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C05 BRCA mutations are associated with higher CAG numbers found in various polyglutamine disorders
  1. Elisabeth Singer1,2,
  2. Ilnaz Sepahi1,2,
  3. Annika Sachs dos Santos1,2,
  4. Cansu-Ebru Oender1,2,
  5. André Koch4,
  6. Andreas Hartkopf4,
  7. Olaf Riess1,2,
  8. Christopher Schroeder1,2,
  9. Huu P Nguyen1,2,3
  1. 1Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
  2. 2Centre for Rare Diseases, University of Tuebingen, Tuebingen, Germany
  3. 3Department of Human Genetics, Ruhr University Bochum, Bochum, Germany
  4. 4Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany


Background The CAG repeat expansion in the HTT gene is a dynamic mutation varying in length in tissues and between generations. The mechanisms behind the instability of CAG expansions are polymerase slippage and DNA repair failure. BRCA1 and BRCA2 are well characterized DNA repair genes and mutations increase the risk of developing breast and ovarian cancer for carriers.

Aim Therefore, in our study we analysed CAG lengths in various polyglutamine containing genes to investigate the potential effect of mutations in the DNA repair genes BRCA1 and BRCA2 on CAG length.

Methods In a cohort of patients from Department of Obstetrics and Gynecology in Tuebingen carrying BRCA1 or BRCA2 mutations, CAG lengths in 6 different polyglutamine disease genes (HD, SCA1, SCA2, SCA3, SCA6 and SCA7) were determined by fragment length analysis. CAG lengths were classified as non-pathological, intermediate and pathological for each disorder. The findings were compared to data on the general population and to a control group from the Department of Obstetrics and Gynecology in Tuebingen.

Results We have found no difference in the overall CAG repeat length in patients carrying BRCA1 or BRCA2 mutations. However, the frequency of patients carrying intermediate CAG lengths was higher in patients carrying BRCA1 and BRCA2 mutations in comparison to the general population.

Conclusion The frequency of intermediate alleles was in our cohort higher than reported for the general population. They further link BRCA mutations to defects in DNA repair possibly contributing to the expansion of the CAG repeats with a mechanism common to different polyglutamine disorders. Further studies are needed in order to evaluate the correlation of specific mutations with CAG size and CAG size with disease prognosis of BRCA1 or BRCA2 mutation carriers.

  • HD
  • BRCA1/2
  • DNA repair

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