy number variation sequencing,CNV-seq)在产前诊断中的应用价值。方法对2018年5月至2020年12月期间采用单核苷酸多态性微阵列(single nucleotide polymorphism array,SNP-array)进行羊水染色体微阵列分析(chromosomal microarray analysis,CMA)的结果进行重分析,对具有临床意义的CNVs以及非整倍体低比例嵌合的样本进行CNV-seq检测。结果对16488例羊水CMA结果进行分析,选取343例存留羊水的DNA样本进行CNV-seq检测,检测成功率为100%。与CMA检测结果相比,完全符合314例(91.5%),部分符合4例(1.2%),漏检25例(7.3%)。对部分符合和漏检的病例的分析提示,CNV-seq的检测盲区为SHOX基因及AZFc区域。结论CNV-seq在产前诊断中具有准确度高、基因组覆盖度好的特点,可稳定检测低比例嵌合,适宜在临床推广,但应充分了解其局限性,针对不同人群选择最适合的产前诊断方法。

Objective To assess the value of next-generation sequencing-based copy number variation sequencing(CNV-seq)for the detection of copy number variations(CNVs)in prenatal diagnosis.Methods The results of single nucleotide polymorphism array(SNP-array)for prenatal diagnosis from May 2018 to December 2020 were reviewed.Selected cases of CNVs of clinical significance or low-percentage mosaic aneuploidies were included.Preserved DNA samples of amniotic fluid DNA were detected by CNV-seq.The results of CNV-seq and CMA were analyzed.Results A total of 16488 data of SNP-array were re-analyzed,and 343 DNA samples were selected for the CNV-seq assay.All samples were successfully analyzed.Compared with the SNP-array,the proportion of full concordance,partial concordance and missed detection was 91.5%(314/343),1.2%(4/343)and 7.3%(25/343),respectively.The non-detection zones of CNV-seq were confirmed,which have encompassed the SHOX gene and AZFc region.Conclusion With a high accuracy and wide genome-wide coverage,CNV-seq is worthy for a wide application in prenatal diagnosis,though the limitation of testing should be taken into consideration,and the appropriate prenatal diagnosis method should be selected for different populations to reduce the occurrence of birth defects.