拷贝数变异测序技术在无创产前筛查高风险且超声表现正常胎儿产前诊断中的价值研究

Value of copy number variation sequencing in the prenatal diagnosis of fetus with high risk in noninvasive prenatal testing and normal ultrasonic performance

目的 探讨拷贝数变异测序技术(CNV-seq)在无创产前筛查(NIPT)高风险且超声表现正常胎儿产前诊断中的临床应用价值。方法 选取2019年8月至2021年9月因单纯NIPT高风险且无超声异常到天津医科大学总医院产前诊断中心自愿接受羊膜腔穿刺术的168例孕妇,采集羊水样本,同时进行染色体核型分析和CNV-seq检测,并对所有病例进行随访。结果 168例羊水样本,羊水细胞培养失败3例,染色体核型分析结果异常62例(37.58%),其中非整倍体异常47例(75.81%)、结构异常9例(14.52%)、嵌合型异常6例(9.68%)。168例羊水样本,CNV-seq检测结果为致病性/可能致病性69例(41.07%)、临床意义不确定性24例(14.29%)、可能良性/良性6例(3.57%)。62例染色体核型分析异常结果中,CNV-seq检测提示致病性变异61例,其中6例染色体核型分析结果为结构异常的病例经CNV-seq检测存在致病性拷贝数变异(CNVs)。CNV-seq检测额外检出8例染色体异常,包括致病性微缺失微重复6例和数目异常2例,将总体染色体异常检出率提高了4.76%。结论 CNV-seq技术在NIPT高风险且超声表现正常胎儿中可以高效、特异地检出常规染色体核型分析无法检出的致病性基因组CNVs,是目前染色体核型分析技术的有效补充,在不增加时间、技术和经济成本的前提下进一步提高产前诊断率,有利于进一步降低活产儿的严重出生缺陷率。

Objective To explore the clinical application value of copy number variation sequencing(CNV-seq)echnology in prenatal diagnosis of fetuses with high risk in non-invasive prenatal testing(NIPT)and normal ultrasound performance.Methods A total of 168 pregnant women with high risk in NIPT and no obvious structural abnormality in fetal ultrasound voluntarily amniocentesis:amniotic fluid samples were collected,CNVs of amniotic fluid cells were detected by CNV-seq technique,and chromosome karyotype analysis was performed. All cases were followed up.Results The culture of amniotic fluid cell in 3 cases failed in a total of 168 samples,and 62(37.58%)abnormal results were detected by karyotype analysis,including 47 cases(75.81%)of aneuploidy abnormality,9 cases(14.52%)of structural abnormality and 6 cases(9.68%)of chimeric abnormality. Among 168 samples,69 cases(41.07%)of pathogenicity and possibly pathogenicity and 24 cases(14.29%)of variant of uncertain significance and 6 cases(3.57%)of benign and possibly benign cases were detected by CNV-seq. Among 62 cases of abnormal karyotype,61 cases of pathogenic variation were detected by CNV-seq,6 cases of which were abnormal in structure with pathogenic CNVs by CNV-seq.CNV-seq additionally detected 8 cases of chromosomal abnormalities,including 6 cases of pathogenic microdeletion and microduplication and 2 cases of chromosome number abnormality,which increased the total detection rate of chromosome abnormality by 4.76%.Conclusions CNV-seq technology in fetus with high-risk NIPT and normal sonographic findings can be efficient and specific to detect the pathogenic genome copy number variation which conventional karyotype analysis can’t detect. CNVseq technology is the effective complement of karyotype analysis technology,which can further improve prenatal diagnostic rate and reduce severe birth defects in live births without increasing the cost in time,technology and economy.