Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 2004 Apr 28;74(6):1270–1275. doi: 10.1086/421442

Offspring Gender Ratio and the Rate of Recurrent Spontaneous Miscarriages in Jewish Women at High Risk for Breast/Ovarian Cancer

Inbar Gal 1, Siegal Sadetzki 2,5, Ruth Gershoni-Baruch 6,7, Bernice Oberman 2, Howard Carp 3,5, Moshe Z Papa 4,5, Tal Diestelman-Menachem 1, Shlomit Eisenberg-Barzilai 1, Eitan Friedman 1,5
PMCID: PMC1182091  PMID: 15116316

Abstract

BRCA1/BRCA2 germline mutations are associated with an increased breast/ovarian cancer risk. Offspring gender ratios may be skewed against male births in BRCA1 mutation carriers. In addition, the lack of viable homozygous BRCA1/BRCA2-mutation carriers implies that recurrent miscarriages may be associated with homozygous fetuses. Jewish Israeli high-risk women who were tested for being carriers of the predominant BRCA1/BRCA2 mutations in Jewish high-risk families were analyzed for the sex of offspring and the rate of spontaneous miscarriages. Overall, 817 women participated: 393 BRCA1/BRCA2-mutation carriers (229 with breast/ovarian cancer) and 424 high-risk noncarriers (208 with breast/ovarian cancer). No differences between the male-to-female offspring ratios of all study groups were noted. Among mutation carriers, the offspring male-to-female ratio was 0.97 (444:460), and among mutation carriers with cancer it was 0.92 (262:284). Similarly, no offspring gender skewing was noted among high-risk noncarriers, regardless of health status. The rates of three or more spontaneous miscarriages among participants with at least one live birth were 4.37% (15/343) among mutation carriers and 3% (12/401) among high-risk women (P = not significant). In conclusion, the offspring gender ratio is similar in high-risk Jewish families and in the general population. The issue of the rate of recurrent miscarriages in high-risk Jewish women is unresolved.

Germline mutations in two genes, BRCA1 (MIM 113705) and BRCA2 (MIM 600185), are estimated to account for ∼80% of all inherited breast and ovarian cancer and <50% of familial site-specific breast cancer (Ford et al. 1994, 1998). In Jewish high-risk individuals of Ashkenazi (East European) decent, three predominant, seemingly founder mutations—185delAG (BRCA1), 5382insC (BRCA1), and 6174delT (BRCA2)—seem to account for a substantial proportion (70%–85%) of germline mutations detected in high-risk families with inherited breast and ovarian cancer, including ∼40%–50% of familes with site-specific breast cancer, and in ⩽2.5% of the general Jewish Ashkenazi population (Berman et al. 1996; Neuhausen et al. 1996, 1998; Roa et al. 1996; Abeliovich et al. 1997; Szabo and King 1997). Notably, other mutations in both BRCA1 and BRCA2 are infrequent among Jewish Ashkenazi women at a high risk for cancer (Shiri-Sverdlov et al. 2000; Kauff et al. 2002).

The only well-established phenotype of heterozygous BRCA1/BRCA2 mutation carriers is an increased risk for breast, ovarian, and, to a lesser extent, other cancers (e.g., pancreatic and prostate) (Ford et al. 1994; Struewing et al. 1997; Breast Cancer Linkage Consortium [BCLC] 1999; Thompson et al. 2002; see also BCLC Web site). A recent report suggested that there is a skewing of offspring gender ratios, favoring female offspring in BRCA1 mutation carriers and not in BRCA2 mutation carriers, an observation that seemingly supported the role that BRCA1 protein plays in X chromosome inactivation (de la Hoya et al. 2003). Another intriguing fact is that no viable homozygous BRCA mutation carriers have been established in any species, including human beings (Gowen et al. 1996; Suzuki et al. 1997; Kuschel et al. 2001). On the basis of the carrier rate in the general population of the mutations predominant in Jewish populations (0.9% for the 185delAG BRCA1 mutation and 1.5% for the 6174delT BRCA2 mutation), the predicted rate of fetuses born to Jewish Ashkenazim being homozygous for one of these two mutations is expected to be between 1 in 20,000 births for 6174delT and 1 in 40,000 births for 185delAG. Taken together, the fact that no homozygous mutation carrier has been reported (Kuschel et al. 2001) and the lack of viable homozygous mutation carriers in animal models (Gowen et al. 1996; Suzuki et al. 1997) led us to hypothesize that a plausible reason for recurrent spontaneous miscarriages among Jewish Ashkenazi women may be fetal homozygosity for the recurring BRCA1/BRCA2 mutations in this ethnic group.

