title: Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency.
abstract: OBJECTIVE
  Primary ovarian insufficiency before the age of 40 years affects 1% of the female population and is characterized by permanent cessation of menstruation. Genetic causes include FMR1 expansion mutations. Previous studies have estimated mutation prevalence in clinical referrals for primary ovarian insufficiency, but these are likely to be biased as compared with cases in the general population. The prevalence of FMR1 expansion mutations in early menopause (between the ages of 40 and 45 years) has not been published.
  
  
  METHODS
  We studied FMR1 CGG repeat number in more than 2,000 women from the Breakthrough Generations Study who underwent menopause before the age of 46 years. We determined the prevalence of premutation (55-200 CGG repeats) and intermediate (45-54 CGG repeats) alleles in women with primary ovarian insufficiency (n = 254) and early menopause (n = 1,881).
  
  
  RESULTS
  The prevalence of the premutation was 2.0% in primary ovarian insufficiency, 0.7% in early menopause, and 0.4% in controls, corresponding to odds ratios of 5.4 (95% confidence interval = 1.7-17.4; P = 0.004) for primary ovarian insufficiency and 2.0 (95% confidence interval = 0.8-5.1; P = 0.12) for early menopause. Combining primary ovarian insufficiency and early menopause gave an odds ratio of 2.4 (95% confidence interval = 1.02-5.8; P = 0.04). Intermediate alleles were not significant risk factors for either early menopause or primary ovarian insufficiency.
  
  
  CONCLUSIONS
  FMR1 premutations are not as prevalent in women with ovarian insufficiency as previous estimates have suggested, but they still represent a substantial cause of primary ovarian insufficiency and early menopause.
authors.affiliation: University of Exeter Medical School, University of Exeter St Luke's, Exeter, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
authors.forename: Minouk J
authors.initials: MJ
authors.lastname: Schoemaker
authors.affiliation: University of Exeter Medical School, University of Exeter St Luke's, Exeter, UK.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Bennett
authors.affiliation: Genetic Epidemiology, University of Southampton, Southampton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK.
authors.forename: James N
authors.initials: JN
authors.lastname: Macpherson
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Jones
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
authors.forename: Danielle H
authors.initials: DH
authors.lastname: Morris
authors.affiliation: Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Orr
authors.affiliation: Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Jacobs
authors.affiliation: Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Swerdlow
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008594:Menopause, Premature / Q000235:genetics*; D008875:Middle Aged; D016649:Primary Ovarian Insufficiency / Q000175:diagnosis / Q000235:genetics*; D011446:Prospective Studies; D019680:Trinucleotide Repeat Expansion; D006113:United Kingdom
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human