Gu Chongjuan, Gao Huan, Li Kuanrong, Dai Xinyu, Yang Zhao, Li Ru, Wen Canliang, He Yaojuan
Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
Front Genet. 2022 Mar 23;13:766492. doi: 10.3389/fgene.2022.766492. eCollection 2022.
Copy number variant (CNV) is believed to be the potential genetic cause of pregnancy loss. However, CNVs less than 3 Mb in euploid products of conceptions (POCs) remain largely unexplored. The aim of this study was to investigate the features of CNVs less than 3 Mb in POCs and their potential clinical significance in pregnancy loss/fetal death. CNV data were extracted from a cohort in our institution and 19 peer-reviewed publications, and only those CNVs less than 3 Mb detected in euploid pregnancy loss/fetal death were included. We conducted a CNV map to analyze the distribution of CNVs in chromosomes using R packages karyoploteR_1.10.5. Gene names and annotated gene types covered by those CNVs were mined from the human Release 19 reference genome file and GENECODE database. We assessed the expression patterns and the consequences of murine knock-out of those genes using TiGER and Mouse Genome Informatics (MGI) databases. Functional enrichment and pathway analysis for genes in CNVs were performed using clusterProfiler V3.12.0. Breakpoints of 564 CNVs less than 3 Mb were obtained from 442 euploid POCs, with 349 gains and 185 losses. The CNV map showed that CNVs were distributed in all chromosomes, with the highest frequency detected in chromosome 22 and the lowest frequency in chromosome Y, and CNVs showed a higher density in the pericentromeric and sub-telomeric regions. A total of 5,414 genes mined from the CNV regions (CNVRs), Gene Ontology (GO), and pathway analysis showed that the genes were significantly enriched in multiple terms, especially in sensory perception, membrane region, and tight junction. A total of 995 protein-coding genes have been reported to present mammalian phenotypes in MGI, and 276 of them lead to embryonic lethality or abnormal embryo/placenta in knock-out mouse models. CNV located at 19p13.3 was the most common CNV of all POCs. CNVs less than 3 Mb in euploid POCs distribute unevenly in all chromosomes, and a higher density was seen in the pericentromeric and sub-telomeric regions. The genes in those CNVRs are significantly enriched in biological processes and pathways that are important to embryonic/fetal development. CNV in 19p13.3 and the variations of and might contribute to pregnancy loss.
拷贝数变异（CNV）被认为是妊娠丢失的潜在遗传原因。然而，整倍体妊娠产物（POC）中小于3 Mb的CNV在很大程度上仍未被探索。本研究的目的是调查POC中小于3 Mb的CNV的特征及其在妊娠丢失/胎儿死亡中的潜在临床意义。从我们机构的一个队列和19篇同行评审的出版物中提取CNV数据，仅纳入在整倍体妊娠丢失/胎儿死亡中检测到的小于3 Mb的CNV。我们使用R包karyoploteR_1.10.5绘制CNV图谱，以分析CNV在染色体上的分布。从人类版本19参考基因组文件和GENECODE数据库中挖掘这些CNV覆盖的基因名称和注释基因类型。我们使用TiGER和小鼠基因组信息学（MGI）数据库评估这些基因的表达模式和小鼠基因敲除的后果。使用clusterProfiler V3.12.0对CNV中的基因进行功能富集和通路分析。从442个整倍体POC中获得了564个小于3 Mb的CNV的断点，其中349个为增益，185个为缺失。CNV图谱显示，CNV分布在所有染色体上，在22号染色体上检测到的频率最高，在Y染色体上的频率最低，并且CNV在着丝粒周围和亚端粒区域显示出更高的密度。从CNV区域（CNVR）、基因本体论（GO）和通路分析中挖掘出的总共5414个基因表明，这些基因在多个术语中显著富集，特别是在感官知觉、膜区域和紧密连接方面。在MGI中总共报告了995个蛋白质编码基因呈现哺乳动物表型，其中276个在基因敲除小鼠模型中导致胚胎致死或胚胎/胎盘异常。位于19p13.3的CNV是所有POC中最常见的CNV。整倍体POC中小于3 Mb的CNV在所有染色体上分布不均，在着丝粒周围和亚端粒区域密度更高。这些CNVR中的基因在对胚胎/胎儿发育重要的生物学过程和通路中显著富集。19p13.3中的CNV以及其他基因的变异可能导致妊娠丢失。
