Abstract for presentation at 11th International Congress of Human Genetics

Haplotype and linkage disequilibrium analysis of BRCA1 and BRCA2 genes: identification of a hemizygous region of BRCA2 in a German high risk breast cancer familiy

  • Wera Hofmann, Department of Tumor Genetics, Max Delbrück Center for Molecular Medicine, Germany
  • Dr Michael Nothnagel, Institute for Medical Informatics and Statistics, University Hospital Schleswig-Holstein, Christian Albrechts University, Germany
  • Verena Gimmel, Department of Tumor Genetics, Max Delbrück Center for Molecular Medicine, Germany
  • Prof Siegfried Scherneck, Department of Tumor Genetics, Max Delbrück Center for Molecular Medicine, Germany

    • The “Berlin Center for Hereditary Breast and Ovarian Cancer” as one of twelve centers of the “German Consortium for Hereditary Breast and Ovarian Cancer” (GCHBOC) investigated about 300 German high-risk breast and/or ovarian cancer families for mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 during 1997-2005. We were interested in understanding the linkage disequilibrium (LD) pattern and the haplotypic structure of the BRCA1 and BRCA2 genes among German women who were previously tested by direct sequencing of all exons and exon-flanking intronic regions of both genes. We therefore performed a haplotype-based study of BRCA1 and BRCA2 based on 22 single nucleotide polymorphisms (SNPs) spanning 80.78 kb of the BRCA1 gene and 25 SNPs spanning 83.01kb of the BRCA2 gene. Out of five different BRCA1 haplotypes with a frequency of > 5%, two common BRCA1 haplotypes accounted for two thirds of all chromosomes in our collective. In contrast, analysis of BRCA2 haplotypes revealed a higher haplotypic diversity where the most abundant haplotype reached a frequency of 17%. We also assessed the pattern and the extent of LD between the SNPs in BRCA1 and BRCA2 and compared the results to data from the International HapMap Project. While most methods agreed on a single coherent region of elevated LD that spanned most of BRCA1, BRCA2 showed low levels of LD in general and only a single area of strong LD. Furthermore, an unusual BRCA2 haplotype was detected in a German high-risk breast cancer familiy. This haplotype is characterized by the loss of a high-LD area in BRCA2 and represents a hemizygous region that results from a disease-causing intragenic deletion. In conclusion, SNP-based haplotype analysis can be an effective approach for identifying patient samples that may contain intragenic deletions leading to hemizygosity.

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