Reversion to Normal of FMR1 Expanded Alleles: A Rare Event in Two Independent Fragile X Syndrome Families

Tabolacci, Elisabetta; Pietrobono, Roberta; Maneri, Giulia; Remondini, Laura; Nobile, Veronica; Monica, Matteo Della; Pomponi, Maria Grazia; Genuardi, Maurizio; Neri, Giovanni; Chiurazzi, Pietro

doi:10.3390/genes11030248

Cited by 9 publications

(8 citation statements)

References 30 publications

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“…Notably, most of the breakpoints of larger deletions seen in the children of PM and FM carriers that have been characterized at the sequence level are associated with microhomologies (MHs) of 2-9 nucleotides [8,[12][13][14][15][16]23,[94][95][96][97][98][99][100][101]. Despite the GC-richness of the FMR1 locus that reduces the sequence space, it is possible that such MHs reflect the mechanism involved in the generation of these deletions.…”

Section: Repeat Contractionsmentioning

confidence: 99%

“…Such MHs are the hallmarks of a process known as microhomology mediated end joining (MMEJ). As illustrated in Breaks with minimal resection could result in deletions within the repeat (contractions), while more extensive resection would result in deletions that extend into the Notably, most of the breakpoints of larger deletions seen in the children of PM and FM carriers that have been characterized at the sequence level are associated with microhomologies (MHs) of 2-9 nucleotides [8,[12][13][14][15][16]23,[94][95][96][97][98][99][100][101]. Despite the GC-richness of the FMR1 locus that reduces the sequence space, it is possible that such MHs reflect the mechanism involved in the generation of these deletions.…”

Section: Repeat Contractionsmentioning

confidence: 99%

“…The consequences of these deletions depend on how far they extend into the 5 and 3 flanking regions. Some cases involve a minimal loss of flanking sequence, with a normal phenotype resulting if the repeat number is now in the normal range [12][13][14][15]. Other cases involve a deletion of the entire FMR1 gene or critical regions of exon 1.…”

Section: Introductionmentioning

confidence: 99%

“…This can result in a deficit of FMRP, resulting in a phenocopy of the symptoms seen in FM carriers [8,16]. Contraction events that generate a single allele that is present in all cells presumably occur prezygotically [9,10,15], but contractions can occur post-zygotically, resulting in individuals who are mosaic for different sized alleles [10,11,[17][18][19][20]. It has been estimated that 38% of FM carriers are mosaic for additional FM alleles, PM alleles, or both [21].…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of Genome Instability in the Fragile X-Related Disorders

Hayward

Usdin

2021

Genes

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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.

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Section: Repeat Contractionsmentioning

confidence: 99%

Section: Repeat Contractionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanisms of Genome Instability in the Fragile X-Related Disorders

Hayward

Usdin

2021

Genes

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“…Such AGG interruptions increase repeat stability, reduce the risk of expansions ( Eichler et al, 1994 ; Nolin et al, 2003 ; Yrigollen et al, 2012 ), and can modulate the disease phenotype ( Matsuyama et al, 1999 ; Sakamoto et al, 2001 ; Charles et al, 2007 ; Braida et al, 2010 ). Moreover, recent evidence has suggested pronounced repeat variability between individuals and within them (mosaicism) that also modulates the disease phenotype ( van Blitterswijk et al, 2013 ; Tabolacci et al, 2020 ). Similar mechanisms have been observed in the transmission/phenotype of related diseases, such as Myotonic Dystrophy type 1 and Huntington’s disease ( Rodriguez and Todd, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Characterization of FMR1 Repeat Expansion and Intragenic Variants by Indirect Sequence Capture

et al. 2021

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Traditional methods for the analysis of repeat expansions, which underlie genetic disorders, such as fragile X syndrome (FXS), lack single-nucleotide resolution in repeat analysis and the ability to characterize causative variants outside the repeat array. These drawbacks can be overcome by long-read and short-read sequencing, respectively. However, the routine application of next-generation sequencing in the clinic requires target enrichment, and none of the available methods allows parallel analysis of long-DNA fragments using both sequencing technologies. In this study, we investigated the use of indirect sequence capture (Xdrop technology) coupled to Nanopore and Illumina sequencing to characterize FMR1, the gene responsible of FXS. We achieved the efficient enrichment (> 200×) of large target DNA fragments (~60–80 kbp) encompassing the entire FMR1 gene. The analysis of Xdrop-enriched samples by Nanopore long-read sequencing allowed the complete characterization of repeat lengths in samples with normal, pre-mutation, and full mutation status (> 1 kbp), and correctly identified repeat interruptions relevant for disease prognosis and transmission. Single-nucleotide variants (SNVs) and small insertions/deletions (indels) could be detected in the same samples by Illumina short-read sequencing, completing the mutational testing through the identification of pathogenic variants within the FMR1 gene, when no typical CGG repeat expansion is detected. The study successfully demonstrated the parallel analysis of repeat expansions and SNVs/indels in the FMR1 gene at single-nucleotide resolution by combining Xdrop enrichment with two next-generation sequencing approaches. With the appropriate optimization necessary for the clinical settings, the system could facilitate both the study of genotype–phenotype correlation in FXS and enable a more efficient diagnosis and genetic counseling for patients and their relatives.

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Paternal retraction of a fragile X allele to normal size, showing normal function over two generations

Bartlett

Archibald

Francis

et al. 2021

American J of Med Genetics Pt A

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The FMR1 premutation (PM:55-199 CGG) is associated with fragile X-associated tremor/ataxia syndrome (FXTAS) and when maternally transmitted is at risk of expansion to a hypermethylated full mutation (FM: ≥ 200 CGG) that causes fragile X syndrome (FXS). We describe a maternally transmitted PM (77 CGG) that was passed to a son (103 CGG), and to a daughter (220-1822 CGG), who were affected with FXTAS and FXS, respectively. The male with the PM showed low-level mosaicism for normal size of 30 and 37 CGG. This male had two offspring: one female mosaic for PM and FM (56, 157, >200 CGG) and another with only a 37 CGG allele detected in multiple tissues, neither with a clinical phenotype. The female with the 37 CGG allele showed normal levels of FMR1 methylation and mRNA and passed this 37 CGG allele to one of her daughters, who was also unaffected. These findings show that postzygotic paternal retraction can lead to low-level mosaicism for normal size alleles, with these normal alleles being functional when passed over two generations.

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Reversion to Normal of FMR1 Expanded Alleles: A Rare Event in Two Independent Fragile X Syndrome Families

Cited by 9 publications

References 30 publications

Mechanisms of Genome Instability in the Fragile X-Related Disorders

Mechanisms of Genome Instability in the Fragile X-Related Disorders

Characterization of FMR1 Repeat Expansion and Intragenic Variants by Indirect Sequence Capture

Paternal retraction of a fragile X allele to normal size, showing normal function over two generations

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