Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency

Murray, Anna; Schoemaker, Minouk J.; Bennett, Cavan; Ennis, Sarah; Macpherson, James; Jones, Michael E.; Morris, Danielle H.; Orr, Nick; Ashworth, Alan; Jacobs, Patricia A.; Swerdlow, Anthony

doi:10.1038/gim.2013.64

Cited by 85 publications

(67 citation statements)

References 24 publications

(34 reference statements)

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“…POI ("POF1" in OMIM 311360) has been consistently associated with women who have the "premutation" state of the Xq27.1 FMR1 gene (i.e., between 55 and 200 tandem copies of the CGG trinucleotide repeat in the gene). In two studies [67,68], 3% of sporadic and 10-13% of familial POI patients carried FRAXA premutations; in a more extensive follow-up, Murray et al [69] found the permutation in 0.7% of 2,000 women with early menopause and in 2% of women with POI (an odds ratio for POI of 5.4 compared with 0.4% in controls). FMR1 has a primary effect in the brain [70], but is also implicated in the DNA damage response [71], and could thereby have a determinative effect on chromosome dynamics and oocyte stability.…”

Section: X-autosomal Translocations and Chromosomal Changesmentioning

confidence: 95%

Dynamics of the Ovarian Reserve and Impact of Genetic and Epidemiological Factors on Age of Menopause1

Pelosi

Simonsick

Forabosco³

et al. 2015

Biology of Reproduction

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The narrow standard age range of menopause, ∼50 yr, belies the complex balance of forces that govern the underlying formation and progressive loss of ovarian follicles (the "ovarian reserve" whose size determines the age of menopause). We show here the first quantitative graph of follicle numbers, distinguished from oocyte counts, across the reproductive lifespan, and review the current state of information about genetic and epidemiological risk factors in relation to possible preservation of reproductive capacity. In addition to structural X-chromosome changes, several genes involved in the process of follicle formation and/or maintenance are implicated in Mendelian inherited primary ovarian insufficiency (POI), with menopause before age 40. Furthermore, variants in a largely distinct cohort of reported genes-notably involved in pathways relevant to atresia, including DNA repair and cell death-have shown smaller but additive effects on the variation in timing of menopause in the normal range, early menopause (age <45), and POI. Epidemiological factors show effect sizes comparable to those of genetic factors, with smoking accounting for about 5% of the risk of early menopause, equivalent to the summed effect of the top 17 genetic variants. The identified genetic and epidemiological factors underline the importance of early detection of reproductive problems to enhance possible interventions.

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Section: X-autosomal Translocations and Chromosomal Changesmentioning

confidence: 95%

Dynamics of the Ovarian Reserve and Impact of Genetic and Epidemiological Factors on Age of Menopause1

Pelosi

Simonsick

Forabosco³

et al. 2015

Biology of Reproduction

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“…This definition has been used elsewhere to define a normal age at menopause. 30 In addition, women were excluded: if they had ever taken fertility medications, if they had ever had a period of 12 months when they could not become pregnant despite regular sexual activity without contraception, if they had never been pregnant, or if the answer to any of these 3 questions was missing.…”

Section: Participation In This Fragile X Analysismentioning

confidence: 99%

FMRI CGG Repeats:Reference Levels and Race-Ethnic Variation in Women With Normal Fertility (Study of Women’s Health Across the Nation)

