Sex ratio skewing of offspring in families with hereditary susceptibility to breast cancer.

T he function of BRCA1 is complex and includes roles in DNA damage repair, cell cycle control, regulation of transcription, and X chromosome inactivation. 2 TSIX is thought to control X chromosome inactivation by blocking the accumulation of XIST on the active X chromosome. BRCA1 co-localises with XIST inactive X chromosomes (Xi) and stabilises Xi. Because of this interaction, the loss of BRCA1 is associated with altered Xi chromatin structure and increased expression of silenced Xi genes. 2 Mouse models have suggested a link between aberrant X chromosome inactivation and sex ratio skewing, with a bias towards male births when TSIX activity is abolished. In addition, nonrandom X chromosome inactivation has been seen in BRCA1 mutation carriers with ovarian cancer. With these data as background, a skewed sex ratio in offspring of BRCA1 mutation carriers was reported, with a bias towards females, compared with offspring of women with BRCA2 mutations and those without mutations in either gene. Others have not found a difference in the sex ratios of offspring of BRCA1 and BRCA2 mutation carriers. Here, we analysed the sex ratio of offspring in a large cohort of BRCA1 and BRCA2 mutation carriers, as well as in HBOC families who tested negative for BRCA1 and BRCA2 mutations or were not tested.