Abstract
It is well established that embryonic chromosomal abnormalities (both in the number of chromosomes and the structure) account for 50% of early pregnancy losses. However, little is known regarding the potential differences in the incidence and distribution of chromosomal abnormalities between patients with sporadic abortion (SA) and recurrent pregnancy loss (RPL), let alone the role of submicroscopic copy-number variations (CNVs) in these cases. The aim of the present study was to systematically evaluate the role of embryonic chromosomal abnormalities and CNVs in the etiology of RPL compared with SA. Over a 3-year period, 1556 fresh products of conception (POCs) from miscarriage specimens were investigated using single nucleotide polymorphism array (SNP-array) and CNV sequencing (CNV-seq) in this study, along with further functional enrichment analysis. Chromosomal abnormalities were identified in 57.52% (895/1556) of all cases. Comparisons of the incidence and distributions of chromosomal abnormalities within the SA group and RPL group and within the different age groups were performed. Moreover, 346 CNVs in 173 cases were identified, including 272 duplications, 2 deletions and 72 duplications along with deletions. Duplications in 16q24.3 and 16p13.3 were significantly more frequent in RPL cases, and thereby considered to be associated with RPL. There were 213 genes and 131 signaling pathways identified as potential RPL candidate genes and signaling pathways, respectively, which were centered primarily on six functional categories. The results of the present study may improve our understanding of the etiologies of RPL and assist in the establishment of a population-based diagnostic panel of genetic markers for screening RPL amongst Chinese women.
Highlights
Spontaneous abortion is the most common complication of pregnancy in women of childbearing age, accounting for about 15% of clinical pregnancy cases during the first trimester [1]
Of the 1556 miscarriage cases included in this study, 963 cases were tested with SNP-array and 594 cases with copy-number variations (CNVs)-seq
We investigated the relationship between maternal age and chromosomal abnormalities, finding that in the sporadic abortion (SA) group, the frequency of chromosomal abnormalities increased with maternal age (Figure 3b), whereas in the recurrent pregnancy loss (RPL) group the frequencies of chromosomal abnormalities were the lowest in the 30–34-year-old age group (Figure 3c)
Summary
Spontaneous abortion is the most common complication of pregnancy in women of childbearing age, accounting for about 15% of clinical pregnancy cases during the first trimester [1]. Human Reproduction and Embryology (ESHRE) November 2017 guidelines as the loss of two or more pregnancies [2], and recurrent miscarriage (RM) by the Royal College of Obstetricians and Gynecologists (RCOG) as at least three consecutive miscarriages before weeks of gestation [3]. The incidence of the latter is 5% and has shown to be exhibiting an increasing trend in recent years [4]. As a complex polygenic and multifactorial disease, there are multiple etiologies underlying RPL, but 50% of cases can be attributed to genetics, such as aneuploidy. A spectrum of non-genetic etiologies of RPL have been identified, including maternal thrombophilic disorders, uterine abnormalities, sperm DNA fragmentation, immune and endocrine disturbances, and even lifestyle factors such as drinking and smoking [5,6]
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