Identification of genetic polymorphisms in unexplained recurrent spontaneous abortion based on whole exome sequencing

Abstract

Background: The precise etiology of approximately 50% of patients with recurrent spontaneous abortion (RSA) is unclear, known as unexplained recurrent spontaneous abortion (URSA). This study identified the genetic polymorphisms in patients with URSA.Methods: Genomic DNA was extracted from 30 couples with URSA and 9 couples with normal reproductive history for whole exome sequencing. Variations in annotation, filtering, and prediction of harmfulness and pathogenicity were examined. Furthermore, predictions of the effects of changes in protein structure, Sanger validation, and functional enrichment analyses were performed. The missense mutated genes with significant changes in protein function, and genes with mutations of premature stop, splice site, frameshift, and in-frame indel were selected as candidate mutated genes related to URSA.Results: In 30 unrelated couples with URSA, 50%, 20%, and 30% had 2, 3, and more than 4 miscarriages, respectively. Totally, 971 maternal and 954 paternal mutations were found to be pathogenic or possibly pathogenic after preliminary filtering. Total variations were not associated with age nor the number of miscarriages. In 28 patients (involving 23 couples), 22 pathogenic or possibly pathogenic variants of 19 genes were found to be strongly associated with URSA, with an abnormality rate of 76.67%. Among these, 12 missense variants showed obvious changes in protein functions, including ANXA5 (c.949G>C; p.G317R),

The association of ZIC5 gene rs965623242 polymorphism with neural tube defects

“…In the first study, a match between rare copy number variations (CNV) in the ZIC5 gene and abnormal voluntary movement was identified in a mouse model of global developmental disorder [29]. In the second study, a Whole Exome Sequencing (WES) study was performed in couples with recurrent miscarriages, and missense, non-pathogenic changes were detected in the ZIC2 and ZIC5 genes in the patient group [30]. In the present study, the polymorphic variant appears to be protective for NTD.…”

Understanding recurrent pregnancy loss: recent advances on its etiology, clinical diagnosis, and management

“…Next generation sequencing (NGS), particularly the exome sequencing, has been extensively used to identify the gene variants underlying human genetic diseases. To date, fourteen studies have been reported to perform exome sequencing for identification of potential genes and genetic mutations contributing to RPL ( Table S1 and S2 [ 128 ], [ 129 ], [ 130 ], [ 131 ], [ 132 ], [ 133 ], [ 134 ], [ 135 ], [ 136 ], [ 137 ], [ 138 ], [ 139 ], [ 140 ], [ 141 ]). Most of these studies focus on the discovery of RPL-associated mutations in women patients, and a total of 66 candidate maternal genes and 12 paternal genes have been reported to be associated with RPL ( Table 1 ).…”

Correlation Between Long non-coding RNA SOX2OT rs9839776 C>T Polymorphism and Unexplained Recurrent Miscarriages

“…Tian et al, 2018) (J. Wang et al, 2021). Additionally, research indicates that polymorphisms in many genes, including those that control cell migration like IGF-2 and PAI-1, are linked to recurrent miscarriage (Shi et al, 2017) (Mou et al, 2022). As a result, a study into the relationships between genetic polymorphisms that govern the migration of cells, invading cells, and recurrent abortions may help us better understand the etiology of recurrent miscarriage.…”