亚微型及复发性染色体拷贝数变异在复发性流产中的作用

Role of subminiature and recurrent chromosome copy number variations in recurrent spontaneous abortion

目的探讨复发性流产(recurrent spontaneous abortion,RSA)相关的关键的染色体拷贝数变异(copy number variation,CNV)区域、候选基因及信号通路。方法基于2016年1月至2022年9月期间于郑州大学第三附属医院检验医学科采用高通量测序技术进行流产组织CNV分析的1870例RSA患者病例资料进行回顾性队列研究。根据孕妇流产年龄和孕周对病例进行分组,采用χ2检验或Fisher精确概率法分析染色体异常及CNV分布情况。通过基因富集分析鉴定RSA相关CNV内基因功能、信号通路。结果1870例样本检出染色体异常1001例(53.53%),其中93例(9.29%)检出140种CNVs,亚微型CNVs(<10 Mb)34种,片段≥10 Mb CNVs 106种。在孕早期RSA(≤12周)样本中检测到具有统计学差异的亚微型致病性CNVs涉及1p36.33p36.23、2q37.3、4p16.3、22q11.21(χ^(2)=6.99,P=0.008),此外,16p11.2、Xp11.23p11.22微缺失首次在流产病例中报道。显著复发的大型CNVs主要涉及18q22q23、4p16p15、9p24p22、8p23p22、Xp22.3区域,所包含流产候选基因主要集中在PI3K-Akt及JAK-STAT信号通路。结论罕见亚微型CNVs和复发性大型CNVs与孕早期RSA相关,GO和KEGG数据库分析发现了潜在的流产候选基因及信号通路,为RSA的遗传学病因提供了新信息。

Objective:To explore the key copy number variation(CNV)regions,abortion candidate genes and signaling pathways associated with recurrent spontaneous abortion(RSA).Methods:A retrospective cohort study was conducted based on the data of 1870 miscarriage cases of RSA patients who received CNV analysis by high-throughput sequencing technology in the Laboratory Medicine Department of the Third Affiliated Hospital of Zhengzhou University from January 2016 to September 2022.These cases were divided into different groups based on the age of miscarriage and gestational age of the pregnant women.Chi-square test or Fisher's exact test was used to analyze the distribution of chromosome abnormalities and CNV.Gene functions and signaling pathways in RSA-related CNV were identified by gene enrichment analysis.Results:Among the 1870 tissues,1001(53.53%)cases were detected with chromosomal abnormalities.A total of 140 CNVs were detected in 93 tissues(9.29%),including 34 submicroscopic CNVs(segment<10 Mb)and 106 large CNVs with segment≥10 Mb.Submicroscopic pathogenicity CNVs with statistical differences were involved 1p36.33p36.23,2q37.3,4p16.3,22q11.21(χ^(2)=6.99,P=0.008)in early RSA embryos(≤12 weeks).16p11.2 and Xp11.23p11.22 microdeletion were firstly reported in abortion cases.Significantly recurrent large CNVs were mainly involved 18q22q23(del/dup),4p16p15,9p24p22,8p23p22,and Xp22.3 regions,and the candidate genes mainly concentrated on PI3K-Akt and JAK-STAT signaling pathway.Conclusion:Rare submicroscopic CNVs and recurrent large CNVs were associated with RSA in early pregnancy.GO and KEGG database analysis revealed potential abortion candidate genes and signaling pathways,providing new information for the genetic etiology of RSA.