The aim of this study was to assess the putative effect of being a BRCA1/BRCA2 germline mutation carrier on offspring gender ratio and on the rate of recurrent spontaneous miscarriages.

Jewish women who were counseled for breast/ovarian cancer risk by the oncogenetics services at the Sheba Medical Center in Tel-Hashomer or at the Institute of Genetics at Rambam Medical Center from January 1, 1999, until December 31, 2002, were eligible. Exclusion criteria were non-Jewish origin and unwillingness to participate. The study participants were subdivided into mutation carriers and noncarriers, and each group was further subdivided into affected (with breast/ovarian cancer) or unaffected.

The study was approved by the institutional review board of both medical centers, and each participant signed a written informed consent. Data regarding offspring gender and reproductive history, along with detailed personal and family history of cancer and demographic data, were collected routinely at counseling. Ethnic origin was ascertained for at least three prior generations, on the basis of the countries of birth of the parents and grandparents. On the basis of personal and family cancer history, “high risk” status was assigned to (1) women who have at least two first-degree relatives with breast cancer, one of whom was diagnosed at <40 years of age, (2) women who have at least one first-degree relative who had ovarian cancer at any age and at least one first-degree relative with breast cancer, and (3) women who have at least two first-degree relatives with breast cancer at any age, one of whom had bilateral breast cancer.

DNA was extracted from peripheral venous leukocytes by use of the PUREGene DNA extraction kit (Gentra Inc.), in accordance with the manufacturer’s recommended protocol. Three predominant Jewish mutations were tested: 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Mutation analysis schemes were based on PCR and restriction enzyme digests that distinguish the wild type from the mutant allele, as described elsewhere (Rohlfs et al. 1997).

Categorical variables were compared with the use of χ2 tests, and continuous variables were compared using t-tests, adjusting for the effect of birth cohort when necessary. All statistical analyses were performed using S-Plus (S-Plus 2000 Professional Release 3, Insightful Corp.).

Overall, 817 women participated in this study, and 393 were carriers of one of the predominant Jewish mutations in BRCA1 (185delAG, n=195; 5382InsC, n=69) or in BRCA2 (6174delT, n=129). Of the 393 carriers, 169 were diagnosed with breast cancer, 47 with ovarian cancer, and 13 with both cancer types. Of the 424 noncarriers, 192 were diagnosed with breast cancer, 13 with ovarian cancer, and 4 with both cancer types. Study participants represent 82.6% of the total 989 women who were eligible for this study.

In both mutation carriers and noncarriers, the mean age of unaffected women was significantly younger than the mean age of women diagnosed with cancer (P=0) (table 1). The mean age at counseling in the noncarrier group was significantly older than that of the carriers (P=.0001) (table 1). Yet, the mean age at counseling in all groups ranged from 44.4 to 53.6 years, which are considered to be ages at which the reproductive cycle has been completed. The mean age at diagnosis of breast cancer was 43.2±8.9 years for carriers and 48.8±9.8 years for noncarriers (P=0); the mean age at diagnosis of ovarian cancer was 51.4±11.0 years for carriers and 57.5±9.4 years for noncarriers (P=.04). The majority of study participants (97.3%), including both carriers and noncarriers, were of Ashkenazi origin, and the rest were of Iraqi origin, of Balkan origin, or born in Israel.

Table 1.

