title: Examination of reproductive aging milestones among women who carry the FMR1 premutation.
abstract: BACKGROUND
  The fragile X premutation is characterized by a large CGG repeat track (55-199 repeats) in the 5' UTR of the FMR1 gene. This X-linked mutation leads to an increased risk for premature ovarian failure; interestingly, the association of repeat size with risk is non-linear. We hypothesize that the premutation-associated ovarian insufficiency is due to a diminished oocyte pool and examined reproductive aging milestones by repeat size group to determine if the same non-linear association is observed.
  
  
  METHODS
  We analyzed cross-sectional reproductive history questionnaire data from 948 women with a wide range of repeat sizes.
  
  
  RESULTS
  We have confirmed the non-linear relationship among premutation carriers for ovarian insufficiency. The mid-range repeat size group (80-100 repeats), not the highest group, had an increased risk for: altered cycle traits (shortened cycle length, irregular cycles and skipped cycles), subfertility and dizygotic twinning. Smoking, a modifiable risk, decreased the reproductive lifespan of women with the premutation by about 1 year, similar to its effect on non-carriers. As expected, premutation carriers were found to be at an increased risk for osteoporosis.
  
  
  CONCLUSIONS
  Possible molecular mechanisms to explain the non-linear repeat size risk for ovarian insufficiency are discussed.
authors.affiliation: Department of Human Genetics, Emory University, 615 Michael Street, Atlanta, GA 30322, USA. egraves@genetics.emory.edu
authors.forename: E G
authors.initials: EG
authors.lastname: Allen
authors.forename: A K
authors.initials: AK
authors.lastname: Sullivan
authors.forename: M
authors.initials: M
authors.lastname: Marcus
authors.forename: C
authors.initials: C
authors.lastname: Small
authors.forename: C
authors.initials: C
authors.lastname: Dominguez
authors.forename: M P
authors.initials: MP
authors.lastname: Epstein
authors.forename: K
authors.initials: K
authors.lastname: Charen
authors.forename: W
authors.initials: W
authors.lastname: He
authors.forename: K C
authors.initials: KC
authors.lastname: Taylor
authors.forename: S L
authors.initials: SL
authors.lastname: Sherman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008597:Menstrual Cycle; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000453:epidemiology; D011247:Pregnancy; D016649:Primary Ovarian Insufficiency / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid; D012098:Reproduction / Q000502:physiology*; D012907:Smoking / Q000503:physiopathology; D014429:Twins, Dizygotic
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human