Sex ratio distortion in offspring of families with BRCA1 or BRCA2 mutant alleles: an ascertainment bias phenomenon?

Breast Cancer Res Treat. 2005 Aug;92(3):273-7. doi: 10.1007/s10549-005-3377-x.


Background: There has been controversy regarding whether BRCA1 germline mutations favor female births or whether the sex imbalances observed are attributable to ascertainment bias. Our aims were to compare the sex ratios among offspring of BRCA1-positive, BRCA2-positive, and BRCA-negative families undergoing genetic testing in clinical programs, and to determine whether ascertainment bias is responsible for the observed preponderance of female offspring.

Patients and methods: A total of 145 breast and/or ovarian cancer families with mutations in BRCA1 (n = 83) or BRCA2 (n = 62), and 90 families without identifiable mutation were collected for the study from familial cancer clinics in Barcelona, Spain, and Boston, US. Sex ratio was analyzed among all births in the families and offspring of all (tested and obligate) carriers. In order to minimize the effect of family history of cancer, the analysis was also performed among offspring of the most recent generation of mutation-positive carriers who did not have affected children and compared with a control group comprised of the offspring of the most recent adult generation of non-carriers from families with a known mutation.

Results: There was a statistically higher proportion of female births in all groups (BRCA1 59% (95% CI = 57-61%), BRCA2 58% (56-61%), and BRCA-negative 59% (56-61%), respectively). The female preponderance persisted in analyses limited to offspring of BRCA1 and BRCA2 carriers (61% (57-65%), and 62% (58-66%), respectively), with no differences between the two mutation groups. In contrast, the excess of female offspring disappeared when ascertainment or recall biases were minimized, 44% (37-52%), and 39% (26-53%) for BRCA1; 51% (44-58%), and 46% (33-60%) for BRCA2.

Conclusions: Our findings suggest that there is no asymmetry in birth outcomes among BRCA1 or BRCA2 mutations carriers. Rather ascertainment bias in families participating in genetic testing, or in the family history information they provide is likely to account for excess of female offspring previously reported.

MeSH terms

  • Bias
  • Boston / epidemiology
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics
  • Case-Control Studies
  • Data Collection
  • Female
  • Genes, BRCA1*
  • Genes, BRCA2*
  • Genetic Testing*
  • Germ-Line Mutation*
  • Heterozygote
  • Humans
  • Male
  • Neoplastic Syndromes, Hereditary / epidemiology
  • Neoplastic Syndromes, Hereditary / genetics
  • Ovarian Neoplasms / epidemiology
  • Ovarian Neoplasms / genetics
  • Pedigree
  • Sex Ratio*
  • Spain / epidemiology