The function of BRCA1 is complex and includes roles in DNA damage repair, cell cycle control, regulation of transcription, and X chromosome inactivation.^1,2 TSIX is thought to control X chromosome inactivation by blocking the accumulation of XIST on the active X chromosome.³ 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.^1,2 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.³ In addition, non-random X chromosome inactivation has been seen in BRCA1 mutation carriers with ovarian cancer.⁴ With these data as background, a skewed sex ratio in offspring of BRCA1 mutation carriers was reported,⁵ 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.^6–8 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.

METHODS

Database

We included data from 1276 families evaluated between 1992 and 1994 (University of Michigan) and between 1994 and 2003 (University of Pennsylvania) in breast cancer risk evaluation clinics and considered to be at increased risk for having a breast cancer susceptibility gene mutation. Individuals were either self referred or physician referred for assessment of inherited susceptibility to breast or ovarian cancer. All individuals providing data signed their informed consent before genetic testing and entry into our database, which includes detailed pedigree information. …