The FMR1 CGG repeat test is not a candidate prescreening tool for identifying women with a high probability of being carriers of BRCA mutations

Ricci, Maria Teresa; Pennese, Loredana; Gismondi, Viviana; Perfumo, Chiara; Grasso, Marina; Gennaro, Elena Di; Bruzzi, Paolo; Varesco, Liliana

doi:10.1038/ejhg.2013.193

Cited by 6 publications

(13 citation statements)

References 10 publications

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“…We, however, were unable to detect any difference in distribution of low FMR1 alleles in comparison to reported distributions in normal infertile populations without known malignancies [1], [12]–[14], nor were we able to demonstrate a relative increase in low FMR1 alleles in BRCA1 /2 carriers with ovarian cancers in comparison to ovarian cancer patients who were not BRCA1 /2 mutation carriers.…”

Section: Discussioncontrasting

confidence: 94%

“…In contrast, even excluding the 78.8% prevalence of low FMR1 alleles in the Austrian study (likely even underreported since rare hom patients were not sub-divided in that study, thus not including hom-high/low and hom-low/low patients), the Dutch [12] reported 35.0% prevalence and the Italians [14] a 32.6% prevalence of low FMR1 alleles. Only the Israeli study [13], therefore, like here reported ovarian cancer data, reported an actually inverted picture of more low FMR1 alleles in BRCA1 /2-negative than BRCA1 /2-positive women.…”

Section: Resultsmentioning

confidence: 77%

“…The possibility that different BRCA1 /2 mutations may exhibit different degrees of dependency with the FMR1 gene was potentially also supported by the trend towards enrichment with low FMR1 alleles among BRCA1 /2 mutation carriers observed in the Italian study (32.6% vs. 23.1%) [14]. Speaking against such an explanation, a recent study, however, suggested other, non- FMR1 -associated molecular mechanisms as causes for BRCA1 -associated POA/OPOI [18].…”

Section: Introductionmentioning

confidence: 94%

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Absence of BRCA/FMR1 Correlations in Women with Ovarian Cancers

et al. 2014

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Previously reported findings in Austrian BRCA1/2 mutation carriers suggested a possible dependency of embryos with BRCA1/2 mutations on so-called low alleles of the fragile X mental retardation 1 (FMR1) gene, characterized by less than 26 CGG repeats (CGGn<26). The hypothesis arose from a study reporting highly statistically significant enrichment of low FMR1 alleles, significantly exceeding low allele prevalence in a general population, suggesting embryo lethality of BRCA1/2 mutations, “rescued” by presence of low FMR1 alleles. Such a dependency would also offer an explanation for the so-called “BRCA-paradox,” characterized by BRCA1/2 deficient embryonic tissues being anti-proliferative (thereby potentially causing embryo-lethality) but proliferative in malignant tumors, including breast and ovarian cancers. Follow up investigations by other investigators, however, at most demonstrated trends towards enrichment but, mostly, no enrichment at all, raising questions about the original observation and hypothesis. We in this study, therefore, investigated CGGn of the FMR1 gene of 86 anonymized DNA samples from women with various forms of ovarian cancer, and were unable to demonstrate differences in prevalence of low FMR1 alleles either between positive and negative ovarian cancer patients for BRCA1/2 or between ovarian cancer patients and reported rates in non-cancer populations. This raises further questions about a suggested dependency between BRCA1/2 and FMR1, but also raises the possibility that investigated Austrian BRCA1/2 carrier populations differ from those in other countries. Either only selected BRCA1/2 mutations, therefore, interact with low FMR1 alleles or the Austrian data reflect only coincidental observations.

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Section: Discussioncontrasting

confidence: 94%

Section: Resultsmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 94%

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Absence of BRCA/FMR1 Correlations in Women with Ovarian Cancers

et al. 2014

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“…Lately, Brandao et al 16 and Ricci et al 17 have independently shown that the distribution of the FMR1 subgenotypes in BRCA mutation carriers compares well with that obtained from non carriers, concluding that BRCA1/2 mutations are not associated with FMR1 low subgenotypes.…”

