The FMR1 premutation and reproduction

Intramural Research Program, Section on Women's Health Research, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1103, USA.
Fertility and sterility (Impact Factor: 4.59). 03/2007; 87(3):456-65. DOI: 10.1016/j.fertnstert.2006.09.004
Source: PubMed


To update clinicians on the reproductive implications of premutations in FMR1 (fragile X mental retardation 1). Fragile X syndrome, a cause of mental retardation and autism, is due to a full mutation (>200 CGG repeats). Initially, individuals who carried the premutation (defined as more than 55 but less than 200 CGG repeats) were not considered at risk for any clinical disorders. It is now recognized that this was incorrect, specifically with respect to female reproduction.
Literature review and consensus building at two multidisciplinary scientific workshops.
Convincing evidence now relates the FMR1 premutation to altered ovarian function and loss of fertility. An FMR1 mRNA gain-of-function toxicity may underlie this altered ovarian function. There are major gaps in knowledge regarding the natural history of the altered ovarian function in women who carry the FMR1 premutation, making counseling about reproductive plans a challenge. Women with premature ovarian failure are at increased risk of having an FMR1 premutation and should be informed of the availability of fragile X testing. Specialists in reproductive medicine can provide a supportive environment in which to explain the implications of FMR1 premutation testing, facilitate access to testing, and make appropriate referral to genetic counselors.

