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

Abstract

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]

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

“…These FMR1 CGG allele distribution differences results are in line with those of Weghofer et al (2012) who previously reported a unique FMR1 CGG allele distribution in BRCA1/BRCA2 mutation carriers undergoing fertility treatment compared with noncarriers recruited from an infertility clinic. In line with our previous data, smaller studies published from Israel (Dagan et al, 2014), Italy (Ricci et al, 2014) and Holland (Brandão et al, 2013) also failed to show the lack of long CGG FMR1 alleles in BRCA mutation carriers. The basic premise of the Weghofer et al (2012) study was that the long CGG allele in the presence of a BRCA mutation may be embryonic lethal, and that rescue may be conferred by the existence of short (<26 repeats) alleles; however, our results do not support this notion.…”

Absence of BRCA/FMR1 Correlations in Women with Ovarian Cancers

“…Interestingly, a similar result was reported in the Israeli study [13], where BRCA1 /2 mutation carriers, a large majority of them already diagnosed with breast cancer, demonstrated only in 24.8% low FMR1 alleles, while random controls demonstrated low FMR1 alleles in 31.5% of women.…”

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

“…Instead, a direct impact of low CGG repeats on these outcomes cannot be ruled out. On the other hand, as proposed by some authors, a low number of CGG repeats supposedly rescued embryos with BRCA1/2 mutation [42,105], even though this association has been refuted by others [10,21].…”