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Review

Mechanisms of Genome Instability in the Fragile X-Related Disorders

Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Academic Editors: David E. Godler and William Ted Brown
Genes 2021, 12(10), 1633; https://doi.org/10.3390/genes12101633
Received: 20 September 2021 / Revised: 12 October 2021 / Accepted: 14 October 2021 / Published: 17 October 2021
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54–200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the FMR1 gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes. View Full-Text
Keywords: repeat mosaicism; chromosome fragility; repeat expansion; repeat contractions; aneuploidy; break induced replication (BIR); base excision repair (BER); microhomology mediated end-joining (MMEJ); mitotic DNA synthesis (MiDAS) repeat mosaicism; chromosome fragility; repeat expansion; repeat contractions; aneuploidy; break induced replication (BIR); base excision repair (BER); microhomology mediated end-joining (MMEJ); mitotic DNA synthesis (MiDAS)
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MDPI and ACS Style

Hayward, B.E.; Usdin, K. Mechanisms of Genome Instability in the Fragile X-Related Disorders. Genes 2021, 12, 1633. https://doi.org/10.3390/genes12101633

AMA Style

Hayward BE, Usdin K. Mechanisms of Genome Instability in the Fragile X-Related Disorders. Genes. 2021; 12(10):1633. https://doi.org/10.3390/genes12101633

Chicago/Turabian Style

Hayward, Bruce E., and Karen Usdin. 2021. "Mechanisms of Genome Instability in the Fragile X-Related Disorders" Genes 12, no. 10: 1633. https://doi.org/10.3390/genes12101633

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