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.