Male to female ratio among offspring of BRCA1 mutation carriers

Abstract

To the editor: It has been reported that the RING domain of BRCA1 protein interacts with the Xist RNA in mammalian cells, thereby influencing X chromosome inactivation [1]. Lee et al. showed that in mice, defective X-chromosome inactivation changes the sex ratio of offspring [2]. In this context it has been suggested that BRCA1 insufficiency may reduce the ability of Xist RNA to accumulate along the X chromosome and lead to a skewed sex ratio in children [3]. In light of this findings, we were interested in the results of de la Hoya and colleagues, who reported an increased ratio of female to male offspring of BRCA1 mutation carriers, but not of BRCA2 mutation carriers [4]. It is well known that studies such as these may be influenced by possible ascertainment biases [5]; in particular if women with daughters are more likely to seek genetic testing than women with only boys or with no children. Recently, several authors observed only slight, statistically insignificant excesses of female offspring of BRCA1 or BRCA2 carriers, suggesting that the observed sex ratio skew against male births might be due to ascertainment bias [6–9]. Studies in which BRCA carriers are ascertained within a consecutive series of breast or ovarian cancer cases, and are unselected for family histories and for sex distribution of children, are ideally suited to study this question as they are free from ascertainment bias [10]. In the course of a national breast cancer survey, through cancer registry of pathology departments we identified 4596 consecutive women with breast cancer diagnosed before age 50 at one of 18 centers situated throughout Poland from 1996–2003. In each center over 70% of affected women offered blood for genetic testing. We were able to obtain a DNA sample for BRCA1 analysis on 3568 of these patients. Three founder mutations in BRCA1 gene (5382insC, C61G, and 4153delA) which cover about 90% of detectable BRCA1/2 mutations in Poland [11] were studied. Among these women 198 mutation carriers were identified (5.54%). Through pedigree review we identified 189 sons and 172 daughters of these 198 BRCA1 mutation carrier women. The male to female ratio was 1.10. According to the Polish Main Statistic Office the male to female ratio in general population at birth is 1.06 [12]. Thus the difference is insignificant (v = 0.08; p = 0.77). In conclussion, our data set, which was obtained on unselected group of female BRCA1 (5382insC, C61G, and 4153delA) mutation carriers, strongly indicate that there is no evidence of sex ratio distoration in offspring. This supports the statement that rather ascertainment bias than X-chromosome inactivation was a cause of observed before a skewed sex ratio between offspring of BRCA1 carriers.