FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure

Abstract

Premature ovarian failure (POF) is the occurrence of menopause before the age of 40 and affects 1% of the female population. Whereas the etiology of POF is largely unexplained, FMR1 premutation carriers are known to be at increased risk of POF compared with the general population. The FMR1 premutation alleles have 55-200 copies of a CGG repeat in the 5' untranslated region of the FMR1 gene. However, functional effects on gene expression may occur even for repeat sizes in what has been considered the "normal" range. To evaluate the role of the FMR1 repeat in POF, repeat sizes were examined in 53 women with idiopathic POF, 161 control women from the general population, and 21 women with proven fertility at an advanced maternal age. A significant increase in the number of FMR1 alleles between and including 35 and 54 CGG repeats was found in the POF patient population; 15 of 106 (14.2%) POF alleles were between and including 35 and 54 repeats, whereas only 21 of 322 (6.5%) alleles in the general population (P=0.02) and 2 of 42 (4.8%) alleles from women with proven late fertility (P=0.09) were of this size (P=0.01 versus combined controls). The effect was also significant for comparisons of genotype repeat size (repeat size weighted by the relative activity of the two FMR1 alleles) and biallelic mean (average size of the two alleles). These results are clinically relevant and suggest that the FMR1 gene plays a more significant role in the incidence of POF than has previously been thought.

Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study

“…14 By contrast, among women with POI but without cases of the fragile X syndrome among close family members, the prevalence of full mutations and premutations was much lower, with the latter varying from 2.2 26 and 2.5 27 to 4.9%. 4 Among infertile women with reduced ovarian reserve but without POI, the prevalence rates of the premutation tended to be even lower, varying between 1.3 28 and 5.6%. 29 In this study, in which the cohorts were selected based on (in) fertility issues entirely unrelated to the fragile X syndrome, the prevalence rates of expanded FMR1 CGG repeats among fertile women were comparable with known population-based incidence rates, whereas those of infertile women were comparable with the incidence rates found in another large scale survey among infertile women.…”

“…28 The number of women with expanded FMR1 CGG repeat numbers in this cohort among the women with overt POI was comparable to the incidence rates reported previously. 4,26 The review of all published controlled studies on the prevalence rates of expanded FMR1 CGG repeat numbers revealed that in the absence of a familial risk, the relative risk of carrying the premutation among infertile women with reduced ovarian reserve and/or POI was marginally increased 13,27 or similar 4,28,29 in all but one study. 30 The prevalence rates of CGG repeat lengths of the intermediate range were similar among infertile women with reduced ovarian reserve and/or POI in all reviewed studies.…”

“…30 The prevalence rates of CGG repeat lengths of the intermediate range were similar among infertile women with reduced ovarian reserve and/or POI in all reviewed studies. 4,[27][28][29][30] Recently, no association with FMR1 CGG repeat length with the onset of natural menopause could be demonstrated. 31 Some of the discordant conclusions given by earlier studies may be explained by the characteristics of the control groups.…”

“…31 Some of the discordant conclusions given by earlier studies may be explained by the characteristics of the control groups. Three studies compared the incidence of expanded FMR1 CGG repeat lengths among women with POI with that of infertile controls, 13 of healthy family members of fragile X relatives, 4 and of postmenopausal women with timely onset of menopause. 30 Two other studies 28,29 compared the incidence of expanded CGG repeat lengths in women with reduced ovarian reserve with that of infertile women with normal ovarian reserve.…”

“…2 Considering the severity of the syndrome, the frequency of the carrier status and the potential long-term benefits to the daughters knowing about their mother's screening result, the installment of population-based screening programs has been advocated repeatedly. [3][4][5] In addition, carrier status testing would also enable women into timely reproductive planning. 6 Even in the absence of a family history of the fragile X syndrome, the cost-effectiveness of prenatal genetic testing programs identifying the carrier status of women has been demonstrated.…”