et al. 2016

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, and potentially women with high normal (35)(36)(37)(38)(39)(40)(41)(42)(43)(44) or low normal (<28) CGG repeats, are at risk of premature ovarian aging. The scarcity of population data on CGG repeats <45 CGG, and variation in raceethnicity, makes it difficult to determine true associations. DNA was analyzed for FMR1 CGG repeat lengths from 803 women (386 caucasians, 219 African Americans, 102 Japanese, and 96 Chinese) from the US-based Study of Women's Health Across the Nation (SWAN). Participants had 1 menses in the 3 months before enrollment, 1 pregnancy, no history of infertility or hormonal therapy, and menopause 46 years. Statistical analyses used Fisher exact tests. Among these women with normal reproductive histories, significant FMR1 repeat length differences were found across race-ethnicity for both the longer (P ¼ .0002) and the shorter (P < .0001) alleles. The trinucleotide length variance was greater for non-Asian than Asian women (P < .0001), despite identical median values. Our data indicate that short allele lengths <25 CGG on one or both alleles are more common in non-Asian than Asian women. We confirm the minor allele in the 35 to 39 CGG range among Asians as reported previously. Only 2 (0.3%) premutation carriers were identified. These data demonstrate that FMR1 distributions do vary by race-ethnicity, even within the ''normal'' range. This study indicates the need to control for race-ethnicity in FMR1 ovarian aging research and provides race-ethnic population data for females separated by allele.

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“…Both Pastore and Barosoain et al reported that women with low (or diminished) ovarian reserve were more likely to have ≥35 CGG repeats as compared to their comparison groups (p=0.0003 and p<0.05) [9,26]. Where the interpretation of the aforementioned [9,24] [25].…”

Section: Discussionmentioning

confidence: 98%

“…Karimov et al analyzed 1056 patients (535 cases with low ovarian reserve and 521 infertile controls [unrelated to ovarian reserve] and oocyte donors) and reported that in addition to PM carriers, women who carried an intermediate ranged mutation (45-54 repeats) exhibited a higher prevalence of DOR [7]. Thereafter, four studies examined repeat lengths ranging from 35 to 54 and ovarian reserve or age at menopause [9,[23][24][25]. Both Pastore and Barosoain et al reported that women with low (or diminished) ovarian reserve were more likely to have ≥35 CGG repeats as compared to their comparison groups (p=0.0003 and p<0.05) [9,26].…”

Section: Discussionmentioning

confidence: 99%

Evidence of an age-related correlation of ovarian reserve and FMR1 repeat number among women with “normal” CGG repeat status

Gustin

Ding

Desai

et al. 2015

J Assist Reprod Genet

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Purpose The objective of this analysis is to examine the relationship between Fragile X Mental Retardation 1 gene (FMR1) cytosine-guanine-guanine (CGG) repeat number and ovarian reserve, with a particular focus exclusively on the range of CGG repeat number below the premutation (PM) range (<55 CGG repeats). Methods Our study included female patients who underwent assessment of FMR1 CGG repeat number and serum antiMullerian hormone (AMH) in 2009-2014. To examine the association between FMR1 repeat number and serum AMH, we created three summary measures of CGG repeat number for the two alleles-BSum,^BMax,^and BGap^(absolute difference). Using multivariable regression models, controlling for age, we then analyzed the impact of these summary measures on AMH.Results A total of 566 patients were included in our study. Using multivariable regression models, we found that the relationship between CGG repeat number and AMH differed depending on age. Specifically, in younger women, AMH increased by 7-8 % (Sum p<0.01, Max p=0.04) for every 1 unit increase in CGG repeat number. In contrast, starting at age 40, there was a 3 to 5 % decline in AMH for every 1 unit increase in CGG repeat number (Sum p<0.01, Max p=0.04). Conclusions This is the first study to report a statistically significant correlation of ovarian reserve and CGG repeat number in women with <55 CGG repeats. Although these women are generally considered to have a normal phenotype, our data suggest that increasing CGG repeat number within this normal range is associated with a more rapid decline in ovarian reserve.

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Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency

Cited by 85 publications

References 24 publications

Dynamics of the Ovarian Reserve and Impact of Genetic and Epidemiological Factors on Age of Menopause1

Dynamics of the Ovarian Reserve and Impact of Genetic and Epidemiological Factors on Age of Menopause1

FMRI CGG Repeats:Reference Levels and Race-Ethnic Variation in Women With Normal Fertility (Study of Women’s Health Across the Nation)

Evidence of an age-related correlation of ovarian reserve and FMR1 repeat number among women with “normal” CGG repeat status

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