Expansion of an FMR1 Grey-Zone Allele to a Full Mutation in Two Generations

Laboratorio de Genética Humana, Unidad de Diagnóstico Genético y Perinatal, Instituto de Biología y Genética Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain.
The Journal of molecular diagnostics: JMD (Impact Factor: 4.85). 08/2009; 11(4):306-10. DOI: 10.2353/jmoldx.2009.080174
Source: PubMed


Fragile X Syndrome is caused by the expansion of an unstable CGG-repeat tract in the 5'-UTR of the FMR1 gene, which generally results in transcriptional silencing and consequent absence of the FMR1 protein. To date, the smallest premutation allele reported to expand to a full mutation allele in a single generation is 59 CGG repeats. Here, we report a single-generation expansion to a full mutation allele (male with approximately 538 CCG repeats) from a mother who is a carrier of a premutation allele of 56 CGG repeats. Furthermore, the maternal grandfather was a carrier of a gray (or intermediate)-zone allele (45 to 54 repeats) of 52 CGG repeats. Thus, in this family, a gray-zone allele expanded to the full mutation range in two generations. Interestingly, the two AGG interruptions present in the grandfather's allele were absent in the mother's premutation allele. These observations underscore the need to consider carriers of alleles of greater than 55 CGG repeats as being at risk for transmission of a full mutation allele in a single generation, and those with even smaller alleles in the gray zone as being at risk of having grandchildren with full mutation alleles.

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Available from: Isabel Fernandez-Carvajal
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    • "Of the 6.6% that expanded within the intermediate range, the offspring allele size never expanded beyond 60 repeats in 1 generation. The smallest reported repeat size to expand to a full mutation in the subsequent generation was 56; the grandmother of the affected child had a repeat size of 52 (Fernandez-Carvajal et al., 2009). No data are available on the stability of transmission of <45 CGG repeats in females. "
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    ABSTRACT: The strongest association between FMR1 and the ovary in humans is the increased risk of premature ovarian failure (POF) in women who carry the premutation level of CGG repeats (55-199 CGGs). Research on the FMR1 gene has extended to other endpoints of relevance in the OB/GYN setting for women, including infertility and ovarian hormones. After reviewing the nomenclature changes that have occurred in recent years, this article reviews the evidence linking the length of the FMR1 repeat length to fertility and ovarian hormones (follicle stimulating hormone and anti-mullerian hormone as the primary methods to assess ovarian reserve in clinical settings). The literature is inconsistent on the association between the FMR1 trinucleotide repeat length and infertility. Elevated levels of follicle stimulating hormone have been found in women who carry the premutation; however the literature on the relationship between anti-mullerian hormone and the CGG repeat length are too disparate in design to make a summary statement. This article considers the implications of two transgenic mouse models (FXPM 130R and YAC90R) for theories on pathogenesis related to ovarian endpoints. Given the current screening/testing recommendations for reproductive age females and the variability of screening protocols in clinics, future research is recommended on pretest and posttest genetic counseling needs. Future research is also needed on ovarian health measurements across a range of CGG repeat lengths in order to interpret FMR1 test results in reproductive age women; the inconsistencies in the literature make it quite challenging to advise women on their risks related to FMR1 repeat length.
    Full-text · Article · Jul 2014 · Frontiers in Genetics
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    • "In any case, there are some differences with the previous studies that we want to highlight. First, in mothers with 50 to 54 repeats (IAs), they expanded to a PM allele in 10 cases and in the range of the smallest PM alleles, 6.4% of alleles of 55 to 59 repeats expanded in a single meiosis to a FM allele [30, 31]. Furthermore, for ICs (not included in Table 6), the smallest maternal allele observed to expand to a FM allele contained 56 repeats. "
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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.
    Full-text · Dataset · Jun 2014
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    • "The ability of AGG/CCT interruptions to alter the positioning of the CGG/CCG repeat may contribute to the “gray zone” between healthy and pre-mutation lengths, where uninterrupted repeats classified as healthy-length can expand, but longer, interrupted repeats do not [23,25-27]. Perhaps by modulating either the ability of the repeat tract to form a nucleosome or by altering its rotational and translational position around the histone core, the interruptions offer some protection from expansion. "
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    ABSTRACT: Fragile X Syndrome (FXS), the most common inherited form of mental retardation, is caused by expansion of a CGG/CCG repeat tract in the 5[prime]-untranslated region of the fragile X mental retardation (FMR1) gene, which changes the functional organization of the gene from euchromatin to heterochromatin. Interestingly, healthy-length repeat tracts possess AGG/CCT interruptions every 9--10 repeats, and clinical data shows that loss of these interruptions is linked to expansion of the repeat tract to disease-length. Thus, it is important to understand how these interruptions alter the behavior of the repeat tract in the packaged gene. To investigate how uninterrupted and interrupted CGG/CCG repeat tracts interact with the histone core, we designed experiments using the nucleosome core particle, the most basic unit of chromatin packaging. Using DNA containing 19 CGG/CCG repeats, flanked by either a nucleosome positioning sequence or the FMR1 gene sequence, we determined that the addition of a single AGG/CCT interruption modulates both the ability of the CGG/CCG repeat DNA to incorporate into a nucleosome and the rotational and translational position of the repeat DNA around the histone core when flanked by the nucleosome positioning sequence. The presence of these interruptions also alters the periodicity of the DNA in the nucleosome; interrupted repeat tracts have a greater periodicity than uninterrupted repeats. This work defines the ability of AGG/CCT interruptions to modulate the behavior of the repeat tract in the packaged gene and contributes to our understanding of the role that AGG/CCT interruptions play in suppressing expansion and maintaining the correct functional organization of the FMR1 gene, highlighting a protective role played by the interruptions in genomic packaging.
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