Demographic and Parity-Related Variables by Study Group

Value for
Carriers
 Noncarriers
Variable Total Unaffected With Breast/Ovarian Cancer P Total Unaffected With Breast/Ovarian Cancer P P for Carriers vs. Noncarriers
N 393 164 229 424 216 208
Age (years):
 N 390 162 228 422 215 207
 Mean±SD 48.11±11.15 44.38±10.75 50.75±1.69 0 51.17±11.6 48.79±11.01 53.65±11.7 0 .0001
 Range 17–86 17–71 29–86 23–87 25–87 23–86
Origin:
 N 387 161 226 423 215 208
 Ashkenazi 376 (97%) 155 (96%) 221 (98%) 419 (99%) 213 (99%) 206 (99%)
 Iran/Iraq 3 2 1 2 2 0
 Yemen 0 0 0 1 0 1
 Balkan 2 0 2 1 0 1
 Israeli-born 6 4 2 .28 0 0 0 .26
No. of live births:
 N 387 (100%) 159 (100%) 228 (100%) 424 (100%) 216 (100%) 208 (100%)
 0 33 (9%) 13 (8%) 20 (9%) 22 (5%) 15 (7%) 7 (3%)
 1 40 (10%) 22 (14%) 18 (8%) 44 (10%) 19 (9%) 25 (12%)
 2 150 (39%) 63 (40%) 87 (38%) 144 (34%) 73 (34%) 71 (34%)
 3 117 (30%) 44 (28%) 73 (32%) 156 (37%) 81 (38%) 75 (36%)
 4 35 (9%) 14 (9%) 21 (9%) 44 (10%) 21 (10%) 23 (11%)
 5+ 12 (3%) 3 (2%) 9 (4%) .39 14 (3%) 7 (3%) 7 (3%) .56 .18
 Mean ±SD 2.33±1.24 2.23±1.2 2.4±1.3 .18 2.5±1.3 2.49±1.3 2.53±1.27 .73 .045
No. of miscarriagesa:
 N 343 (100%) 144 (100%) 199 (100%) 401 (100%) 200 (100%) 201 (100%)
 0 230 (67%) 100 (69%) 130 (65%) 283 (71%) 136 (68%) 147 (73%)
 1 74 (22%) 30 (21%) 44 (22%) 79 (20%) 41 (21%) 38 (19%)
 2 24 (7%) 12 (8%) 12 (6%) 27 (7%) 17 (9%) 10 (5%)
 3+ 15 (4%) 2 (1%) 13 (7%) .11 12 (3%) 6 (3%) 6 (3%) .5 .65
 Mean ±SD .52±.94 .41±.70 .59±1.08 .079 .44±.87 .50±.95 .39±.79 .19 .274
Male-to-female offspring ratio:
 All 444:460 (.98) 542:522 (1.038)
 BRCA1 286:303 (.943)
 185delAG 215:219 (.98)
 5382InsC 71:84 (.84)
 BRCA2 158:157 (1.006)
Open in a new tab
a

Number of spontaneous miscarriages among women who have had at least one live birth.

Of the study participants, 91% of the mutation carriers and 95% of the noncarriers gave birth at least once. A statistically significant difference in the mean number of children was noted between carriers (2.33 ± 1.24) and noncarriers (2.51±1.3) (P=.045). No significant differences in the distribution of the number of children were noted between affected and unaffected women within each group.

The total number of males born to noncarriers was 542, compared with 522 females (rate ratio 1.038). Among mutation carriers, there were 444 male offspring, compared with 460 female offspring (rate ratio 0.965). Analysis of offspring gender ratio by specific mutation type shows that there were 215 boys and 219 girls (rate ratio 0.98) among 185delAG BRCA1 mutation carriers, 71 boys and 84 girls (rate ratio 0.84) among 5382InsC BRCA1 mutation carriers, and 158 boys and 157 girls (rate ratio 1.006) among 6174delT BRCA2 mutation carriers. Combined analyses of all BRCA1 carriers (185delAG and 5382InsC) showed that there were 286 male and 303 female offspring (rate ratio 0.943). The differences in rate ratios between all groups (by specific mutation and by BRCA1 clustering) are statistically insignificant (table 1).

