AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission

Yrigollen, Carolyn M.; Martorell, Loreto; Durbin‐Johnson, Blythe; Naudó, Montserrat; Genovès, Jordi; Murgia, Alessandra; Polli, Roberta; Zhou, Lili; Barbouth, Deborah; Rupchock, Abigail; Finucane, Brenda; Latham, Gary J.; Hadd, Andrew G.; Berry‐Kravis, Elizabeth; Tassone, Flora

doi:10.1186/1866-1955-6-24

Cited by 97 publications

(105 citation statements)

References 26 publications

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“…However, the presence of AGG interruptions in both intermediate and premutation alleles has been shown to decrease the rate of instability (any change in CGG repeat size) and magnitude of size change in both paternal and maternal transmissions (12,25,26).…”

Section: Introductionmentioning

confidence: 99%

Distribution of AGG interruption patterns within nine world populations

Yrigollen

Sweha

Durbin‐Johnson

et al. 2014

IRDR

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The CGG trinucleotide repeat within the FMR1 gene is associated with multiple clinical disorders, including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X syndrome. Differences in the distribution and prevalence of CGG repeat length and of AGG interruption patterns have been reported among different populations and ethnicities. In this study we characterized the AGG interruption patterns within 3,065 normal CGG repeat alleles from nine world populations including Australia, Chile, United Arab Emirates, Guatemala, Indonesia, Italy, Mexico, Spain, and United States. Additionally, we compared these populations with those previously reported, and summarized the similarities and differences. We observed significant differences in AGG interruption patterns. Frequencies of longer alleles, longer uninterrupted CGG repeat segments and alleles with greater than 2 AGG interruptions varied between cohorts. The prevalence of fragile X syndrome and FMR1 associated disorders in various populations is thought to be affected by the total length of the CGG repeat and may also be influenced by the AGG distribution pattern. Thus, the results of this study may be important in considering the risk of fragile X-related conditions in various populations

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Section: Introductionmentioning

confidence: 99%

Distribution of AGG interruption patterns within nine world populations

Yrigollen

Sweha

Durbin‐Johnson

et al. 2014

IRDR

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“…10 CGG repeats [23,[109][110][111]. These AGG interspersions (1 to 3 in normal and intermediate alleles, 0 to 1 in the premutated condition), accountable for allelic stability of the CGG expansion, may deeply influence the risk of full gene mutation and are also inherited (Fig.…”

Section: Introductionmentioning

confidence: 99%

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Noto

Harrity

Walsh

et al. 2016

J Assist Reprod Genet

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Purpose This is a comprehensive review of the literature in this field attempting to put the FMR1 gene and its evaluation into context, both in general and for the reproductive health audience. Methods Online database search of publications with systematic review of all papers relevant to ovarian reserve and assisted reproduction was done. Results Relevant papers were identified and assessed, and an attempt was made to understand, rationalize and explain the divergent views in this field of study. Seminal and original illustrations were employed. Conclusions FMR1 is a highly conserved gene whose interpretation and effect on outcomes remains controversial in the reproductive health setting. Recent re-evaluations of the commonly accepted normal range have yielded interesting tools for possibly explaining unexpected outcomes in assisted reproduction. Fragile X investigations should perhaps become more routinely assessed in the reproductive health setting, particularly following a failed treatment cycle where oocyte quality is thought to be a contributing factor, or in the presence of a surprise finding of diminished ovarian reserve in a young patient.

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“…A full mutation arises from the expansion of a maternal premutation allele. The risk of a maternal premutation allele expanding to a full mutation during transmission is influenced by the presence of AGG interruptions within the alleles [21,23], which can also affect the magnitude of expansion, particularly in the intermediate and premutation range [21,22].…”

Section: Introductionmentioning

confidence: 99%

“…FMR1 alleles with CGG repeats in the normal range are typically stably transmitted, while gray zone and premutation alleles are unstable and can expand from generation to generation [21,22]. A full mutation arises from the expansion of a maternal premutation allele.…”

Section: Introductionmentioning

confidence: 99%

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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AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission

Cited by 97 publications

References 26 publications

Distribution of AGG interruption patterns within nine world populations

Distribution of AGG interruption patterns within nine world populations

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Contraction of a Maternal Fragile X Mental Retardation 1 Premutation Allele

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