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

Abstract

The relationship between FMR1 CGG premutation status and decreased ovarian responsiveness is well established. The association between FMR1 CGG repeat number in the currently defined normal range (less than 45 repeats) and ovarian reserve, however, is controversial. This retrospective study examined whether variation in CGG repeat number in the normal range was associated with markers of ovarian response in IVF cycles. The first IVF cycle of 3006 patients with FMR1 CGG repeat analysis was examined. Only patients carrying two alleles with less than 45 CGG repeats were included for analysis. The CGG repeat number furthest from the modal peak was plotted against number of mature oocytes retrieved and no correlation was identified. Patients were also separated into biallelic genotype groups, based on the recently proposed narrower "new normal" range of 26-34 CGG repeats. A linear regression showed that none of the biallelic genotype groups were associated with a decreased oocyte yield. The euploidy rates after comprehensive chromosomal screening were equivalent among the genotype groups. No difference was found in the rate of cycle cancellation for poor response. Despite increasing use, FMR1 CGG repeats in the normal range cannot be used as a predictor of ovarian response to gonadotrophin stimulation.

The importance of redundancy of functional ovarian reserve when investigating potential genetic effects on ovarian function

“…Morin et al were unable to demonstrate any association of FMR1 mutations and ovarian response, which is not surprising given that their study cohort had evidence of even more favorable ovarian reserve [5]. Finally, in another highly selected group [6], were only able to demonstrate an effect of FMR1 among subjects who were homozygous low/low [9].…”

“…One lesson we can derive from the three recently published FMR1 studies [4][5][6] is that, in order to achieve interpretable results, studies of genetic effects on FOR should be performed on women who no longer exhibit significant redundancies in FOR. If studies are performed in young, good prognosis patients, then cross-sectional studies will have less power to detect an effect.…”

“…Only after the review process when the reviewer asked for the analysis to be age stratified, was the effect of the homozygous low alleles detectable. Furthermore, with mean age of 33.5 years, mean FSH 6.6 mIU/mL, and mean AMH 2.2 ng/mL, their study population was even younger and more favorably selected than the prior two studies reviewed [4,5].…”

“…Recently, Morin et al reported that CGG n is not predictive of ovarian response in IVF cycles [5]. However, once again, the patient population investigated was largely comprised of good prognosis patients.…”

“…We will address three of these recent studies [4][5][6] that each investigated young healthy fertility patients and found only limited evidence of effect of FMR1, within the classical normal range, on indicators of ovarian reserve. We maintain that, when studying a genetic condition that may predispose to age related loss of FOR, the conclusions of a study will have little meaning unless a population at risk was studied and that young healthy fertility patients are low risk for low FOR.…”