高通量测序技术在低龄孕妇胎儿染色体非整倍体疾病无创产前检测中的应用研究 [中文引用][英文引用]

目的 探讨传统血清学筛查、超声筛查及HTS检测应用于染色体非整倍体产前检测的检测效率，评价HTS及联合筛查对胎儿染色体非整倍体疾病检测的灵敏度和特异度及临床可行性。方法 收集2013年1月1日至2013年12月31日进行HTS检测的低龄孕妇资料1612例。本研究以核型分析为金标准，血清学筛查高风险、超声筛查异常或HTS检测阳性者在知情同意基础上进行核型分析。其余病例随访至胎儿出生后。结果 血清学筛查、超声筛查、HTS对低龄孕妇胎儿染色体非整倍体疾病检测的灵敏度分别为65%（13/20）、24%（6/25）、92%（23/25），特异度分别为42.52%（608/1430）、91.50%（1442/1576）、99.56%（1569/1576），阳性预测值分别为1.56%（13/835）、4.29%（6/140）、76.67%（23/30）。超声联合血清学筛查、超声联合HTS的检测灵敏度分别为68%（17/25）、96%（24/25），特异度分别为40.55%（647/1576）、91.24%（1438/1576），阳性预测值分别为1.78%（17/954）、14.81%（24/162）。结论 HTS检测T21、T18的灵敏度高、假阳性率低，而且HTS可以检测13、X、Y染色体非整倍体等目前血清学筛查无法检测的染色体疾病，因此HTS检测应用于胎儿染色体非整倍体的产前筛查具有临床可行性；与血清学筛查、超声筛查相比，HTS检测效率较高，且无孕周限制，可避免因较高假阳性而造成的不必要的侵入性产前诊断；相比于超声联合血清学筛查，超声联合HTS具有更高的灵敏度、更低的假阳性率，可以缓解产前诊断工作的压力。

Objective To discuss the detection efficiency of traditional serological screening, ultrasound screening and HTS in the prenatal testing of chromosome aneuploidy. Meanwhile, sensitivity, specificity and clinical feasibility of HTS and combined screening for fetal chromosomal aneuploid are evaluated. Method The subject collect information of 1612 cases who have HTS testing during 2013.01.01 and 2013.12.31. In this study, the gold standard is karyotype analysis. On the basis of informed consent, karyotype analysis was taken in pregnant women who had abnormal serological screening result, abnormal ultrasound screening or HTS positive. The remaining cases were followed up until after birth. Results For the prenatal detection of fetal chromosomal aneuploidy in younger pregnant women, sensitivities of serological screening, ultrasound scanning and HTS respectively was 65% (13/20), 24% (6/25) and 92% (23/25); specificities respectively was 42.52%（608/1430）, 91.50% (1442/1576) and 99.56%（1569/1576）; meanwhile, positive predictive values respectively was 1.56% (13/835), 4.29% (6/140) and 76.67% (23/30). Sensitivities of ultrasound combined with serological screening and ultrasound combined with HTS separately was 68% (17/25), 96% (24/25); specificities separately was 40.55% (647/1576), 91.24% (1438/1576); and positive predictive values separately was 1.78% (17/954), 14.81% (24/162). Conclusions The sensitivity of HTS for T21,T18 is higher, while false positive rate is lower; meanwhile, HTS can detect 13, X, Y chromosome aneuploidy which currently serological screening cannot detect. Therefore, HTS used in the prenatal screening of fetal chromosomal aneuploidy is clinically feasible. Compared with serological screening and ultrasound screening, HTS has higher detection efficiency, with no gestational age and age limit; it can avoid unnecessary invasive prenatal diagnosis caused by high false positive. Meanwhile, compared with ultrasound combined with serological screening, the sensitivity of ultrasound combined with HTS is higher, while false positive rate is lower, which can relieve the pressure of prenatal diagnosis.