Intermediate and normal sized CGG repeat on the FMR1 gene does not negatively affect donor ovarian response

Lledó, Belén; Guerrero, Jaime; Ortíz, J A; Morales, Ruth; Ten, Jorge; Llácer, J.; Giménez, Joaquím; Bernabéu, Rafael

doi:10.1093/humrep/der415

Cited by 23 publications

(29 citation statements)

References 18 publications

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“…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: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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“…5,13 Prior investigations of young egg donors reported conflicting results. [14][15][16] These studies, however, did not include donors who were biallelic low in FMR1. Monoallelic low FMR1 donors also in this study did not yet demonstrate significant differences in FOR between carriers of low alleles and donors who lacked such alleles.…”

Section: Discussionmentioning

confidence: 99%

Early decline in functional ovarian reserve in young women with low (CGGn < 26) FMR1 gene alleles

Gleicher

Himaya

et al. 2015

Translational Research

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“…Indeed, workers in the neurological field could not find any atypical phenotype association below 45 CGG repeats [87]. Some studies have shown, however, that reproductive function may be significantly impacted in this range [36]; however, other studies have shown no obvious impact [22,58]. The American College of Obstetrics and Gynecology Genetics Committee, and the American College of Medical Genetics (ACMG), explicitly state that an FMR1 CGG repeat length of <45 'is not associated with an abnormal phenotype' [66].…”

Section: The Cgg Mutationsmentioning

confidence: 98%

“…Among the three mutation ranges investigated (premutation, intermediate and high normal) none showed a statistically significant association with infertility nor with ovarian reserve indicators. Slightly earlier, Lledo et al also published results on the use of FMR1 screening in young oocyte donors in predicting the ovarian follicular development [58]; numerous papers on the other hand report a substantial link between FMR1 mutations and ovarian reserve [11,33,86].…”

Section: Cgg Mutations and Biomarkers Of Ovarian Reservementioning

confidence: 99%

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Noto

Harrity

Walsh

et al. 2016

J Assist Reprod Genet

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Purpose This is a comprehensive review of the literature in this field attempting to put the FMR1 gene and its evaluation into context, both in general and for the reproductive health audience. Methods Online database search of publications with systematic review of all papers relevant to ovarian reserve and assisted reproduction was done. Results Relevant papers were identified and assessed, and an attempt was made to understand, rationalize and explain the divergent views in this field of study. Seminal and original illustrations were employed. Conclusions FMR1 is a highly conserved gene whose interpretation and effect on outcomes remains controversial in the reproductive health setting. Recent re-evaluations of the commonly accepted normal range have yielded interesting tools for possibly explaining unexpected outcomes in assisted reproduction. Fragile X investigations should perhaps become more routinely assessed in the reproductive health setting, particularly following a failed treatment cycle where oocyte quality is thought to be a contributing factor, or in the presence of a surprise finding of diminished ovarian reserve in a young patient.

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Intermediate and normal sized CGG repeat on the FMR1 gene does not negatively affect donor ovarian response

Cited by 23 publications

References 18 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

Early decline in functional ovarian reserve in young women with low (CGGn < 26) FMR1 gene alleles

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

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