Human Genetics

, Volume 117, Issue 4, pp 376–382 | Cite as

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

  • Karla L. Bretherick
  • Margo R. Fluker
  • Wendy P. Robinson
Original Investigation


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.


Premature Ovarian Failure Premutation Carrier Premutation Allele Androgen Receptor Locus Premature Ovarian Failure Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank the POF patients for participating in this study and Ruby Jiang for technical assistance. This work was supported by Canadian Institutes of Health Research Grant MOP-38051 to W.P.R. K.B. is funded by the Institute of Genetics at the Canadian Institutes of Health Research, the Michael Smith Foundation for Health Research, and the Interdisciplinary Women’s Reproductive Health training program at the BC Research Institute for Children’s and Women’s Health.


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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Karla L. Bretherick
    • 2
    • 3
  • Margo R. Fluker
    • 4
    • 5
  • Wendy P. Robinson
    • 1
    • 2
    • 3
  1. 1.BC Research Institute for Children’s and Women’s HealthVancouverCanada
  2. 2.Department of Medical GeneticsUniversity of British ColumbiaVancouverCanada
  3. 3.BC Research Institute for Children’s and Women’s HealthVancouverCanada
  4. 4.Department of Obstetrics and GynaecologyUniversity of British ColumbiaVancouverCanada
  5. 5.Genesis Fertility Centre VancouverCanada

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