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目的探讨染色体微阵列分析(CMA)在高危妊娠产前诊断中的应用,观察其中临床意义不明的染色体拷贝数变异(VOUS)结果构成及相关特性,分析将该技术广泛应用于产前染色体病诊断临床检测的可行性。方法选择2014年1月1日至2017年6月1日期间于北京协和医院就诊并接受产前诊断,同时进行CMA及核型分析检测的孕妇308例,对其CMA检测的结果进行分类分析并与核型分析相比较,分析其中不明确意义结果的构成以及相关特性。结果所有入组病例中88.0%为各种胎儿结构异常、软指标异常、胎儿生长受限及胎儿水肿。全基因组检测未发现明确染色体拷贝数改变(CNV)或明确多态性改变的病例217例,占70.5%;发现明确致病性染色体数目或片段异常共44例,占14.3%。其中发现染色体非整倍体异常21例,性染色体数目异常6例,染色体致病性CNV结果17例。此外发现不明意义的CNV诊断结果47例,占总病例数的15.3%。其中致病性判读为偏良性的23例,临床意义不明为21例,含符合报告标准的杂合性缺失(LOH)1例,偏致病性的3例。进一步分析各种VOUS病例的片段大小分布及判读依据类型。与核型分析的异常阳性率10.7%比较,全基因染色体芯片诊断明确致病性的染色体异常阳性率为14.2%,诊断阳性率提升3.5%。结论全基因组染色体芯片对于超声发现胎儿结构异常的遗传诊断能力较核型分析有较大的提升,但同时也会有VOUS病例增加遗传咨询的难度。目前国内产前诊断VOUS结果的比例较高,这与本地化数据库不完善,缺乏国内具体的芯片结果判读标准等有关。
Objective To investigate the application of chromosomal microarray analysis (CMA) in the prenatal diagnosis of high-risk pregnancies, and to investigate the composition and related characteristics of the chromosomal copy number variation (VOUS) with unknown clinical significance. The method is widely used in the diagnosis of prenatal chromosome disease Feasibility of clinical testing. Methods A total of 308 pregnant women were enrolled in Peking Union Medical College Hospital from January 1, 2014 to June 1, 2017 and received prenatal diagnosis. CMA and karyotype analysis were also performed. The results of CMA detection were classified and analyzed Compared with the karyotype analysis, the structure and related characteristics of the indeterminate result are analyzed. Results 88.0% of all enrolled patients were all kinds of fetal structural abnormalities, soft index abnormalities, fetal growth restriction and fetal edema. There were 217 cases (70.5%) with clear CNV or clear polymorphism in genome-wide test, and 44 cases (14.3%) were found with clear pathogenic chromosome number or abnormality. Among them, 21 aneuploidy chromosomes, 6 chromosomal abnormalities and 17 pathogenic CNV were found. In addition, 47 cases of unknown diagnosis of CNV were found, accounting for 15.3% of the total number of cases. Among them, 23 cases were pathogenic interpretation of benign, 21 cases of unknown clinical significance, including compliance with the report of the loss of heterozygosity (LOH) in 1 case, pathogenicity in 3 cases. Further analysis of various VOUS cases fragment size distribution and interpretation based on the type. Compared with the abnormal positive rate of karyotype analysis of 10.7%, the positive rate of chromosomal abnormality with pathogenicity diagnosed by whole genome chromosome was 14.2%, and the positive rate of diagnosis was increased by 3.5%. Conclusion The genome-wide chromosomal microarray has a great improvement on the genetic diagnosis of fetal structural abnormalities compared with karyotyping. However, it is also difficult to increase the genetic counseling in VOUS cases. At present, there is a high proportion of prenatal diagnosis of VOUS in China, which is related to the imperfection of localized database and the lack of specific domestic standards for interpretation of chip results.