The significance of fragile X mental retardation gene 1 CGG repeat sizes in the normal and intermediate range in women with primary ovarian insufficiency

Voorhuis, Marlies; Onland‐Moret, N. Charlotte; Janse, Femi; Amstel, Hans Kristian Ploos van; Goverde, Angelique J.; Lambalk, Cornelis B.; Laven, Joop; Schouw, Yvonne T. van der; Broekmans, Frank J.; Fauser, Bart C.J.M.

doi:10.1093/humrep/deu095

Cited by 30 publications

(24 citation statements)

References 51 publications

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“…Intraclass correlation coefficients (ICC [3,1]) indicated excellent reliability at 0.99 for both alleles. The allele with the lower CGG repeat length was designated allele-1 and the one with the higher repeat length as allele-2, consistent with the terminology used in prior reports (e.g., Gleicher et al, 2009a; Voorhuis et al, 2014). …”

Section: Methodsmentioning

confidence: 89%

“…We employed an analytic technique that focused on the larger allele as the primary predictor while covarying for the size of the smaller allele, which is the method that has been used most widely in the extant literature (Gleicher et al, 2009a,b; Lledo et al, 2012; Voorhuis et al, 2014; Schufreider et al, 2015). This strategy was successful in detecting robust CGG associations in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Although there are a variety of possible analytic methods to account for the presence of two X chromosomes in females, there is little consensus in the field as to which analytic technique is optimal. We selected this analytic technique based on established precedent, as this is the most common method used to account for two alleles in females in the extant literature (Gleicher et al, 2009a,b; Lledo et al, 2012; Voorhuis et al, 2014; Schufreider et al, 2015). We did not have activation ratio data available (i.e., the percent of cells carrying any given allele on the active X chromosome), which prevented us from employing other techniques that account for the relative influence of each allele (i.e., Allen et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

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Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

et al. 2018

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Historically, investigations of FMR1 have focused almost exclusively on the clinical effects of CGG expansion within the categories of the premutation (55–200 CGG repeats) and fragile X syndrome (>200 CGG repeats). However, emerging evidence suggests that CGG-dependent phenotypes may occur across allele sizes traditionally considered within the “normal” range. This study adopted an individual-differences approach to determine the association between language production ability and CGG repeat length across the full range of normal, intermediate, and premutation alleles. Participants included 61 adult women with CGG repeats within the premutation (n = 37), intermediate (i.e., 41–54 repeats; n = 2), or normal (i.e., 6–40 repeats; n = 22) ranges. All participants were the biological mothers of a child with a developmental disorder, to control for the potential effects of parenting stress. Language samples were collected and the frequency of language disfluencies (i.e., interruptions in the flow of speech) served as an index of language production skills. Verbal inhibition skills, measured with the Hayling Sentence Completion Test, were also measured and examined as a correlate of language disfluency, consistent with theoretical work linking language disfluency with inhibitory deficits (i.e., the Inhibition Deficit Hypothesis). Blood samples were collected to determine FMR1 CGG repeat size. A general linear model tested CGG repeat size of the larger allele (allele-2) as the primary predictor of language disfluency, covarying for education level, IQ, age, and CGG repeats on the other allele. A robust curvilinear association between CGG length and language disfluency was detected, where low-normal (∼ <25 repeats) and mid-premutation alleles (∼90–110 repeats) were linked with higher rates of disfluency. Disfluency was not associated with inhibition deficits, which challenges prior theoretical work and suggests that a primary language deficit could account for elevated language disfluency in FMR1-associated conditions. Findings suggest CGG-dependent variation in language production ability, which was evident across individuals with and without CGG expansions on FMR1.

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Section: Methodsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

et al. 2018

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“…12 Five of these articles reported separate results for females. [9][10][11]16,19 Nine of the 10 studies that included females reported the total allelic distribution, 9,11,[15][16][17][18][19][20][21] and none of those publications reported the FMR1 distribution of the higher allele separate from the lower allele. The recent article by Voorhuis et al 10 did report separate results for the higher and lower alleles among females from the general population, but their population included women with early menopause at ages 40 to 45 and infertility.…”

Section: Existing Population Data In the Range Ofmentioning

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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“…Subsequently, Pastore et al reported that 14.5 % of DOR patients (n=62) exhibited a high normal number of CGG repeats (35-44) [9]. More recently, researchers have been unable to reconfirm the aforementioned findings nor establish a correlation of CGG repeat number (<55) with measures of ovarian reserve [11,12].…”

Section: Introductionmentioning

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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The significance of fragile X mental retardation gene 1 CGG repeat sizes in the normal and intermediate range in women with primary ovarian insufficiency

Cited by 30 publications

References 51 publications

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

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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