Context Defects in X-chromosome inactivation distort sex ratio in mice. The BRCA1 gene is also involved in X-chromosome inactivation,
suggesting the possibility that some sex-ratio distortion may be associated
with BRCA1-related human cancer syndromes.
Objective To determine whether BRCA1 mutations are associated
with distortion of the sex ratio of births in families with breast cancer,
ovarian cancer, or both.
Design and Setting Analysis of germline mutations in participants from Spain who had been
screened for BRCA between 1998 and 2002.
Participants Sixty-eight families with at least 3 breast cancer cases or ovarian
cancer cases, or both types of cancer in 2 generations (germline mutations: BRCA1, n = 17; BRCA2, n = 15;
and BRCA unrelated, n = 36). An average of 4 relatives
per family were tested for the corresponding BRCA mutation.
Main Outcome Measure Male and female births registered in breast and/or ovarian pedigrees
tested for the presence of BRCA1 and BRCA2 germline mutations.
Results Of BRCA1-related breast and/or ovarian cancer
pedigrees, there was a 2-fold excess of female births (218 female vs 109 male
births). Of BRCA2-related or BRCA-unrelated breast and/or ovarian cancer pedigrees, there was not an
excess of female births (175 female/150 male and 344 female/315 male, respectively).
Of 327 BRCA1 births, 218 (67%) were female births
compared with 54% among BRCA2 pedigrees (175/327; P<.001) and 52% among BRCA-unrelated
pedigrees (344/659; P<.001). Female births increased
in the offspring of BRCA1 carriers compared with BRCA2 carriers (67% vs 52%; P =
Conclusion In these families with breast and/or ovarian cancer, mutations in BRCA1 but not BRCA2 were associated
with a sex ratio skewed against male births.