染色体微阵列分析技术在产前致病性拷贝数变异诊断中的应用

The Application of Chromosome Microarray Analysis in Prenatal Diagnosis of Pathogenic Copy Number Variation

目的:探讨染色体微阵列分析(CMA)技术在产前致病性拷贝数变异(CNV)诊断中的应用价值。方法:收集2017年3月至2020年4月在重庆市妇幼保健院行羊膜腔穿刺术且要求行CMA检测的单胎妊娠孕妇共4430例。根据羊水穿刺的临床指征分为6组:A组:单一高龄组;B组:单一唐氏筛查高风险组;C组:单一超声检查异常组;D组:单一无创产前检测(NIPT)高风险组;E组:超声检查异常合并高龄/唐氏筛查高风险/NIPT高风险两个或两个以上指征,F组:NIPT高风险合并高龄/唐氏筛查高风险/超声异常两个或两个以上指征;G组:其他组。结果:(1)4430例中CMA检测胎儿异常率11.74%,其中非整倍体异常119例(2.69%),CNVs 381例(8.60%),包含致病性拷贝数变异(pCNVs)77例。(2)不同临床指征的羊水CMA检测结果提示,单一临床指征中D组染色体异常总检出率(33.20%),CNVs检出率(19.31%),非整倍体率(10.89%),包括性染色体非整倍体率(6.93%)均显著高于其他各组(P<0.05)。C组的总检出率仅次于D组。E、F组总检出率(19.76%,55.00%),包括非整倍体率(11.01%,42.50%)均显著高于C、D组(P<0.05)。(3)77例pCNVs中,31例为染色体大片段缺失和(或)重复,其中8例遗传自平衡易位的父母。46例染色体微缺失/微重复综合征,包括23例染色体微缺失/微重复性pCNVs和23例神经发育障碍的易感性CNVs。结论:CMA检测是产前遗传学诊断的有效方法之一。NIPT和超声检查是筛查羊水染色体异常的有效手段,针对不同种类的胎儿pCNVs,应合理建议核型分析或家系CMA验证的方法确定pCNVs来源和致病性,再结合超声检查、胎儿CMA结果以及双亲表型,为妊娠提供合理的指导意见,并对出生后的胎儿定期做随访,为产前胎儿评估积累更多的经验。

Objective:To explore the application of chromosome microarray analysis(CMA)in prenatal diagnosis of pathogenic copy number variation(CNV).Methods:4430 singleton pregnanct women who underwent amniocentesis and required CMA testing during mid-trimesters in Chongqing maternal and child health hospital from March 2017 to April 2020 were collected According to the clinical indications of amniocentesis,they were divided into 7 groups:A was isolated advanced age group,B was isolated Down′s syndrome screening high-risk group,C was isolated ultrasonic abnormal group,D was isolated non-invasive prenatal test(NIPT)high-risk group,E was two or more indications of abnormal ultrasound combined with advanced age/high risk of Down′s syndrome screening/high risk of NIPT,F was NIPT high-risk combined with advanced age/Down′s syndrome screening high-risk/ultrasonic abnormal with two or more indications.Results:(1)The abnormal rate of fetus detected by CMA was 11.74%in 4430 cases,including 119 cases of aneuploidy(2.69%),381 cases of CNVs(8.60%)with 77 cases of pathogenic copy number variation(pCNVs).(2)The results of amniotic fluid CMA with different clinical indications showedthat the occurrence of the total chromosome abnormalities(33.20%),CNVs(19.31%),and aneuploidy(10.89%)including the sex chromosome aneuploidy(6.93%)was the highest in D group compared with other groups(P<0.05).The total detection rate of group C was second only to group D The total detection rates of E and F group(19.76%,55.00%),including aneuploidy(11.01%,42.50%)were higher than those in group C and D(P<0.05).(3)Among the 77 cases of pCNVs,31 cases were diagnosed as large chromosomal fragments deletions and/or duplications,of which included 8 cases inherited from their parents who were confirmed with chromosomal balanced translocation.23 cases of pathogenic CNVs and 23 susceptible CNVs with neurodevelopmental disorders were detected in 46 cases of chromosomal microdeletion/microduplication syndromes.Conclusions:CMA detection is one of the effective methods for prenatal genetic diagnosis.NIPT and ultrasound examination are effective screening method for chromosomal abnormalities in amniotic fluid.The method of karyotype analysis or family CMA should be reasonably recommended for different kinds of fetal pCNVs,to determine the source and pathogenicity of the pCNVs,and then combined with ultrasound examination,fetal CMA results and parental phenotype to provide reasonable guidance for pregnancy,and follow up the fetus after birth regularly to accumulate more experience for prenatal fetal evaluation.