Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?

Manor, Esther; Jabareen, Azhar; Magal, Nurit; Kofman, Arei; Hagerman, Randi J.; Tassone, Flora

doi:10.3389/fgene.2017.00158

Cited by 8 publications

(8 citation statements)

References 40 publications

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“…Retractions from FM to normal allele size have been reported to be rare by some studies [ 15 ], but more common by others [ 16 ]. These have also been reported in the prenatal setting [ 17 ] without postnatal follow-up. The cause of these retractions is unknown but may be due to excision of the expanded FM or PM CGG repeat in the early postzygotic period, producing mosaic normal size/grey zone size (GZ 45-54 CGGs)/PM/FM results with tissue variability.…”

Section: Discussionsupporting

confidence: 58%

Prenatal Diagnosis of Fragile X Syndrome in a Twin Pregnancy Complicated by a Complete Retraction

Prawer

Hunter

Cronin

et al. 2018

Genes

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Fragile X syndrome (FXS) is usually associated with a CGG repeat expansion >200 repeats within the FMR1 gene, known as a full mutation (FM). FM alleles produce abnormal methylation of the FMR1 promoter with reduction or silencing of FMR1 gene expression. Furthermore, premutation (PM: 55–199 CGGs) and full mutation alleles usually expand in size when maternally transmitted to progeny. This study describes a PM allele carried by the mother decreasing to a normal sized allele in a male from a dichorionic diamniotic (DCDA) twin pregnancy, with the female twin inheriting FM (200–790 CGGs), PM (130 CGGs) and normal-sized (39 CGGs) alleles. Further evidence of instability of the maternal PM allele was shown by a male proband (older brother) mosaic for PM (CGG 78 and 150 CGGs) and FM (200–813 CGGs), and a high level of FMR1 promoter methylation, between 50 and 70%, in multiple tissues. The fully-retracted, normal-sized allele was identified by PCR CGG sizing in the male twin, with no evidence of a FM allele identified using Southern blot analysis in multiple tissues collected postnatally and prenatally. Consistent with this, prenatal PCR sizing (35 CGGs) showed inconsistent inheritance of the maternal normal allele (30 CGGs), with single-nucleotide polymorphism (SNP) linkage analysis confirming that the abnormal FMR1 chromosome had been inherited from the mother’s PM chromosome. Importantly, the male twin showed no significant hypermethylation of the FMR1 promoter in all pre and postnatal tissues tested, as well as normal levels of FMR1 mRNA in blood. In summary, this report demonstrates the first postnatal follow up of a prenatal case in which FMR1 mRNA levels were approaching normal, with normal levels of FMR1 promoter methylation and normal CGG size in multiple pre and postnatally collected tissues.

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Section: Discussionsupporting

confidence: 58%

Prenatal Diagnosis of Fragile X Syndrome in a Twin Pregnancy Complicated by a Complete Retraction

Prawer

Hunter

Cronin

et al. 2018

Genes

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“…Contracted alleles detected in FXS families in a non-mosaic state have already been reported by us, in an unaffected boy who inherited an allele of 43 CGGs derived from a large PM (around 190 CGGs) carried by his mother [21]. Similar reverted and non-mosaic alleles have been described in FXS families both in unaffected females [19,22] and in unaffected males [23,24]. Contracted alleles in the range of normality have also been detected along with expanded ones in FXS mosaic males, such as in the four affected boys reported by Maia et al [25], who inherited the normal allele by their FM or PM mother, or as in a monozygous male twin, who derived the normal allele from his PM mother [26].…”

Section: Discussionsupporting

confidence: 80%

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

Tabolacci

Pietrobono

Maneri

et al. 2020

Genes

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Fragile X syndrome (FXS) is mostly due to the expansion and subsequent methylation of a polymorphic CGG repeat in the 5’ UTR of the FMR1 gene. Full mutation alleles (FM) have more than 200 repeats and result in FMR1 gene silencing and FXS. FMs arise from maternal premutations (PM) that have 56–200 CGGs; contractions of a maternal PM or FM are rare. Here, we describe two unaffected boys in two independent FXS families who inherited a non-mosaic allele in the normal and intermediate range, respectively, from their mothers who are carriers of an expanded CGG allele. The first boy inherited a 51 CGG allele (without AGG interruptions) from his mother, who carries a PM allele with 72 CGGs. The other boy inherited from his FM mother an unusual allele with 19 CGGs resulting from a deletion, removing 85 bp upstream of the CGG repeat. Given that transcription of the deleted allele was found to be preserved, we assume that the binding sites for FMR1 transcription factors are excluded from the deletion. Such unusual cases resulting in non-mosaic reduction of maternal CGG expansions may help to clarify the molecular mechanisms underlying the instability of the FMR1 gene.

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“…Although this is a genetic event rarely described, few cases of contraction of a maternal high premutation/full mutation FMR1 allele during transmission have been reported ( Yrigollen et al, 2014 ; Miranda et al, 2015 ; Maia et al, 2017 ). More unique it is the case of contraction of an expanded FMR1 unstable allele to a normal size, recently reported ( Manor et al, 2017 ).…”

Section: Discussionmentioning

confidence: 94%

FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the FMR1 Gene

et al. 2018

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Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the FMR1 gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5′UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with one FXS child and another sibling presenting mild intellectual disability and behavioral features evocative of FXS. Genetic characterization of the undiagnosed sibling revealed mosaicism in both the CGG expansion size and the methylation levels in the different tissues analyzed. This report shows that in the same family, two siblings carrying different CGG repeats, one in the full-mutation range and the other in the premutation range, present methylation mosaicism and consequent decreased FMRP production leading to FXS and FXS-like features, respectively. Decreased FMRP levels, more than the number of repeats seem to correlate with the severity of FXS clinical phenotypes.

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Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?

Cited by 8 publications

References 40 publications

Prenatal Diagnosis of Fragile X Syndrome in a Twin Pregnancy Complicated by a Complete Retraction

Prenatal Diagnosis of Fragile X Syndrome in a Twin Pregnancy Complicated by a Complete Retraction

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

FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the FMR1 Gene

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