Association of skewed X-chromosome inactivation with FMR1 CGG repeat length and anti-Mullerian hormone levels: a cohort study

Background: Premutation range CGGn repeats of the FMR1 gene denote risk toward primary ovarian insufficiency (POI), also called premature ovarian failure (POF). This prospective cohort study was undertaken to determine if X-chromosome inactivation skew (sXCI) is associated with variations in FMR1 CGG repeat length and, if so, is also associated with age adjusted antimullerian hormone (AMH) levels as an indicator of functional ovarian reserve (FOR). Methods: DNA samples of 58 women were analyzed for methylation status and confirmation of CGG(n) repeat length. Based on previously described FMR1 genotypes, there were 18 women with norm FMR1 (both alleles in range of (GG(n=26-34)), and 40 women who had at least one allele at CGG(n<26) or CGG(>34) (not-norm FMR1). As part of a routine evaluation of ovarian reserve, patients at our fertility center have their serum AMH assessed at first visit. Regression models were used to test the association of ovarian reserve, as indicated by serum AMH, with sXCI. Results: sXCI was significantly lower among infertility patients with norm FMR1 (6.5 +/- 11.1, median and IQR) compared to those with not-norm FMR1 (12.0 +/- 14.6, P = 0.005), though among young oocyte donors the opposite effect was observed. Women age >30 to 38 years old demonstrated greater ovarian reserve in the presence of lower sXCI as evidenced by significantly higher AMH levels (GLM sXCI_10%, f = 11.27; P = 0.004). Conclusions: Together these findings suggest that FMR1 CGG repeat length may have a role in determining X-chromosome inactivation which could represent a possible mechanism for previously observed association of low age adjusted ovarian reserve with FMR1 variations in repeat length. Further, larger, investigations will be required to test this hypothesis.