Fragile X-associated disorders: a clinical overview

Gallagher, A. T.; Hallahan, Brian

doi:10.1007/s00415-011-6161-3

Cited by 92 publications

(78 citation statements)

References 157 publications

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“…1 The full mutation range g.5061CGG(4200) instigates gene inactivation and loss of FMR1 protein, thereby causing fragile X syndrome, an X-linked condition, the leading cause of inherited intellectual disability in humans. 2,3 Gleicher et al 4-6 have constructed a 'private' classification of subgenotypes within the normal FMR1 range (up to 55 repeats). As such, they labeled alleles of 26-34 CGG repeats g.5061CGG(26_34) as 'normal' , alleles of less than 26 repeats as 'low range' g.5061CGG(5_25) and those of more than 34 repeats as 'high range' g.5061CGG(35_55).…”

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confidence: 99%

BRCA1/2 mutations and FMR1 alleles are randomly distributed: a case control study

et al. 2013

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BRCA mutation carriers were reported to display a skewed distribution of FMR1 genotypes, predominantly within the low normal range (CGG repeat number o26). This observation led to the interpretation that BRCA1/2 mutations are embryo-lethal, unless rescued by 'low FMR1 alleles'. We undertook to re-explore the distribution of FMR1 alleles subdivided into low, normal and high (o26, 26-34, and 434 CGG repeats, respectively) subgenotypes, on a cohort of 125 Ashkenazi women, carriers of a BRCA1/2 founder mutation. Ashkenazi healthy females (n ¼ 368), tested in the frame of the Israeli screening population program, served as controls. BRCA1/2 carriers and controls demonstrated a comparable and non-skewed FMR1 subgenotype distribution. Taken together, using a homogeneous ethnic group of Ashkenazi BRCA1/2 mutation carriers, we could not confirm the reported association between FMR1 low genotypes and BRCA1/2 mutations. The notion that BRCA1/2 mutations are embryo-lethal unless rescued by the low FMR1 subgenotypes is hereby refuted. European Journal of Human Genetics ( Expansion of the CGG segment to the so-called pre-mutation range (approximately g.5061CGG (55_200)) is associated with neuropsychiatric risks and primary ovarian insufficiency. 1 The full mutation range g.5061CGG(4200) instigates gene inactivation and loss of FMR1 protein, thereby causing fragile X syndrome, an X-linked condition, the leading cause of inherited intellectual disability in humans. 2,3 Gleicher et al 4-6 have constructed a 'private' classification of subgenotypes within the normal FMR1 range (up to 55 repeats). As such, they labeled alleles of 26-34 CGG repeats g.5061CGG(26_34) as 'normal' , alleles of less than 26 repeats as 'low range' g.5061CGG(5_25) and those of more than 34 repeats as 'high range' g.5061CGG(35_55). Repeats within the median range g.5061CGG(29_30) correspond allegedly with the switching point between positive and negative message and peak translation of the gene product of FMR1. [4][5][6][7] Individuals were then defined as 'normal' if both alleles were in the 'normal' range, as 'heterozygous' if one allele was outside the 'normal' range and as homozygous if both alleles were outside of the range. These genotypes were further subdivided based on whether FMR1 alleles were above (high) or below (low) the normal range. [4][5][6][7]

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BRCA1/2 mutations and FMR1 alleles are randomly distributed: a case control study

et al. 2013

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“…FraX is caused by expansion of an unstable CGG repeat located in the 5′ untranslated region (NM_002024.5:c.-129_-127(6_4200) ) of the Fragile X mental retardation 1 gene (FMR1) on the Xq27.3 chromosome band. [1][2][3] In normal individuals, the number of CGG repeats does not exceed 55. Alleles that contain between 55 and 200 CGG repeats are called premutations and can expand to a full mutation (4200 repeats) in the offspring when maternally transmitted.…”

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Improving preimplantation genetic diagnosis for Fragile X syndrome: two new powerful single-round multiplex indirect and direct tests

et al. 2015

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Fragile X syndrome (FraX) is caused by the expansion of an unstable CGG repeat located in the Fragile X mental retardation 1 gene (FMR1) gene. Preimplantation genetic diagnosis (PGD) can be proposed to couples at risk of transmitting the disease, that is, when the female carries a premutation or a full mutation. We describe two new single-cell, single-round multiplex PCR for indirect and direct diagnosis of FraX on biopsied embryos. These tests include five unpublished, highly heterozygous simple sequence repeats, and the co-amplification of non-expanded CGG repeats for the direct test. Heterozygosity of the new markers ranged from 69 to 81%. The mean rate of non-informative marker included in the tests was low (26% and 23% for the new indirect and direct tests, respectively). This strategy allows offering a PGD for FraX to 96% of couples requesting it in our centre. A conclusive genotype was obtained in all cells with a rate of cells presenting an allele dropout ranging from 17% for the indirect test to 26% for the direct test. The new indirect test was applied for eight PGD cycles: 32 embryos were analysed, 9 were transferred and 3 healthy babies were born. By multiplexing these highly informative markers, robustness of the diagnosis is improved and the loss of potentially healthy embryos (because they are non-diagnosed or misdiagnosed) is limited. This may increase the chances of success of couples requesting a PGD for FraX, in particular, when premature ovarian insufficiency in premutated women leads to a reduced number of embryos available for analysis.

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“…As a consequence of their tight epigenetic regulation imprinted genes are thought to be particularly sensitive to alterations in gene dosage and maternal duplications can lead to a number of neurodevelopment disorders (McNamara & Isles 2013). Fragile X syndrome CGG repeat expansion within the FMR1 gene promoter attracts DNA hypermethylation resulting in inhibition of transcription and loss of the protein FMRP is ubiquitously expressed and especially abundant in neurons, where it regulates multiple processes related to RNA metabolism, especially the transport and localization of mRNA to dendrites and synapses (Gallagher & Hallahan 2012) Herb et al (2012) went on to show that foragers who reverted to nursing behavior upon returning to a hive now depleted of nurse bees, also showed the original epigenetic profile of a nurse. Again, this firmly underscores the link between the epigenome of the brain and behavior.…”

Section: Genes Sensitive To Alterations In Their Epigenetic Regulationmentioning

confidence: 99%

Neural and behavioral epigenetics; what it is, and what is hype

Isles

2015

Genes Brain and Behavior

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The ability to examine epigenetic mechanisms in the brain has become readily available over the last 20 years. This has led to an explosion of research and interest in neural and behavioral epigenetics. Of particular interest to researchers, and indeed the lay public, is the possibility that epigenetic processes, such as changes in DNA-methylation and histone modification, may provide a biochemical record of environmental effects. This has led to some fascinating insights into how molecular changes in the brain can control behavior. However, some of this research has also attracted controversy and, as is dealt with here, some overblown claims. This latter problem is partly linked to the shifting sands of what is defined as 'epigenetics'. In this review, I provide an overview of what exactly epigenetics is, and what is hype, with the aim of opening up a debate as to how this exciting field moves forward.

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Fragile X-associated disorders: a clinical overview

Cited by 92 publications

References 157 publications

BRCA1/2 mutations and FMR1 alleles are randomly distributed: a case control study

BRCA1/2 mutations and FMR1 alleles are randomly distributed: a case control study

Improving preimplantation genetic diagnosis for Fragile X syndrome: two new powerful single-round multiplex indirect and direct tests

Neural and behavioral epigenetics; what it is, and what is hype

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