Evidence of an age-related correlation of ovarian reserve and FMR1 repeat number among women with “normal” CGG repeat status

Abstract

Purpose The objective of this analysis is to examine the relationship between Fragile X Mental Retardation 1 gene (FMR1) cytosine-guanine-guanine (CGG) repeat number and ovarian reserve, with a particular focus exclusively on the range of CGG repeat number below the premutation (PM) range (<55 CGG repeats). Methods Our study included female patients who underwent assessment of FMR1 CGG repeat number and serum antiMullerian hormone (AMH) in 2009-2014. To examine the association between FMR1 repeat number and serum AMH, we created three summary measures of CGG repeat number for the two alleles-BSum,^BMax,^and BGap^(absolute difference). Using multivariable regression models, controlling for age, we then analyzed the impact of these summary measures on AMH.Results A total of 566 patients were included in our study. Using multivariable regression models, we found that the relationship between CGG repeat number and AMH differed depending on age. Specifically, in younger women, AMH increased by 7-8 % (Sum p<0.01, Max p=0.04) for every 1 unit increase in CGG repeat number. In contrast, starting at age 40, there was a 3 to 5 % decline in AMH for every 1 unit increase in CGG repeat number (Sum p<0.01, Max p=0.04). Conclusions This is the first study to report a statistically significant correlation of ovarian reserve and CGG repeat number in women with <55 CGG repeats. Although these women are generally considered to have a normal phenotype, our data suggest that increasing CGG repeat number within this normal range is associated with a more rapid decline in ovarian reserve.

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

“…With intermediate (45)(46)(47)(48)(49)(50)(51)(52)(53)(54) and premutation carriers (55-200 CGG repeats), we notice a translation fault which can be held accountable for mRNA production levels [93] not balanced through an equivalent rise in FMRP that frequently is normal or somewhat reduced. By consequence, the mRNA levels build-up in the cells where it is hypothesized to exert cytotoxic effects (RNA/protein toxic gain-of-function disorder).…”

“…This 'normal' range, however, may not in fact be a homogenous population. Gleicher et al reported the intermediate genotype (45)(46)(47)(48)(49)(50)(51)(52)(53)(54) repeats) expresses a minor instability unrelated to a definite phenotype or to the fragile X syndrome (FXS) within one generation, even though the risk is consistent in two generations [113]. These intermediate carriers, compared to 'normal', show a greater prevalence of subfertility, menstrual cycle anomalies, overall earlier than anticipated menopause (by ∼7 years), premature ovarian failure (32 vs 1 %), increased prevalence of osteoporosis, higher rate of aneuploidy, miscarriage and even perhaps non-identical twinning rates [85,94].…”

“…Scientists have discovered a considerable number of genes and candidate genes on both X chromosome arms, that in many ways link strongly the X chromosome to human reproductive capability [49,50]. The existing association between the FMR1 gene, in the premutation range (previously not considered a risk for any medical condition) and primary ovarian insufficiency (POI), is acknowledged by many authors [46,107]. However, in 2009, the work of Gleicher and colleagues confirmed that the length of the CGG repeats, primarily in the 'new' normal range, paralleled the FSH and AMH values, and similarly the clinical picture [39].…”

FMR1 genotype interacts with parenting stress to shape health and functional abilities in older age

“…Because we did not have activation ratio data, one X chromosome was selected for analysis in the present study as follows. Although we considered alternative approaches [Kline et al, 2014; Gustin et al, 2015], we followed the approach of Hunter et al [2012]. We selected the longer allele in mothers who had one expanded (i.e., > 40 CGGs) allele and one normal allele (n = 218) and in the one case who had two expanded alleles.…”

FMR1 gene CGG repeat variation within the normal range is not predictive of ovarian response in IVF cycles

“…These findings have prompted some investigators to questions if the true normal range of CGG repeats should be narrowed to 26-34 repeats (Gleicher et al, 2014). These suggestions, however, remain controversial, as other studies have either failed to demonstrate that variation in the normal CGG repeat range is associated with markers of ovarian reserve (Schufreider et al, 2015) or suggested that the effect of CGG repeat number is modified by the patient's age (Gustin et al, 2015;Pastore et al, 2014). Therefore, no consensus has been reached on whether CGG repeat number in the normal range affects ovarian reserve or whether this effect is only present in a subset of the infertile population.…”