Identification of a 2244 base pair interstitial deletion within the human ESR1 gene in the Spanish population

BACKGROUND: The ESR1 AGATA haplotype is comprised by five markers located within introns 5 and 6 of the human Estrogen Receptor 1 (ESR1) gene. This haplotype has been studied in several male urogenital tract anomalies and male infertility. In one of these studies we observed a deviation of Hardy-Weinberg equilibrium (DHW) for the ESR1 AGATA marker rs3020375 in two groups of healthy controls. In the present study we investigate 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 Spanish general population controls and 162 idiopathic infertile men. MAIN OUTCOME MEASUREMENTS: Segregation analyses of genetic markers in family units and case-control genetic association studies. RESULTS: We identified a new interstitial 2,244 base pair deletion within the intron 6 of the human ESR1 gene as the cause for the observed DHW. This new variant presents a 10% allelic frequency in the Spanish general population and it is associated with idiopathic male infertility (O.R.=1.51; p=0.03). Percentage of infertile couples in which both members carried ESR1 deletion (10.08%) is also higher than the expected value (6%) (p=0.03). CONCLUSSIONS: We have characterized a novel structural variation in human ESR1 gene. Data available indicate a deleterious action of ESR1 deletion not only over male fertility but also over couple fertility. The potential effects of this deletion over different estrogen-related diseases need to be determined.