Fragile X full mutation expansions are inhibited by one or more AGG interruptions in premutation carriers

Nolin, Sarah L.; Glicksman, Anne; Ersalesi, Nicole; Dobkin, Carl; Brown, W. Ted; Cao, Ran; Blatt, Eliot B.; Sah, Sachin; Latham, Gary J.; Hadd, Andrew G.

doi:10.1038/gim.2014.106

Cited by 120 publications

(143 citation statements)

References 26 publications

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“…A subsequent study also confirmed the association between PM allele length and FM expansion risk [61]. Unstable allelic transmissions are also related to the lower density of repeat-stabilizing AGG anchors located at the 5′ end of the FMR1 CGG-repeat region [62,63,64,65,66]. Uninterrupted CGG tracts are thought to mediate allelic instability via the formation of stable, hair-pin structures that promote strand slippage during replication.…”

Section: Repeat Instability Of Pm-sized Allelesmentioning

confidence: 91%

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Rajan‐Babu

Chong

2016

Genes

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Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and autism. Molecular diagnostic testing of FXS and related disorders (fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS)) relies on a combination of polymerase chain reaction (PCR) and Southern blot (SB) for the fragile X mental retardation 1 (FMR1) CGG-repeat expansion and methylation analyses. Recent advancements in PCR-based technologies have enabled the characterization of the complete spectrum of CGG-repeat mutation, with or without methylation assessment, and, as a result, have reduced our reliance on the labor- and time-intensive SB, which is the gold standard FXS diagnostic test. The newer and more robust triplet-primed PCR or TP-PCR assays allow the mapping of AGG interruptions and enable the predictive analysis of the risks of unstable CGG expansion during mother-to-child transmission. In this review, we have summarized the correlation between several molecular elements, including CGG-repeat size, methylation, mosaicism and skewed X-chromosome inactivation, and the extent of clinical involvement in patients with FMR1-related disorders, and reviewed key developments in PCR-based methodologies for the molecular diagnosis of FXS, FXTAS and FXPOI, and large-scale (CGG)n expansion screening in newborns, women of reproductive age and high-risk populations.

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Section: Repeat Instability Of Pm-sized Allelesmentioning

confidence: 91%

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Rajan‐Babu

Chong

2016

Genes

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“…Recent studies propose that genetic and environmental factors may influence the process of expansions differently from those leading to repeat contractions [24,39], though their outcomes show the same underlying process. The bulk of evidence suggests that expansion can occur during transcription or open chromatin configuration involving DNA repair independently from genomic replication.…”

Section: Discussionmentioning

confidence: 99%

“…A man with a premutation or full mutation allele passes on a premutation allele to all his daughters and the increase in size is generally small [24]. Cases of contractions of maternal premutation alleles have been reported, but are rare [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Contraction of a Maternal Fragile X Mental Retardation 1 Premutation Allele

et al. 2015

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Fragile X syndrome (FXS) is mainly caused by an expansion of a cytosine-guanine-guanine (CGG) trinucleotide repeat (greater than 200) in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene resulting in gene silencing, methylation, and absence of FMRP. FXS involves a wide spectrum of phenotypes including intellectual disabilities, autism spectrum disorder (ASD), maladaptive behaviors or symptoms, social anxiety, mood disorders and physical features. Carriers of premutation alleles (55 -200 CGG repeats) can manifest with neurodevelopmental phenotypes and are at risk for the neurodegenerative fragile X-associated tremor/ataxia syndrome (FX-TAS) and about 20% of women with a premutation develop fragile Xassociated primary ovarian insufficiency (FXPOI). These phenotypes are believed to be caused by a distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Premutation alleles are unstable and depending on the CGG length and the presence of AGG interruptions have the potential to expand to larger premutation or full mutation alleles during transmission from mothers to their children. The contraction of a CGG repeat allele, although rare, has been observed. Here, we report the case of a three-generation family, who was identified as part of a pilot study of newborn screening for FXS. Specifically, the maternal grandmother carried a premutation allele (109 CGG repeats), which contracted to an intermediate size allele (52 CGG repeats) in her son, the father of a newborn girl (proband). This allele expanded to a premutation allele of 59 CGG repeats in the proband newborn. A premutation allele of 61 CGG repeats was detected in the proband's sister who demonstrated social phobia but normal cognition. The proband newborn showed some fragile X associated physical stigmata but normal cognition. Intriguingly, all FMR1 CGG expanded allele showed no AGG interruptions. This case shows a remarkable instability of premutation alleles throughout the three generations likely arising from different mechanisms.

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“…In addition to the risk of FXTAS and FXPOI, female PM carriers are also at risk of transmitting a FM allele to their children. This risk is directly related to the number of maternal CGG-repeats but is reduced by the presence of one or more AGG interruptions in the repeat tract (Eichler et al 1994; Latham et al 2014; Nolin et al 2015; Nolin et al 2013; Yrigollen et al 2012; Yrigollen et al 2014). In contrast to PM alleles, most FM alleles are epigenetically silenced (Coffee et al 2002; Coffee et al 1999; Kumari and Usdin 2010; Oberle et al 1991; Pieretti et al 1991; Sutcliffe et al 1992), and thus make little of the FMR1 gene product, FMRP, a protein important for learning and memory.…”

Section: Introductionmentioning

confidence: 99%

Recent advances in assays for the fragile X-related disorders

2017

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The Fragile X-related disorders are a group of 3 clinical conditions resulting from the instability of a CGG-repeat tract at the 5’ end of the FMR1 transcript. Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) are disorders seen in carriers of FMR1 alleles with 55–200 repeats. Female carriers of these premutation (PM) alleles are also at risk of having a child who has an FMR1 allele with >200 repeats. Most of these full mutation (FM) alleles are epigenetically silenced resulting in a deficit of the FMR1 gene product, FMRP. This results in Fragile X Syndrome (FXS), the most common heritable cause of intellectual disability and autism. The diagnosis and study of these disorders is challenging in part because the detection of alleles with large repeat numbers has, until recently, been either time-consuming or unreliable. This problem is compounded by the mosaicism for repeat length and/or DNA methylation that is frequently seen in PM and FM carriers. Furthermore, since AGG interruptions in the repeat tract affect the risk that a FM allele will be maternally transmitted, the ability to accurately detect these interruptions in female PM carriers is an additional challenge that must be met. This review will discuss some of the pros and cons of some recently described assays for these disorders, including those that detect FMRP levels directly, as well as emerging technologies that promise to improve the diagnosis of these conditions and to be useful in both basic and translational research settings.

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Fragile X full mutation expansions are inhibited by one or more AGG interruptions in premutation carriers

Cited by 120 publications

References 26 publications

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Contraction of a Maternal Fragile X Mental Retardation 1 Premutation Allele

Recent advances in assays for the fragile X-related disorders

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