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: 4.3). 03/2007; 87(3):456-65. DOI: 10.1016/j.fertnstert.2006.09.004
Source: PubMed

ABSTRACT 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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    • "It was initially thought that females with a PM were completely asymptomatic, but it was soon realized that this is not the case: in 1996, a family was described in which the women with a PM presented with clinical symptoms seemingly unrelated to ID: a premature ovarian failure leading to premature menopause [9]. Over the years these findings have been confirmed in numerous studies, all pointing to fragile X-associated primary ovarian insufficiency (FXPOI), as a phenotypic characteristic of PM carriers although only about 13–26% of them present with this trait [10]. Interestingly, full mutation carriers do not seem to present FXPOI. "
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    ABSTRACT: Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P < 0.001). Furthermore, in mothers with intermediate alleles (45-54 repeats), there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55-59 repeats), there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of <59 repeats is somewhat higher than in other published series. These findings are important for genetic counselling.
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    • "The most common are chromosomal aberrations including Turner's syndrome (Baronchelli et al., 2012). Premutation of the FMR1 gene is responsible for 2 – 5% of sporadic cases with POI presenting with SA (Wittenberger et al., 2007; De Vos et al., 2010). Other known genetic causes are mutations in genes for oocytesecreted factors, GDF9 (growth differentiation factor 9) and BMP15 (Dixit et al., 2006; Kovanci et al., 2007), for oocyte nuclear transcription factors NOBOX and FIGLA (Qin et al., 2007; Zhao et al., 2008) and for the hormone receptors FSHR and NR5A1 (Aittomaki et al., 1995; Janse et al., 2012). "
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    ABSTRACT: Can high-resolution array comparative genomic hybridization (CGH) analysis of DNA samples from women with primary ovarian insufficiency (POI) improve the diagnosis of the condition and identify novel candidate genes for POI?
    Human Reproduction 06/2014; 29(8). DOI:10.1093/humrep/deu149 · 4.59 Impact Factor
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    • "Premutation carriers were originally considered to be unaffected, but in recent years consensus has been growing among researchers and practitioners that at least some premutation carriers display signs of impairment, with high levels of premutation-containing mRNA suspected to result in ''toxicity'' leading to disease (Berry-Kravis et al. 2004). As such, FXS is now considered to be part of a multigenerational collection of clinical conditions including the Fragile X Tremor Ataxia Syndrome (FXTAS) and Primary Ovarian Insufficiency (POI; Chonchaiya et al. 2009; Hagerman and Hagerman 2004; Wittenberger et al. 2007). These difficulties are not uncommon, with prevalence rates for female carriers over the age of 50 reported to be 18.6 and 16.5% for POI and FXTAS, respectively (Rodriguez-Revenga et al. 2009). "
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    ABSTRACT: Health symptoms of mothers of adolescents and adults with fragile X syndrome (FXS; n = 112) were compared to a nationally-representative sample of mothers of similarly-aged children without disabilities (n = 230) as well as to a sample of mothers of adolescents and adults with autism spectrum disorders (ASD; n = 96). Health symptoms experienced in the previous 24 h were recorded during 8 consecutive days of a daily diary study. Both mothers of a son or daughter with FXS and mothers of a son or daughter with ASD had a higher proportion of days with headaches, backaches, muscle soreness, fatigue, and hot flashes than mothers of children without disabilities. Mothers of children with disabilities appear to be at particular risk for health problems, highlighting a need for comprehensive services for families across the lifespan.
    Journal of Autism and Developmental Disorders 12/2011; 42(9):1836-46. DOI:10.1007/s10803-011-1422-7 · 3.06 Impact Factor


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