Mosaicism for the full mutation and a microdeletion involving the CGG repeat and flanking sequences in theFMR1 gene in eight fragile X patients

Grasso, Marina; Faravelli, Francesca; Nigro, Cristiana Lo; Chiurazzi, Pietro; Sperandeo, Maria Pia; Argusti, Alessandra; Pomponi, Maria Grazia; Lecora, M.; Sebastio, Gianfranco; Perroni, L; Andria, Generoso; Neri, Giovanni; Bricarelli, Franca Dagna

doi:10.1002/(sici)1096-8628(19990730)85:3<311::aid-ajmg24>3.0.co;2-a

Cited by 27 publications

(27 citation statements)

References 14 publications

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“…The most logical mechanism for normal-size allele generation in our mosaic case is a deletion/regression within the frame of the full mutation restricted to the CGG repeat itself3 , 6 , 7 , 12 as the primers we used for PCR were designed in the repeat flanking regions. Only one case of maternal premutation reversion to a normal-size allele resulting in a non-mosaic male is reported so far,13 but in our opinion the frequency of such cases might be underestimated because of lack of clinical manifestation.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that mosaicism for methylated full mutation and an unmethylated premutation account for more than 40% of affected males 3. To the best of our knowledge, mosaic cases of full mutation/normal allele or full mutation/deletion are rarely detected 3 – 7. The precise DNA diagnosis and assessment of the expansion is technically very complicated.…”

Section: Introductionmentioning

confidence: 99%

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Fragile X mosaic male full mutation/normal allele detected by PCR/MS-MLPA

Todorov

Тодорова²,

Kirov³

et al. 2009

Case Reports

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We report on a fragile X mosaic male full mutation/normal allele detected by PCR and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). This combined analysis provides a diagnostic approach for fragile X syndrome (FXS). The method assesses the presence of expansion (full mutation), the CpG methylation status and could determine copy number changes (large deletions/duplications) along the FMR1 and FMR2 (fragile X mental retardation) genes. The method avoids detection of premutations, which makes it applicable for newborn screening. It can also be used in clarification of mosaic cases. The PCR results in our patient showed one normal allele; three repeats larger than his mother's one. The MS-MLPA showed hypermethylated full mutation pattern in the proband. Both results are compatible with FXS mosaic case full mutation/normal allele. The patient demonstrates atypical mild clinical manifestation of the disease, which correlates to the presence of a normal size allele in the patient's cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fragile X mosaic male full mutation/normal allele detected by PCR/MS-MLPA

Todorov

Тодорова²,

Kirov³

et al. 2009

Case Reports

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“…The presence of deletions encompassing the CGG repeat, as well as sequences flanking the CGG tract, has been noted in a small number of FXS males. 12,15,16,31 Interestingly, in many of these events, the 5 0 breakpoint mapped to a 'deletion hotspot' region. 31 It was demonstrated that…”

Section: Discussionmentioning

confidence: 99%

A unique case of reversion to normal size of a maternal premutation FMR1 allele in a normal boy

Tabolacci¹,

Pomponi²,

Pietrobono³

et al. 2007

Eur J Hum Genet

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Fragile X syndrome (FXS) is caused mostly by expansion and subsequent methylation of the CGG repeat in the 5 0 UTR of the FMR1 gene, resulting in silencing of the gene, absence of FMRP and development of the FXS phenotype. The expansion also predisposes the CGG repeat and the flanking regions to further instability that may lead to mosaics between a full mutation and a premutation or, rarely, a normal or deleted allele. Here, we report on a 10-year-old boy with no FXS phenotype, who has a normal CGG tract, although he inherited the maternal expanded allele that causes FXS in his two brothers. Southern blotting demonstrated that the mother carries a premutation allele (B190 CGG), whereas the propositus shows a normal 5.2 kb fragment after HindIII digestion and a smaller 2.2 kb fragment after double HindIII-EagI digestion, without any apparent mosaicism in peripheral blood leukocytes. PCR and sequence analysis of the FMR1 5 0 UTR revealed an allele of 43 repeats, with two interspersed AGG triplets in position 10 and 25 and an exceptional CCG triplet in position 17. This latter creates an abnormal EagI site compatible with the smaller 2.2 kb fragment observed with Southern blotting. Haplotype analysis proved that the rearranged allele originated from the maternal expanded allele. To the best of our knowledge, this is the first nonmosaic case of reduction in the CGG tract of the FMR1 gene, resulting in a normal allele.

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“…While expansions predominate, contractions are also seen including reversions of PM alleles into the normal size range (Mornet et al, 1996; Vaisanen et al, 1996; Gasteiger et al, 2003; Tabolacci et al, 2008b) and FMs into the PM range (Malzac et al, 1996; Loesch et al, 1997). It is some combination of these expansions and contractions that accounts for the repeat length mosaicism that is often seen in PM and FM carriers (Rousseau et al, 1991; Nolin et al, 1994; Prior et al, 1995; Cohen et al, 1996; de Graaff et al, 1996; Dobkin et al, 1996; Maddalena et al, 1996; Mila et al, 1996; Grasso et al, 1999; Petek et al, 1999; Schmucker and Seidel, 1999; Garcia Arocena et al, 2000; Fan et al, 2005; Govaerts et al, 2007; Todorov et al, 2009; Ferreira et al, 2013; Pretto et al, 2013; Santa Maria et al, 2013). …”

Section: Repeat Instability At the Fx Locusmentioning

confidence: 99%

Repeat-mediated genetic and epigenetic changes at the FMR1 locus in the Fragile X-related disorders

et al. 2014

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The Fragile X-related disorders are a group of genetic conditions that include the neurodegenerative disorder, Fragile X-associated tremor/ataxia syndrome (FXTAS), the fertility disorder, Fragile X-associated primary ovarian insufficiency (FXPOI) and the intellectual disability, Fragile X syndrome (FXS). The pathology in all these diseases is related to the number of CGG/CCG-repeats in the 5′ UTR of the Fragile X mental retardation 1 (FMR1) gene. The repeats are prone to continuous expansion and the increase in repeat number has paradoxical effects on gene expression increasing transcription on mid-sized alleles and decreasing it on longer ones. In some cases the repeats can simultaneously both increase FMR1 mRNA production and decrease the levels of the FMR1 gene product, Fragile X mental retardation 1 protein (FMRP). Since FXTAS and FXPOI result from the deleterious consequences of the expression of elevated levels of FMR1 mRNA and FXS is caused by an FMRP deficiency, the clinical picture is turning out to be more complex than once appreciated. Added complications result from the fact that increasing repeat numbers make the alleles somatically unstable. Thus many individuals have a complex mixture of different sized alleles in different cells. Furthermore, it has become apparent that the eponymous fragile site, once thought to be no more than a useful diagnostic criterion, may have clinical consequences for females who inherit chromosomes that express this site. This review will cover what is currently known about the mechanisms responsible for repeat instability, for the repeat-mediated epigenetic changes that affect expression of the FMR1 gene, and for chromosome fragility. It will also touch on what current and future options are for ameliorating some of these effects.

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Mosaicism for the full mutation and a microdeletion involving the CGG repeat and flanking sequences in theFMR1 gene in eight fragile X patients

Cited by 27 publications

References 14 publications

Fragile X mosaic male full mutation/normal allele detected by PCR/MS-MLPA

Fragile X mosaic male full mutation/normal allele detected by PCR/MS-MLPA

A unique case of reversion to normal size of a maternal premutation FMR1 allele in a normal boy

Repeat-mediated genetic and epigenetic changes at the FMR1 locus in the Fragile X-related disorders

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