Role of MUTYH gene variants in the etiology of recurrent pregnancy loss

Abstract

Background/Objectives: Recurrent pregnancy loss (RPL), is defined as the loss of two or more pregnancies before 24 weeks of gestation that affects 1-2% of pregnancies worldwide. The cause of RPL cannot be explained in about half of the cases. Recent studies suggest that mitochondrial dyshomeostasis and oxidative stress may play a role in RPL. The mutY DNA glycosylase (MUTYH) is a novel candidate gene in RPL involved in repair of oxidative stress induced DNA damage. This study aimed to investigate the association of MUTYH gene variants and RPL. Methods: Variant analysis was performed on whole exome sequencing data from 10 couples and an additional 25 female patients examined due to the RPL in the first trimester. Results: All patients had normal karyotypes and had no other causing factor related to infertility. In three female patients (8%), heterozygous pathogenic missense (rs143353451 and rs374950566) and nonsense (rs121908380) variants were detected in MUTYH gene. Protein modeling of these variants was performed by UniProt automated modeling and showed that mutated MUTYH residues are located within conserved motifs at the surface of the molecule. Conclusion: Findings of this study suggest that pathogenic variants of MUTYH gene might be crucial in the trigger of oxidative stress in human placenta and thus contribute to RPL etiology. Additive interaction of other heterozygous variants in RPL related genes should be explored and further functional studies should be conducted to explain the role of these variants in female infertility.