Background: The ESR1 AGATA haplotype is composed of five markers located within introns 5 and 6 of the human oestrogen receptor 1 (ESR1) gene. This haplotype has been studied in several male urogenital tract anomalies and male infertility. In one of these studies, a deviation from Hardy-Weinberg equilibrium (DHW) was found for the ESR1 AGATA marker rs3020375 in two groups of healthy controls. In the present study, we investigated whether the observed DHW is caused by structural variants present within the ESR1 gene.
Participants: 229 family units achieving pregnancy through assisted reproductive technologies (n = 129) or by natural means (n = 100), 2465 general Spanish population controls and 162 men with idiopathic infertility.
Main outcome measurements: Segregation analyses of genetic markers in family units and case-control genetic association studies.
Results: We identified a new interstitial deletion of 2244 base pairs within intron 6 of the human ESR1 gene as the cause for the observed DHW. This new variant presents a 10% allelic frequency in the general Spanish population and it is associated with idiopathic male infertility (OR = 1.51; p = 0.03). The percentage of infertile couples in which both members carried the ESR1 deletion (10.08%) was also a higher than expected value of 6% (p = 0.03).
Conclusions: We have characterised a novel structural variation in human ESR1 gene. The available data indicate a deleterious action of the ESR1 deletion in both male and couple fertility. The potential effects of this deletion on other oestrogen-related diseases need to be determined.