Novel Variants in Candidate Genes in Patients Affected by Recurrent Pregnancy Loss

Introduction: Recurrent pregnancy loss (RPL) is a frequently women infertility-related disease. It affects approximately ~1% of women in the general population and more than 50% of the cases remains unexplained. This fact suggests that genetic factors may contribute towards the development of the disease. Many studies have aimed to identify the genes that play an important role in the physiopathology of the disease. However, the molecular based techniques such as Sanger sequencing are limited because there are hundreds of genes involved in the implantation process. Therefore, next generation sequencing (NGS) could be an efficient approach to fing out new variants associated with the disease.

Methods: A retrospective study was done with 49 women affected by RLP. We performed whole-exome sequencing of each patient. A bioinformatics analysis was done to search for non-synonymous sequence variants in a subset of 234 candidate RLP genes.

Results: We found 27 coding variants in 22 candidate genes related to the disease. These variants were found in evolutive conserve regions, thus having potentially deleterious effect on the protein function. All these variants belongs to many molecular cascades important in the implantation process such as trophoblast/endometrium interaction, coagulation, angiogenesis, immunological function response/modulation, metabolism, extracellular matrix remodelling, steroidal nuclear receptor activation and specific cell function regulation.

Conclusions: The NGS approache and the bioinformatics analysis used in this study are efficient tools to look for variants that may have moderate/strong functional effects, associated with RLP aetiology. We hope that some of these variants (and genes) will be used, after their definitive functional validation, as RSA biomarkers.

Keywords: Recurrent pregnancy loss; molecular aetiology; complex disease; next generation sequencing; human infertility.