FMR1 low sub-genotype does not rescue BRCA1/2-mutated human embryos and does not explain primary ovarian insufficiency among BRCA1/2-carriers.

STUDY QUESTION Can we confirm in our population whether FMRI low sub-genotypes are associated with BRCA1/2 mutations, as recently proposed? SUMMARY ANSWER Our results indicate that the distribution of the FMR1 sub-genotypes in female BRCA1/2-mutation carriers is significantly different from what has been reported previously and resembles that of the control population. FMRI low sub-genotypes are not associated with BRCA1/2 mutations and this association is also absent among male mutation carriers. WHAT IS KNOWN ALREADY Recently, BRCA1 mutations were reported to be associated with primary ovarian insufficiency (POI) in female carriers. In animal models, BRCA2-deficiency also results in impaired oogenesis. A recent study has reported that the POI in BRCA1/2-mutation carriers is most likely due to low FMR1 sub-genotype (CGG n < 26) and the authors also suggested that low sub-genotypes of the FMR1 gene might be important to rescue the BRCA1/2 embryos, which would otherwise be embryonically-lethal. STUDY DESIGN, SIZE, DURATION This retrospective study was performed in October and November of 2012, using genetic material of 464 patients who underwent genetic screening in our centre in the past. PARTICIPANTS/MATERIALS, SETTING, METHODS We tested the FMR1 sub-genotypes in 60 female and 29 males with either BRCA1 or BRCA2 mutations and 375 controls by PCR amplification and size fragment analysis. MAIN RESULTS We did not find any evidence for an association of FMR1 low sub-genotypes and BRCA1/2 mutations. LIMITATIONS, REASONS FOR CAUTION This association study assumes that the female BRCA1/2 population tested has POI. WIDER IMPLICATIONS OF THE FINDINGS Low FMR1 sub-genotypes are not responsible for the presumed rescue of embryos with BRCA1/2 mutations. Furthermore, the molecular mechanism of the POI in BRCA1/2-female carriers is not likely to be associated with low FMR1 sub-genotype. STUDY FUNDING/COMPETING INTEREST(S) The Department of Clinical Genetics of the Maastricht University Medical Centre supported the study. The authors do not have any competing interests to declare.