Section: Discussionmentioning

confidence: 99%

BRCA1/2 mutations and FMR1 alleles are randomly distributed: a case control study

et al. 2013

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BRCA mutation carriers were reported to display a skewed distribution of FMR1 genotypes, predominantly within the low normal range (CGG repeat number o26). This observation led to the interpretation that BRCA1/2 mutations are embryo-lethal, unless rescued by 'low FMR1 alleles'. We undertook to re-explore the distribution of FMR1 alleles subdivided into low, normal and high (o26, 26-34, and 434 CGG repeats, respectively) subgenotypes, on a cohort of 125 Ashkenazi women, carriers of a BRCA1/2 founder mutation. Ashkenazi healthy females (n ¼ 368), tested in the frame of the Israeli screening population program, served as controls. BRCA1/2 carriers and controls demonstrated a comparable and non-skewed FMR1 subgenotype distribution. Taken together, using a homogeneous ethnic group of Ashkenazi BRCA1/2 mutation carriers, we could not confirm the reported association between FMR1 low genotypes and BRCA1/2 mutations. The notion that BRCA1/2 mutations are embryo-lethal unless rescued by the low FMR1 subgenotypes is hereby refuted. European Journal of Human Genetics ( Expansion of the CGG segment to the so-called pre-mutation range (approximately g.5061CGG (55_200)) is associated with neuropsychiatric risks and primary ovarian insufficiency. 1 The full mutation range g.5061CGG(4200) instigates gene inactivation and loss of FMR1 protein, thereby causing fragile X syndrome, an X-linked condition, the leading cause of inherited intellectual disability in humans. 2,3 Gleicher et al 4-6 have constructed a 'private' classification of subgenotypes within the normal FMR1 range (up to 55 repeats). As such, they labeled alleles of 26-34 CGG repeats g.5061CGG(26_34) as 'normal' , alleles of less than 26 repeats as 'low range' g.5061CGG(5_25) and those of more than 34 repeats as 'high range' g.5061CGG(35_55). Repeats within the median range g.5061CGG(29_30) correspond allegedly with the switching point between positive and negative message and peak translation of the gene product of FMR1. [4][5][6][7] Individuals were then defined as 'normal' if both alleles were in the 'normal' range, as 'heterozygous' if one allele was outside the 'normal' range and as homozygous if both alleles were outside of the range. These genotypes were further subdivided based on whether FMR1 alleles were above (high) or below (low) the normal range. [4][5][6][7]

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“…Gleicher and coworkers presented ovarian cancer patients with BRCA1/2 mutations had no relative increased low FMR1 alleles compared to the patients without BRCA1/2 mutations (Gleicher et al 2014). Ricci et al (2014) also illustrated FMR1 genetic testing was inappropriate to prescreen the related BRCA mutations. Dagan et al (2014) strengthened the evidence by the parallel epidemiological studies.…”

Section: Low Numbers Of Cgg Repeatmentioning

confidence: 99%

Pathological Effects of the FMR1 CGG-Repeat Polymorphism (5-55 Repeat Numbers): Systematic Review and Meta-Analysis

Yang

Fan

Chen

et al. 2016

Tohoku J. Exp. Med.

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The fragile X mental retardation 1 (FMR1) gene contains a highly polymorphic trinucleotide (CGG) repeat and consists of various allelic forms. Traditionally, 55-200 repeats and over 200 CGG repeats have been highlighted to be associated with ovarian dysfunction and neuro-psychiatric risks. However, previous studies had paid little attention to the allelic forms of 5-55 CGG repeats. Herein, we sought to evaluate the pathological features of FMR1 allelic category with a range of 5-55 CGG repeats. We further classified the spectrum of CGG sizes (5-55 repeats) into three sub-groups as low numbers of CGG repeat (< 26 repeats), normal CGG count (26-34 repeats), and small CGG expansion (35-54 repeats). Our systematic review documented that low numbers of CGG repeat (< 26 repeats) revealed a close relationship with premature ovarian failure. Correspondingly, the meta-analysis showed that small CGG expansion, involving allelic sizes with 35-54 (n = 8, OR = 1.22, 95% CI: 0.75-2.00, P > 0.05) and 41-54 (n = 7, OR = 1.62, 95% CI: 1.14-2.30, P < 0.05), was both linked to the risk of ovarian dysfunction. Additionally, small CGG expansion exerts significant influence on male Parkinsonism cohorts (OR = 2.17, 95% CI: 1.50-3.14, P < 0.05), mental retardation, and repeat instability. Our data provide evidence that the CGG-repeat numbers below 26 or above 34 of FMR1 gene are also associated with disease risks and thus should be regarded as pathological genotypes for a routine test.

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The FMR1 CGG repeat test is not a candidate prescreening tool for identifying women with a high probability of being carriers of BRCA mutations

Cited by 6 publications

References 10 publications

Absence of BRCA/FMR1 Correlations in Women with Ovarian Cancers

Absence of BRCA/FMR1 Correlations in Women with Ovarian Cancers

BRCA1/2 mutations and FMR1 alleles are randomly distributed: a case control study

Pathological Effects of the FMR1 CGG-Repeat Polymorphism (5-55 Repeat Numbers): Systematic Review and Meta-Analysis

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