Early decline in functional ovarian reserve in young women with low (CGGn < 26) FMR1 gene alleles

Mouse fmr1 models, and recent cross-sectional human data, suggest that different triple CGGn ranges of the fragile X mental retardation 1 (FMR1) gene are associated with variations in ovarian aging and infertility treatment outcomes. The FMR1 mutation affecting reproductive function most negatively in humans is the so-called low mutation, characterized by CGGn < 26. We here present a first longitudinal study of selected young women with normal functional ovarian reserve (FOR). In a prospective cohort study, we selected among 233 young oocyte donors (mean age 24.8 ± 3.3 years) as study population of 66 who had more than 1 anti-Müllerian hormone (AMH) level drawn over a 4-year period. AMH curves, as reflection of FOR, were then statistically compared between women with and without low FMR1 alleles. Biallelic low FMR1 (hom-low/low) donors already at initial presentation demonstrated significantly lower FOR than donors with biallelic normal (norm) FMR1 (CGGn = 26-34; P = 0.001). Although monoallelic low FMR1 at initial presentation was not yet associated with decreased FOR, it over 4 years did demonstrate significantly enhanced declines in FOR (P = 0.046). Including repeat measurements, low/low (P = 0.006) and high/high (CGGn > 34) alleles (P < 0.001) demonstrated lower FOR by AMH than norm donors. Even monoallelic low FMR1 alleles are, thus, already at young female ages associated with accelerated declines in FOR. Low FMR1 alleles, therefore, potentially represent a screening tool for women at genetic risk toward premature ovarian senescence, representing in all races circa 10% of the female population.