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.
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: Marsha Mailick Seltzer; Erin T Barker; Jan S Greenberg; Jinkuk Hong; Christopher Coe; David Almeida Journal: Health Psychol Date: 2011-12-12 Impact factor: 4.267
Authors: Marsha Mailick; Jinkuk Hong; Jan Greenberg; Leann Smith Dawalt; Mei Wang Baker; Paul J Rathouz Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2017-04-13 Impact factor: 3.568
Authors: Andrea H Weinberger; Philip H Smith; Sharon S Allen; Kelly P Cosgrove; Michael E Saladin; Kevin M Gray; Carolyn M Mazure; Cora Lee Wetherington; Sherry A McKee Journal: Nicotine Tob Res Date: 2015-04 Impact factor: 4.244