Copy Number Variation Analysis of Euploid Pregnancy Loss

Abstract

Objectives: 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.Methods: 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.Result: 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.Conclusion: 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 ARID3A and FSTL3 might contribute to pregnancy loss.

Comparison of aneuploidy rate in spontaneous abortion chorionic villus between D6 and D5 thawed-frozen blastocyst transfer

“…It was reported that these abnormalities account for more than 87 ~ 93% of chromosomal abnormalities in SA-CV [ 28 , 29 ]. Although copy number variants(CNVs) less than 3 Mb in euploid POCs distribute in all chromosomes, the clinical significance of these variants is unclear [ 30 ]. Therefore, karyotyping analysis is the main method of assessing chromosomal results in SA-CV.…”

Clinical application of single nucleotide polymorphism microarray analysis in pregnancy loss in Northwest China

“…These abnormalities include variations in chromosome numbers and fragment duplications/deletions (Rai and Regan, 2006;Nikitina et al, 2020). Recent studies have shown that multiple chromosome microduplications and microdeletions may contribute to SA by affecting pregnancy-related genes or Frontiers in Genetics frontiersin.org pathways (Bagheri et al, 2015;Pauta et al, 2018;Wang et al, 2020;Gu et al, 2022) (Zhang et al, 2018;Qu et al, 2019). The SNP array incorporates genome-wide SNP typing probes unlike conventional platforms.…”

“…Although there have been many literature reports on different detection methods to explore the genetic causes of miscarriage tissue ( Sahoo et al, 2017 ; Pauta et al, 2018 ; Devall and Coomarasamy, 2020 ; Wang et al, 2020 ; Chen et al, 2021 ; Gu et al, 2022 ), there are no data on genetic testing of pregnancy loss in Northwest China at present. Therefore, it is crucial to explore the genetic etiology of pregnancy loss to provide effective targeted genetic counseling and testing.…”

Integrative analysis of circulating microRNAs and the placental transcriptome in recurrent pregnancy loss

“…This discovery may be due to the thorough control of the included population of pregnant women with normal fetal CNV, which is missing in other studies (Yang et al, 2018;Jairajpuri et al, 2021). From the genetic perspective, embryonic numerical and structural chromosomal abnormalities are known genetic causes of RPL, accounting for more than 50% of miscarriages (Wang et al, 2020b;Gu et al, 2022). Excluding the abortion caused by such genetic factors may more clearly identify the unknown pathogenesis of RPL.…”