Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families

Hum Genet. 2005 Jul;117(2-3):119-32. doi: 10.1007/s00439-005-1297-9. Epub 2005 May 10.


The Quebec population contains about six-million French Canadians, descended from the French settlers who colonized "Nouvelle-France" between 1608 and 1765. Although the relative genetic contribution of each of these founders is highly variable, altogether they account for the major part of the contemporary French-Canadian gene pool. This study was designed to analyze the role of this founder effect in the introduction and diffusion of the BRCA1 recurrent R1443X mutant allele. A highly conserved haplotype, observed in 18 French-Canadian families and generated using 17 microsatellite markers surrounding the BRCA1 locus, supports the fact that the R1443X mutation is a founder mutation in the Quebec population. We also performed haplotyping analysis of R1443X carriers on 19 other families from seven different nationalities; although the same alleles are shared for three markers surrounding the BRCA1 gene, distinct haplotypes were obtained in four families, suggesting multiple origins for the R1443X mutation. Ascending genealogies of the 18 French Canadian families and of controls were reconstructed on an average depth of 10 generations. We identified the founder couple with the highest probability of having introduced the mutation in the population. Based on the descending genealogy of this couple, we detected the presence of geographical concentration in the diffusion pattern of the mutation. This study demonstrates how molecular genetics and demogenetic analyses can complement each other to provide findings that could have an impact on public health. Moreover, this approach is certainly not unique to breast cancer genetics and could be used to understand other complex traits.

MeSH terms

  • Alleles
  • Amino Acid Substitution
  • BRCA1 Protein / genetics*
  • Breast Neoplasms / genetics*
  • Family
  • Female
  • Founder Effect*
  • Genes, BRCA1
  • Haplotypes / genetics
  • Humans
  • Male
  • Microsatellite Repeats / genetics
  • Ovarian Neoplasms / genetics*
  • Pedigree
  • Point Mutation*
  • Quantitative Trait Loci / genetics
  • Quebec
  • Risk Factors


  • BRCA1 Protein