核型正常产前诊断中染色体微阵列的应用分析

Analysis of application of chromosomal microarray analysis in prenatal diagnosis of normal karyotype

摘要

目的 探讨染色体微阵列(CMA)在核型正常的羊水产前诊断中染色体微缺失或微重复的临床意义。方法 收集2017年1月至2021年6月在汕头大学医学院附属粤北人民医院行羊膜腔介入性产前诊断的877例羊水标本,进行核型及CMA检测,以核型正常的794例羊水标本为研究对象,对CMA检测的异常结果进行分析。结果 在794例核型正常的标本中,CMA检测异常35例,产前诊断指征中,胎儿超声异常13例,占37.14%(13/35);血清学筛查高风险10例,占28.57%(10/35);高龄妊娠6例,占17.14%(6/35);无创产前检测(NIPT)提示异常3例,不良孕产史3例.CMA检测较核型分析额外检出4.41%(35/794)的异常标本;其中,致病性拷贝数变异(CNVs)17例,检出率为2.14%(17/794),临床意义不明CNVs12例,检出率为1.51%(12/794),纯合区域(ROH)异常6例,检出率为0.76%(6/794).在17例致病性CNVs中,检出的CNVs片段范围在147.00kb~4.30Mb,检出5种已知微缺失/微重复综合征,分别为16p11.2微重复综合征、16p13.11微缺失综合征、肾囊肿和糖尿病(RCAD)综合征、22q11.21微重复综合征、DiGeorge综合征.在12例临床意义不明CNVs中,检出的CNVs片段范围在369.00kb~5.70Mb,对7例胎儿的父母进行了外周血CMA验证,其中4例(编号18、编号19、编号23、编号29)遗传自表型正常的母亲,2例(编号22、编号28)遗传自表型正常的父亲,1例(编号20)考虑为新发病例.在6例ROH异常的CNVs中,检出的CNVs片段范围在21.80~83.00Mb,对2例胎儿的父母进行了外周血CMA验证,其中1例(编号32)排除了20号染色体单亲二倍体(UPD)的可能,1例(编号33)仅对母亲进行了CMA验证,其结果显示正常,考虑为父源性。结论 CMA检测可以检出核型分析难以测查的微缺失、微重复、单亲二倍体及杂合性缺失等基因组失衡现象,是产前诊断核型分析的有效补充检测技术.

Abstract

Objective To investigate the clinical significance of chromosomal microdeletion and microduplication detected by chromosomal microarray analysis (CMA) in prenatal diagnosis of amniotic fluid of normal karyotype. Methods A total of 877 amniotic fluid samples were collected from patients who underwent invasive prenatal diagnosis via amniocentesis at Yuebei People's Hospital Affiliated to Shantou University Medical College between January 2017 and June 2021. Karyotype and CMA were performed on these samples. Among them, 794 samples with normal karyotype were selected as the study subjects, and the abnormal results of CMA detection were analyzed. Results A total of 794 specimens underwent karyotyping and CMA testing. Among the 794 specimens with normal karyotypes, CMA testing showed abnormalities in 35 cases. Among the prenatal diagnostic indications, there were 13 cases (37.14%, 13/35) with abnormal fetal ultrasound findings, 10 cases (28.57%, 10/35) identified as high risk by serum screening, 6 cases (17.14%, 6/35) from advanced maternal age pregnancies, 3 cases with abnormal results from non-invasive prenatal testing (NIPT), and 3 cases with a history of adverse pregnancy outcomes. CMA testing detected abnormalities in 4.41% (35/794) of specimens that were not identified by karyotype analysis. Among these, there were 17 pathogenic copy number variations (CNVs), with a detection rate of 2.14% (17/794), 12 CNVs of unclear clinical significance with a detection rate of 1.51% (12/794), and 6 cases of abnormal regions of homozygosity (ROH), with a detection rate of 0.76% (6/794). Among the 17 cases of pathogenic CNVs, the detected CNV segments ranged from 147.00kb to 4.30Mb, five known microdeletion/microduplication syndromes were identified, including the 16p11.2 microduplication syndrome, 16p13.11 microdeletion syndrome, renal cysts and diabetes (RCAD) syndrome, 22q11.21 microduplication syndrome, and DiGeorge syndrome. Among the 12 cases of CNVs with unclear clinical significance, the detected CNV segments ranged from 369.00kb to 5.70Mb, peripheral blood CMA verification was performed on the parents of seven fetuses. Of these, four cases (Case 18, Case 19, Case 23, and Case 29) were inherited from phenotypically normal mothers, two cases (Case 22 and Case 28) were inherited from phenotypically normal fathers, and one case (Case 20) was considered a de novo case. Among the six cases of CNVs with ROH abnormalities, the detected CNV segments ranged from 21.80Mb to 83.00Mb, peripheral blood CMA verification was performed on the parents of two fetuses. In one case (Case 32), the possibility of uniparental disomy (UPD) on chromosome 20 was excluded, and in one case (Case 33), only the mother underwent CMA verification, which returned a normal result, suggesting paternal origin. Conclusion CMA can detect genomic imbalances such as microdeletion, microduplication, uniparental disomy and loss of heterozygosity that are difficult to detect through karyotype, it is an effective supplementary detection technology to karyotype analysis in prenatal diagnosis.

关键词

产前诊断 / 染色体核型 / 染色体微阵列 / 微缺失/微重复

Key words

prenatal diagnosis / chromosomal karyotype / chromosomal microarray analysis / microdeletion/microduplication

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