FMR1 CGG allele length in Israeli BRCA1/BRCA2 mutation carriers and the general population display distinct distribution patterns

Abstract

Premature ovarian failure and diminished ovarian reserve have been noted both in female BRCA1/BRCA2 mutation carriers and in carriers of the Fragile X syndrome FMR1 gene CGG repeat size premutation. Based on the observation that BRCA mutation carriers do not harbour long CGG repeats in the FMR1 gene, it was hypothesized that BRCA-associated premature ovarian failure is mediated via FMR1. To test this notion, we evaluated the distribution of constitutional FMR1 genotypes in 188 BRCA1/BRCA2 mutation-positive Jewish Ashkenazi women and 15 708 female, mostly Ashkenazi controls in Israel. BRCA1/BRCA2 mutation carriers displayed a unique distribution of FMR1 genotypes compared with controls (p = 0·018) with a prominence of the shorter CGG alleles (<26 repeats). There was no allele size distribution differences within BRCA carriers when comparing cancer free (n = 95) and breast cancer affected women (n = 93) (p = 0·43). In conclusion, BRCA mutation carriers exhibit a distinct CGG FMR1 repeat size pattern compared with the general population, but it is unlikely to account for the reported diminished ovarian reserve or act as a modifier breast cancer gene in BRCA mutation carriers.

Association of skewed X-chromosome inactivation with FMR1 CGG repeat length and anti-Mullerian hormone levels: a cohort study

“…Interaction with Xist has previously also been reported for the BRCA1 gene, 31,32 in itself an interesting finding, as we [36] and others [37] reported distinct CGG n distribution patterns in the FMR1 gene in BRCA mutation carriers.…”

“…Since evidence presented here suggests that CGG n of the FMR1 gene appears associated with sXCI, how the FMR1 gene’s CGG n might affect initiation of Xist inactivation of one X chromosome raises further interesting questions. Interaction with Xist has previously also been reported for the BRCA1 gene, 31,32 in itself an interesting finding, as we [ 36 ] and others [ 37 ] reported distinct CGG n distribution patterns in the FMR1 gene in BRCA mutation carriers.…”

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

“…Dagan et al (2014) strengthened the evidence by the parallel epidemiological studies. Laitman et al (2014) also explored the distribution of FMR1 CGG repeat sizes. Although they believed that the lower FMR1 alleles indeed had a discrepancy between BRCA mutation carriers and general population, it was still unlikely to serve as a regulator of breast cancer in associated BRCA mutations, nor as a prediction of diminished ovarian reserve (Laitman et al 2014).…”

“…Laitman et al (2014) also explored the distribution of FMR1 CGG repeat sizes. Although they believed that the lower FMR1 alleles indeed had a discrepancy between BRCA mutation carriers and general population, it was still unlikely to serve as a regulator of breast cancer in associated BRCA mutations, nor as a prediction of diminished ovarian reserve (Laitman et al 2014). The above-mentioned papers can not be determined the association between the low numbers of FMR1 CGG repeat and BRCA1/2-associated cancers.…”

Age of natural menopause onset in BRCA1/2 carriers – systematic review and meta-analysis

“…„Breast cancer genes” BRCA1 and BRCA2 are by far the most widely studied human genes, and consequences of germline pathogenic variants of both genes for cancer risk are very well described [ 1 ]. Non-oncological implications of germline BRCA1 and BRCA2 genes, complicating reproductive health, including early natural menopause, reduced ovarian reserve and unresolved association between BRCA1 and BRCA2 pathogenic variants, premature ovarian failure and CGG repeat number in FMR1 gene, are far less described [ 2 - 6 ].…”