Of the study participants who had been pregnant at some time in their life (n=343 and n=401 among mutation carriers and noncarriers, respectively), 231 reported having at least one spontaneous miscarriage: 113 (33%) of the carriers and 118 (30%) of the noncarriers (P=.34). In terms of unaffected women only, there were 44 carriers (31%) and 64 noncarriers (33%) who reported having at least one spontaneous miscarriage (P=.87). Among mutation carriers who had been pregnant, 15 (4.37%) had three or more spontaneous miscarriages (2 unaffected women and 13 women with breast/ovarian cancer, P=.11), and, among noncarrier women who had been pregnant, there were 12 women (3%) with three or more spontaneous miscarriages, evenly distributed among affected and unaffected individuals (P=.5). The mean number of spontaneous abortions for women who had been pregnant was 0.41 ± 0.7 for unaffected mutation carriers and 0.50 ± 0.95 for noncarriers (P=.8).

Among mutation carriers, though the mean rate of spontaneous miscarriages was higher among affected women, compared with asymptomatic mutation carriers, the difference was of borderline significance statistically (P=.079). However, these differences could not be shown when stratification for age at counseling was performed.

In this study, no apparent differences in male-to-female offspring ratio were noted in Jewish women who are BRCA1 or BRCA2 mutation carriers, and the offspring gender ratio was within that reported for the general Western world populations, −1.06 (Davis et al. 1998). In Israel, the male-to-female ratios were 1.059 (70,173:66,217) in 2000 and 1.045 (71,318:68,217) in 2002 (Central Bureau of Statistics 2001, 2003). In the present study, for high-risk noncarriers, the ratios were also within those of the general population, regardless of disease status. Our data differ from those in a recent report on Spanish BRCA1-mutation carriers: in that study, a two-fold excess of female offspring was noted in BRCA1 mutation carriers (de la Hoya et al. 2003). Notably, among the Spanish mutation carriers, there were three families who are carriers of the 185delAG BRCA1 mutation. In these three families, the ratio of male to female offspring was 0.533 (24:45). By contrast, in the present study, which encompassed 195 185delAG-mutation carriers, representing 174 independent families, there were 215 boys and 219 girls—a male-to-female ratio of 0.981. The reasons for the inconsistent results in terms of the effect of BRCA1 mutation on offspring gender ratio in both studies may be attributed to several factors, and the difference in sample size may be the single most important factor. Additionally, the number of families analyzed herein is larger than the number of families analyzed in the Spanish study, and, therefore, our observations are independent of other confounding familial variables. Alternatively, the precise location of gene mutations may affect the resulting protein function, with respect to its putative role in X chromosome inactivation. Another possibility is that there are other genetic factors that control offspring gender ratio in the Spanish population and are in association with BRCA1 mutations (either genetically or functionally) but are nonexistent in the Jewish Ashkenazi population. The need to assess these factors in a larger study is apparent.

No differences with regard to the rate of recurrent spontaneous miscarriages among all study groups were shown. However, the finding that the rate of recurrent spontaneous miscarriages among all subsets of study participants was higher than that reported for the average risk population (.8%–1%) (Stirrat 1990; Katz and Kuller 1994; Bick et al. 1998) is intriguing, but should be interpreted very cautiously. The often-quoted reference numbers for recurrent (⩾3) miscarriages in the general population (.8%–1%) are based on historical, non-Israeli controls (Alberman 1988; Bick et al. 1998). In addition, in the study by Roman et al. (1978), which analyzes the data set that is most often cited, there were no women who were pregnant >4 times, whereas, in the present study, all but one of the women who had ⩾3 spontaneous miscarriages were pregnant at least 5 times. Thus, comparison of the literature-based historical data on non-Jewish women with the current data is invalid. However, given the biological plausibility that BRCA1/BRCA2 proteins are involved in determining fetal outcome (Gowen et al. 1996; Suzuki et al. 1997), the need for a larger study that will compare spontaneous miscarriage rates among mutation carriers and high-risk women with the rates among an ethnically matched, average-risk population is obvious. This preliminary observation, if confirmed, may signify that, in genetically homogeneous populations with a limited repertoire of mutations in BRCA1/BRCA2, the study of recurrent miscarriages should include testing for germline mutations in both genes, especially if there is a suggestive family history.