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Available from: Lawrence Nelson, Sep 23, 2015
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    • "Autoimmune and metabolic etiologies may or may not be genetic. Irrespective , etiology remains to be elucidated in most cases and until a decade ago few specific causes were known beyond X-chromosomal abnormalities, Fragile X mental retardation 1 (FMR1) premutation and FSH receptor (FSHR) in the Finnish population (Simpson, 1975; Aittomäki et al., 1995; Wittenberger et al., 2007). Most cases of isolated POI still appear sporadically, but 10 –15% has an affected first-degree relative, indicating significant genetic etiology (Van Kasteren et al., 1999). "
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    ABSTRACT: Primary ovarian insufficiency (POI) is characterized by marked heterogeneity, but with a significant genetic contribution. Identifying exact causative genes has been challenging, with many discoveries not replicated. It is timely to take stock of the field, outlining the progress made, framing the controversies and anticipating future directions in elucidating the genetics of POI. A search for original articles published up to May 2015 was performed using PubMed and Google Scholar, identifying studies on the genetic etiology of POI. Studies were included if chromosomal analysis, candidate gene screening and a genome-wide study were conducted. Articles identified were restricted to English language full-text papers. Chromosomal abnormalities have long been recognized as a frequent cause of POI, with a currently estimated prevalence of 10-13%. Using the traditional karyotype methodology, monosomy X, mosaicism, X chromosome deletions and rearrangements, X-autosome translocations, and isochromosomes have been detected. Based on candidate gene studies, single gene perturbations unequivocally having a deleterious effect in at least one population include Bone morphogenetic protein 15 (BMP15), Progesterone receptor membrane component 1 (PGRMC1), and Fragile X mental retardation 1 (FMR1) premutation on the X chromosome; Growth differentiation factor 9 (GDF9), Folliculogenesis specific bHLH transcription factor (FIGLA), Newborn ovary homeobox gene (NOBOX), Nuclear receptor subfamily 5, group A, member 1 (NR5A1) and Nanos homolog 3 (NANOS3) seem likely as well, but mostly being found in no more than 1-2% of a single population studied. Whole genome approaches have utilized genome-wide association studies (GWAS) to reveal loci not predicted on the basis of a candidate gene, but it remains difficult to locate causative genes and susceptible loci were not always replicated. Cytogenomic methods (array CGH) have identified other regions of interest but studies have not shown consistent results, the resolution of arrays has varied and replication is uncommon. Whole-exome sequencing in non-syndromic POI kindreds has only recently begun, revealing mutations in the Stromal antigen 3 (STAG3), Synaptonemal complex central element 1 (SYCE1), minichromosome maintenance complex component 8 and 9 (MCM8, MCM9) and ATP-dependent DNA helicase homolog (HFM1) genes. Given the slow progress in candidate-gene analysis and relatively small sample sizes available for GWAS, family-based whole exome and whole genome sequencing appear to be the most promising approaches for detecting potential genes responsible for POI. Taken together, the cytogenetic, cytogenomic (array CGH) and exome sequencing approaches have revealed a genetic causation in ∼20-25% of POI cases. Uncovering the remainder of the causative genes will be facilitated not only by whole genome approaches involving larger cohorts in multiple populations but also incorporating environmental exposures and exploring signaling pathways in intragenic and intergenic regions that point to perturbations in regulatory genes and networks. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
    Full-text · Article · Aug 2015 · Human Reproduction Update
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    • "One clinically significant risk associated with the FMR1 premutation in women is for fragile X-associated primary ovarian insufficiency (FXPOI). Approximately 20–25 % of carriers will develop premature ovarian failure (POF), or cessation of menses prior to age 40 compared to 1 % of the general population (Sherman 2000; Wittenberger et al. 2007). FXPOI can manifest in a spectrum of symptoms related to early onset ovarian changes and may present distinct challenges according to stage of life (Allen et al. 2007; Rohr et al. 2008; Sullivan et al. 2005; Welt et al. 2004; Wheeler et al. 2014). "
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    ABSTRACT: Women who carry an FMR1 (i.e., fragile X) premutation have specific health risks over their lifetime. However, little is known about their experience understanding these risks and navigating their health needs. The aim of this study was to use qualitative analysis to uncover both barriers and facilitators to personal healthcare using a framework of the Health Belief Model. Five focus groups were conducted with a total of 20 women who carry the FMR1 premutation using a semi-structured discussion guide. All sessions were transcribed verbatim and independently coded by two researchers. The coders used a deductive - inductive approach to determine the prominent themes related to the participants' experiences seeking healthcare for premutation-related conditions. Salient barriers to personal healthcare included difficult clinical translation of research findings, lack of knowledge among healthcare providers and among the women themselves, different priorities, and shortage of premutation-specific support and targeted educational materials. Facilitators included family members, national and community support organizations, research studies, compassionate physicians, and other premutation carriers. Addressing barriers to personal healthcare through up-to-date educational materials can help diminish misperceptions regarding health risks. Targeted educational materials will aid in information sharing and awareness for women who carry the FMR1 premutation and their physicians.
    Full-text · Article · Jul 2015 · Journal of Genetic Counseling
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    • "It has been known for decades that premutation range mutations of the fragile X mental retardation (FMR1) gene (CGGn55-200) are associated with greatly increased female risk of primary ovarian insufficiency (POI; Wittenberger et al., 2007). Neither endocrinologists nor geneticists, however, considered the possibility that the gene, beyond widely investigated neuro-psychiatric effects, giving it the name “fragile X chromosome,” may also have a role in ovarian function. "
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    ABSTRACT: This manuscript describes the 6 year evolution of our center's research into ovarian functions of the FMR1 gene, which led to the identification of a new normal CGGn range of 26-34. This "new" normal range, in turn, led to definitions of different alleles (haplotypes) based on whether no, one or both alleles are within range. Specific alleles then were demonstrated to represent distinct ovarian aging patterns, suggesting an important FMR1 function in follicle recruitment and ovarian depletion of follicles. So called low alleles, characterized by CGGn<26, appear associated with most significant negative effects on reproductive success. Those include occult primary ovarian insufficiency (OPOI), characterized by prematurely elevated follicle stimulating hormone (FSH) and prematurely low anti-Müllerian hormone, and significantly reduced clinical pregnancy rates in association with in vitro fertilization (IVF) in comparison to women with normal (norm) and high (CGGn>34) alleles. Because low FMR1 alleles present in approximately 25% of all females, FMR1 testing at young ages may offer an opportunity for earlier diagnosis of OPOI than current practice allows. Earlier diagnosis of OPOI, in turn, would give young women the options of reassessing their reproductive schedules and/or pursue fertility preservation via oocyte cryopreservation when most effective.
    Full-text · Article · Aug 2014 · Frontiers in Genetics
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