SNP-array技术在具有不良孕产史的高龄孕妇中的应用

The application of single nucleotide polymorphism microarray technology during advanced maternal age with adverse pregnancy history

目的探讨染色体核型分析与单核苷酸多态性微阵列芯片技术(Single Nucleotide Polymorphism array,SNP-array)在具有不良孕产史的高龄孕妇的遗传学检查应用价值。方法回顾分析366例孕中期(16^+6-21^+6孕周)具有不良孕产史的高龄孕妇,行介入性产前诊断抽羊水标本,并详细收集孕妇临床资料,同时行染色体核型分析与染色体微阵列芯片检测。染色体微阵列分析采Illumina Human Cyto SNP12微阵列芯片进行全基因组拷贝数变异(CopyNumber Variations,CNVs)检测,结合查询国际病理性CNVs数据库(ClinGen、ClinVar、DECIPHER、OMIM)、正常人基因组变异数据库(Database of Genomic Variants,DGV)以及PubMed文献数据库等对检出的CNVs的致病性进行分析。结果366例具有不良孕产史的高龄孕妇的羊水样本中,染色体核型异常检出18例,检出率4.92%(18/366),SNP-array检出39例异常,检出率10.66%(39/366),SNP-array异常率出率高于染色体核型异常检出率,并且差异具有统计学意义(P<0.05)。检出的18例染色体异常核型主要是:5例21-三体综合征;2例18-三体综合征;1例超雌综合征,1例超雄综合征,1例克氏综合征,2例嵌合体,2例衍生染色体,1例染色体增加,1例染色体缺失。对于这些染色体非整倍体、大片段异常,芯片结果与之相符;另外有1例染色体平衡易位,1例染色体倒位,而芯片未见异常。另外23例染色体核型未见异常而芯片异常,主要为:3例致病性,1例疑似致病性,以及19例临床意义未明。结论对具有不良孕产史的高龄孕妇的产前样本,且SNP-array检测有助于发现染色体核型分析无法检出的染色体亚显微结构异常,SNP-array有利于发现更多未知的综合征型疾病,为遗传病诊断及咨询提供相关依据。

Objective:To evaluate the application value of single nucleotide polymorphism microarray technology in advanced maternal age with adverse pregnancy history.Methods:We retrospectively analyzed 366 cases of advanced maternal age with adverse pregnancy history in the second trimester of pregnancy(17-21^+6 weeks),performed interventional prenatal diagnosis and collected amniotic fluid samples,collected clinical data of pregnant women in detail,and performed karyotype analysis and chromosome microarray microarray detection.Illumina Human Cyto SNP12 microarray chips were adopted for chromosome microarray analysis to test the Copy Number Variations(CNVs),and query the international pathological CNVs Database(ClinGen,ClinVar,DECIPHER,OMIM)and the Database of Genomic Variants.DGV)and PubMed literature database were used to analyze the pathogenicity of CNVs detected.Results:Among the amniotic fluid samples of 366 elderly pregnant women with adverse pregnancy history,chromosomal karyotype abnormalities were detected in 18 cases,with a detection rate of 4.92%(18/366),and 39 cases of SNP-array abnormalities were detected,with a detection rate of 10.66%(39/366).The abnormal rate of SNP-array was higher than that of chromosomal karyotype abnormalities,and the difference was statistically significant(P<0.05).The abnormal karyotypes of 18 cases were mainly as follows:5 cases of 21-trisomy syndrome;Two cases of 18-trisomy syndrome;There were 1 case of super female syndrome,1 case of super male syndrome,1 case of Klinefelter syndrome,2 cases of chimera,2 cases of chromosome derivation,1 case of chromosome increase and 1 case of chromosome deletion.For the chromosome aneuploidy and large fragment abnormality,the microarray results were consistent with them.In addition,there was 1 balanced translocation and 1 chromosome inversion,and no abnormality was found in the chip.In addition,there were no abnormalities of chromosome karyotypes in 23 cases,and microarray abnormalities,mainly including 3 cases of pathogenicity,1 case of suspected pathogenicity,and 19 cases of unclear clinical significance.Conclusion:For the samples of advanced maternal age with adverse pregnancy history,SNP-array detection is helpful to detect chromosomal submicroscopic abnormalities that cannot be detected by karyotype analysis.SNP-array may facilitate discovery of new syndromes and provide a basis for genetic counseling and prenatal diagnosis.