核型分析联合其他遗传学检测技术在高龄孕妇产前诊断中的应用

Application of karyotype analysis combined with other genetic testing techniques in prenatal diagnosis of pregnant women at an advanced maternal age

目的探讨核型分析联合单核苷酸多态性微阵列技术(single nucleotide polymorphism array,SNP array)或荧光原位杂交技术(fluorescence in situ hybridization,FISH)或细菌人工染色体微珠标记技术(BACs on Beads,BoBs)在高龄孕妇产前诊断中的应用价值。方法回顾性研究因高龄行产前诊断的930例孕妇,全部行核型分析,联合BoBs检测420例,联合SNP array检测343例,联合FISH检测167例,分析其染色体结果及妊娠结局。结果930例胎儿中,核型异常192例(20.7%),三体综合征中以21-三体居多,性染色体异常中以克氏征居多。在核型联合其他检测中,联合SNP array检测可显著提高胎儿染色体异常检出率,差异有统计学意义(χ^(2)=6.191,P=0.013)。对于染色体嵌合体的诊断,核型联合FISH检测可更精准地确定嵌合类型及比例。孤立性高龄胎儿染色体异常风险相对较低,高龄合并无创高危胎儿染色体异常率最高,在高龄合并超声软指标中,随超声软指标数目增多,染色体异常率随之升高(P=0.001)。高龄孕妇年龄与核型异常、非整倍体尤其21三体的发生率呈正相关(P<0.05)。结论孤立性高龄孕妇胎儿染色体异常风险相对较低,高龄合并无创高危胎儿染色体异常的风险高,随超声软指标数目增多、孕妇年龄增长胎儿染色体异常的风险增加,核型联合FISH检测可更精准地确定嵌合类型及比例,核型分析联合其他检测尤其与SNP array技术可显著提高染色体异常检出率,有利于遗传咨询及再生育指导,是高龄孕妇首选的产前诊断方案。

Objective To investigate the potential of karyotype analysis combined with single nucleotide polymorphism(SNP)array,or fluorescence in situ hybridization(FISH),or bacterial artificial chromosomes(BACs)-on-Beads(BoBs)technology in prenatal diagnosis of pregnant women at an advanced maternal age.Methods A total of 930 pregnant women who received prenatal diagnosis due to an advanced maternal age were retrospectively studied.All of them underwent karyotype analysis,including 420,343 and 167 cases tested by karyotype analysis combined with BoBs,SNP array,and FISH,respectively.Chromosomal results and pregnancy outcomes were analyzed.Results Among 930 fetuses,192 cases(20.7%)had an abnormal karyotype,with the trisomy 21 and Klinefelter syndrome as the predominant trisomy syndrome and sex chromosome abnormality,respectively.Karyotype analysis combined with SNP array significantly enhanced the detection rate of fetal chromosomal abnormalities than that in combination with other tests(χ^(2)=6.191,P=0.013).For the diagnosis of chromosomal chimerism,karyotype combined with FISH could more accurately determine the type and proportion of chimerism.The risk of chromosomal abnormalities in isolated fetuses delivered by pregnant women at an advanced maternal age was relatively low,which was the highest in high-risk fetuses examined by noninvasive prenatal testing with their mothers at an advanced maternal age.In the combination of soft ultrasound markers and advanced maternal age,the rate of chromosomal abnormalities increased with the increasing number of soft ultrasound markers(P=0.001).There was a positive correlation of the age of pregnant women at an advanced maternal age with the incidence of abnormal karyotype,aneuploidy,especially trisomy 21(P<0.05).Conclusion The risk of chromosomal abnormalities in isolated fetuses delivered by pregnant women at an advanced maternal age is relatively low,but it is high in high-risk fetuses examined by noninvasive prenatal testing with their mothers of advanced maternal.The risk of chromosomal abnormalities in fetuses increases with the increased number of soft ultrasound markers and the age of pregnant women.Karyotype analysis combined with FISH can more accurately determine the type and proportion of chimerism,which,combined with other tests,especially SNP array,can significantly improve the detection rate of chromosomal abnormalities.Karyotype analysis is conducive to genetic counseling and fertility guidance,and it is the preferred prenatal diagnosis program for pregnant women at an advanced maternal age.