The limitations of this study should be pointed out. The study population was highly selected for a personal and family history of breast/ovarian cancer. Therefore, the carriers do not represent the total carrier population, and the noncarriers do not represent the general Israeli population. The effect of this inherent limitation on offspring gender ratio is minimal, in all likelihood, since the results were compared within each group and with valid reliable data derived from the Israeli population. Another drawback of the study is the significant age differences among the four subsets of analyzed groups, though the mean ages of all groups were beyond the reproductive period. Although the younger age of mutation carriers, affected and unaffected, may result in a lower number of live births, this fact by itself could not have a significant effect on offspring gender ratio.

We conclude that among Jewish women at high risk for developing breast/ovarian cancer, either because of family history or by virtue of being BRCA1/BRCA2 mutation carriers, there is no skewing of offspring gender ratio. The issue of the rate of recurrent spontaneous miscarriages among Jewish BRCA1/BRCA2 mutation carriers and high-risk women is yet to be resolved by analysis of an appropriate control group.

Acknowledgments

This work was supported partially by a grant from the Middle East Cancer Consortium to Eitan Friedman. This work was performed in part to fulfill the obligations of Inbar Gal for her master’s thesis at the Department of Human Genetics, Sackler School of Medicine, Tel-Aviv University, Israel.

Electronic-Database Information

URLs for data presented herein are as follows:

