Article

The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease

  • Nature Genetics volume 4, pages 398403 (1993)
  • doi:10.1038/ng0893-398
  • Download Citation
Received:
Accepted:
Published online:

Abstract

Huntington's disease (HD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene. We have assessed 360 HD individuals from 259 unrelated families and found a highly significant correlation (r = 0.70, p = 10−7) between the age of onset and the repeat length, which accounts for approximately 50% of the variation in the age of onset. Significant associations were also found between repeat length and age of death and onset of other clinical features. Sib pair and parent–child analysis revealed that the CAG repeat demonstrates only mild instability. Affected HD siblings had significant correlations for trinucleotide expansion (r = 0.66, p < 0.001) which was not apparent for affected parent–child pairs.

  • Subscribe to Nature Genetics for full access:

    $59

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    Huntington's chorea (Springer-Verlag, New York, 1981).

  2. 2.

    Huntington's disease (W.B. Saunders, London, 1991).

  3. 3.

    et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature 306, 234–238 (1983).

  4. 4.

    Huntington Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington disease chromosomes. Cell 72, 971–983 (1993).

  5. 5.

    et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252, 1711–1714 (1991).

  6. 6.

    et al. Myotonic dystrophy mutation an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255, 1253–1255 (1992).

  7. 7.

    et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256–1258 (1992).

  8. 8.

    et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68, 799–808 (1992).

  9. 9.

    , , , & Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).

  10. 10.

    et al. Variation of the CCG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell 67, 1047–1058 (1991).

  11. 11.

    et al. Expansion of an unstable trinucleotide (CAG) repeat in spinocerebellar ataxia type 1. Nature Genet. 4, 221–226 (1993).

  12. 12.

    & Dynamic mutations: A new class of mutations causing human disease. Cell 70, 709–712 (1992).

  13. 13.

    On planting alfalfa and growing orchids: The cloning of the gene causing Huntington disease. Clin. Genet. 43, 217–222 (1993).

  14. 14.

    Questions of expansion. Nature Genet 4, 8–9 (1993).

  15. 15.

    , , , & Relationship between parental trinucleotide CTG repeat length and severity of myotonic dystrophy in offspring. J. Am. med. Assoc. 269, 1960–1965 (1993).

  16. 16.

    , , , & Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy. Nature Genet. 1, 192–195 (1992).

  17. 17.

    et al. The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy. J. med. Genet. 29, 774–779 (1992).

  18. 18.

    et al. Meiotic stability and genotype-phenotype correlation of the expanded trinucleotide repeat sequence in X-linked spinal and bulbar muscular atrophy. Nature Genet. 2, 301–304 (1992).

  19. 19.

    , , & , Huntington's chorea. In Progress in neurogenetics (eds Barbeau, A. & Brunnett, J.R.) 645–650 (Excerpta Medica, Amsterdam, 1969).

  20. 20.

    & A genetic model for age of onset in Huntington disease. Am. J. hum. Genet. 37, 350–357 (1985).

  21. 21.

    , , & Factors related to onset age in Huntington's disease. Am. J. hum. Genet. 34, 481–488 (1982).

  22. 22.

    , & Huntington disease in Georgia: age at onset. Am. J. hum. Genet. 43, 695–704 (1988).

  23. 23.

    , & Age of onset in siblings of persons with juvenile onset Huntington disease. Clin. Genet 28, 100–105 (1985).

  24. 24.

    The heterozygote frequency for Huntington's chorea. In Huntington's chorea, 1872–1972 (eds Barbeau A., Chase T.N. & Paulson G.W.) 191–198 (Raven Press, New York).

  25. 25.

    et al. Analysis of human Y chromosome specific reiterated DNA in chromosome variants. Proc. natn. Acad. Sci. U.S.A. 74, 1245–1249 (1977).

  26. 26.

    , , & A PCR method for accurate assessment of trinucleotide repeat expansion in Huntington disease. Hum. molec. Genet. 6, 635–636 (1993).

  27. 27.

    & Applied regression analysis 2nd edn (Wiley, New York, 1981).

Download references

Author information

Affiliations

  1. Department of Medical Genetics, University of British Columbia, 416-2125 East Mall, Vancouver, British Columbia V6T 1Z4, Canada

    • Susan E. Andrew
    • , Y. Paul Goldberg
    • , Berry Kremer
    • , Håkan Telenius
    • , Jane Theilmann
    • , Shelin Adam
    • , Elizabeth Starr
    • , Ferdinando Squitieri
    • , Biaoyang Lin
    • , Michael A. Kalchman
    • , Rona K. Graham
    •  & Michael R. Hayden
  2. Neurodegenerative Disorders Centre, University of British Columbia, 416-2125 East Mall, Vancouver, British Columbia V6T 1Z4, Canada

    • Berry Kremer
    •  & Michael R. Hayden

Authors

  1. Search for Susan E. Andrew in:

  2. Search for Y. Paul Goldberg in:

  3. Search for Berry Kremer in:

  4. Search for Håkan Telenius in:

  5. Search for Jane Theilmann in:

  6. Search for Shelin Adam in:

  7. Search for Elizabeth Starr in:

  8. Search for Ferdinando Squitieri in:

  9. Search for Biaoyang Lin in:

  10. Search for Michael A. Kalchman in:

  11. Search for Rona K. Graham in:

  12. Search for Michael R. Hayden in: