Maternal <i>FMR1</i> premutation allele expansion and contraction in fraternal twins

Alfaro, Maria P.

doi:10.1002/ajmg.a.36123

Cited by 8 publications

(8 citation statements)

References 37 publications

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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: 81%

“…Despite the fact that contraction events were reported to be independent of AGG presence [8], in the present cases, the two reverted alleles derived from maternal expanded CGG repeats without AGG interruptions. In other published cases of contracted alleles, AGG interruptions were absent except for one female who inherited a 54 CGG grey zone allele by her mother, carrier of a 93 CGG PM [19]. In a recent paper, a model for CGG instability has been refined studying 5508 transmissions alleles from males and females [20].…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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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“…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. Most notably, Alfaro et al reported both expansion and contraction of a maternal PM (93 CGGs) carrier in fraternal twins in the postnatal setting [ 18 ]. This report detailed dizygous twins where the male twin demonstrated a FM expansion and the female twin showed a retraction of the mother’s PM allele to the GZ range (54 CGGs).…”

Section: Discussionmentioning

confidence: 99%

“…Whilst a number of cases of contractions into the grey zone or normal range have been previously reported [ 16 , 18 , 21 , 23 ], this is the first study to provide postnatal follow-up (repeat sizes, methylation in multiple tissues and FMR1 mRNA levels in blood) of a normal sized allele in a male twin (with a FM female sibling). Retraction to the normal CGG size in a male twin of a PM mother is an important finding in prenatal diagnosis that should not be underestimated and may be underdiagnosed due to testing regimes.…”

Section: Discussionmentioning

confidence: 99%

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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“…Vits et al [27] reported a contraction from 110 CGG repeats in the mother to 44 CGG repeats in her daughter [27]. In Alfaro et al [51], a mother's premutation (93 CGG repeats) expanded to > 200 CGG repeats in one male and contracted to 54 CGG repeats in a female twin [51]. Tabolacci et al [25] described the case of reversion from a maternal premutation allele of about 190 CGG repeat to a normal size allele of 43 CGG repeats in the male child.…”

Section: Discussionmentioning

confidence: 96%

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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Maternal FMR1 premutation allele expansion and contraction in fraternal twins

Cited by 8 publications

References 37 publications

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

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

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

Contraction of a Maternal Fragile X Mental Retardation 1 Premutation Allele

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