  1. BCLC, http://www.humgen.nl/lab-devilee/BCLC/statbite.htm
  2. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/

References

  1. Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, Sagi M, Zlotogora J, Heching N, Peretz T (1997) The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 60:505–514 [PMC free article] [PubMed] [Google Scholar]
  2. Alberman E (1988) The epidemiology of repeated abortion. In: Beard RW, Sharp F (eds) Early pregnancy loss: mechanisms and treatment. RCOG, London, pp 9–17 [Google Scholar]
  3. Berman DB, Wagner-Costalas J, Schultz DC, Lynch HT, Daly M, Godwin AK (1996) Two distinct origins of a common BRCA1 mutation in breast-ovarian cancer families: a genetic study of 15 185delAG-mutation kindreds. Am J Hum Genet 58:1166–1176 [PMC free article] [PubMed] [Google Scholar]
  4. Bick RL, Madden J, Heller KB, Toofanian A (1998) Recurrent miscarriage: causes, evaluation, and treatment. Medscape Womens Health 3:2 [PubMed] [Google Scholar]
  5. Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91:1310–1316 10.1093/jnci/91.15.1310 [DOI] [PubMed] [Google Scholar]
  6. Davis DL, Gottlieb MB, Stampnitzky JR (1998) Reduced ratio of male to female births in several industrial countries: a sentinel health indicator? JAMA 279:1018–1023 [DOI] [PubMed] [Google Scholar]
  7. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE (1994) Risks of cancer in BRCA1-mutation carriers: the Breast Cancer Linkage Consortium. Lancet 343:692–695 10.1016/S0140-6736(94)91578-4 [DOI] [PubMed] [Google Scholar]
  8. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families: the Breast Cancer Linkage Consortium. Am J Hum Genet 62:676–689 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gowen LC, Johnson BL, Latour AM, Sulik KK, Koller BH (1996) Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat Genet 12:191–194 [DOI] [PubMed] [Google Scholar]
  10. de la Hoya M, Fernandez JM, Tosar A, Godino J, Sanchez de Abajo A, Vidart JA, Perez-Segura P, Diaz-Rubio E, Caldes T (2003) Association between BRCA1 mutations and ratio of female to male births in offspring of families with breast cancer, ovarian cancer, or both. JAMA 290:929–931 [DOI] [PubMed] [Google Scholar]
  11. Katz VL, Kuller JA (1994) Recurrent miscarriage. Am J Perinatol 11:386–397 [DOI] [PubMed] [Google Scholar]
  12. Kauff ND, Perez-Segura P, Robson ME, Scheuer L, Siegel B, Schluger A, Rapaport B, Frank TS, Nafa K, Ellis NA, Parmigiani G, Offit K (2002) Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families. J Med Genet 39:611–614 10.1136/jmg.39.8.611 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kuschel B, Gayther SA, Easton DF, Ponder BA, Pharoah PD (2001) Apparent human BRCA1 knockout caused by mispriming during polymerase chain reaction: implications for genetic testing. Genes Chromosomes Cancer 31:96–98 10.1002/gcc.1122 [DOI] [PubMed] [Google Scholar]
  14. Neuhausen SL, Mazoyer S, Friedman L, Stratton M, Offit K, Caligo A, Tomlinson G, Cannon-Albright L, Bishop T, Kelsell D, Solomon E, Weber B, Couch F, Struewing J, Tonin P, Durocher F, Narod S, Skolnick MH, Lenoir G, Serova O, Ponder B, Stoppa-Lyonnet D, Easton D, King MC, Goldgar DE (1996) Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet 58:271–280 [PMC free article] [PubMed] [Google Scholar]
  15. Neuhausen SL, Godwin AK, Gershoni-Baruch R, Schubert E, Garber J, Stoppa-Lyonnet D, Olah E, et al (1998) Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. Am J Hum Genet 62:1381–1388 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Roa BB, Boyd AA, Volcik K, Richards CS (1996) Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14:185–187 [DOI] [PubMed] [Google Scholar]
  17. Rohlfs EM, Learning WG, Friedman KJ, Couch FJ, Weber BL, Silverman LM (1997) Direct detection of mutations in the breast and ovarian cancer susceptibility gene BRCA1 by PCR-mediated site-directed mutagenesis. Clin Chem 43:24–29 [PubMed] [Google Scholar]
  18. Roman E, Doyle P, Beral V, Alberman E, Pharoah P (1978) Fetal loss, gravidity, and pregnancy order. Early Hum Dev 2:131–138 10.1016/0378-3782(78)90005-1 [DOI] [PubMed] [Google Scholar]
  19. Shiri-Sverdlov R, Oefner P, Green L, Baruch RG, Wagner T, Kruglikova A, Haitchick S, Hofstra RM, Papa MZ, Mulder I, Rizel S, Bar Sade RB, Dagan E, Abdeen Z, Goldman B, Friedman E (2000) Mutational analysis of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast cancer. Hum Mutat 16:491–501 [DOI] [PubMed] [Google Scholar]
  20. Central Bureau of Statistics (2001) Births. In: Statistical abstract of Israel, no 52. State of Israel, chapter 3.11 [Google Scholar]
  21. ——— (2003) Births. In: Statistical abstract of Israel, no 54. State of Israel, chapter 3.11 [Google Scholar]
  22. Stirrat GM (1990) Recurrent miscarriage. II. Clinical associations, causes, and management. Lancet 336:728–733 10.1016/0140-6736(90)92215-4 [DOI] [PubMed] [Google Scholar]
  23. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA (1997) The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336:1401–1408 10.1056/NEJM199705153362001 [DOI] [PubMed] [Google Scholar]
  24. Suzuki A, de la Pompa JL, Hakem R, Elia A, Yoshida R, Mo R, Nishina H, Chuang T, Wakeham A, Itie A, Koo W, Billia P, Ho A, Fukumoto M, Hui CC, Mak TW (1997) Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev 11:1242–1252 [DOI] [PubMed] [Google Scholar]
  25. Szabo CI, King MC (1997) Population genetics of BRCA1 and BRCA2. Am J Hum Genet 60:1013–1020 [PMC free article] [PubMed] [Google Scholar]
  26. Thompson D, Easton DF, Breast Cancer Linkage Consortium (2002) Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94:1358–1365 [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES