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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2018.00292

FXPOI: Pattern of AGG interruptions does not show an association with age at amenorrhea among women with a premutation

 Emily G. Allen1, 2*, Anne Glicksman3, Nicole Tortora3, Krista Charen1, 2, Weiya He1, 2, Ashima Amin1, 2, Heather Hipp2, Lisa Shubeck1, 2,  Sarah L. Nolin3 and  Stephanie Sherman1, 2
  • 1Department of Human Genetics, Emory University School of Medicine, United States
  • 2Department of Gynecology and Obstetrics, Emory University School of Medicine, United States
  • 3Institute for Basic Research in Developmental Disabilities (IBR), United States

Fragile X-associated primary ovarian insufficiency (FXPOI) occurs in about 20% of women who carry a premutation allele (55-200 CGG repeats). These women develop hypergonadotropic hypogonadism and have secondary amenorrhea before age 40. A non-linear association with repeat size and risk for FXPOI has been seen in multiple studies women with a premutation: those with a mid-range of repeats are at highest risk (~70-100 CGG repeats). Importantly, not all carriers with 70-100 repeats experience FXPOI. We investigated whether AGG interruptions, adjusted for repeat size, impacted age at secondary amenorrhea. We have reproductive history information and AGG interruption data on 262 premutation women: 164 had an established age at amenorrhea (for some, age at onset of FXPOI) or menopause, 16 had a surgery involving the reproductive system such as a hysterectomy, and 82 women were still cycling at the last interview. Reproductive status was determined using self-report reproductive questionnaires and interviews with a reproductive endocrinologist. For each of these 262 women, FMR1 repeat size and number of AGG interruptions were determined. We confirmed the association of repeat size with age at amenorrhea or menopause among women with a premutation. As expected, both premutation repeat size and the quadratic form of repeat size (i.e., squared term) were significant in a survival analysis model predicting age at amenorrhea (p<0.0001 for both variables). When number of AGG interruptions was added to the model, this variable was not significant (p=0.59). Finally, we used a regression model based on the 164 women with established age at amenorrhea to estimate the proportion of variance in age at amenorrhea explained by repeat size and its squared term. Both terms were again highly significant (p<0.0001 for both), but together only explained 13% of the variation in age at amenorrhea. The non-linear association between age at amenorrhea and FMR1 repeat size has been described in several studies. We have determined that AGG interruption pattern does not contribute to this association. Because only 13% of the variation is described using repeat size, it is clear that further research of FXPOI is needed to identify other factors that affect the risk for FXPOI.

Keywords: FXPOI, POF, FMR1, fragile x, premutation, Menopause, Infertility

Received: 28 Feb 2018; Accepted: 13 Jul 2018.

Edited by:

Renate K. Hukema, Erasmus Medical Center, Erasmus University Rotterdam, Netherlands

Reviewed by:

Bruna De Felice, Università degli Studi della Campania "Luigi Vanvitelli" Caserta, Italy
Limor Man, Weill Cornell Medicine, Cornell University, United States  

Copyright: © 2018 Allen, Glicksman, Tortora, Charen, He, Amin, Hipp, Shubeck, Nolin and Sherman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Emily G. Allen, Emory University School of Medicine, Department of Human Genetics, 615 Michael St, Suite 301, Whitehead Building, Atlanta, 30322, GA, United States,