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

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.

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References

  1. 1

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

    Book  Google Scholar 

  2. 2

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

    Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

    Brook, J.D. 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).

    CAS  Article  Google Scholar 

  9. 9

    La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E. & Fischbeck, K.H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).

    CAS  Article  Google Scholar 

  10. 10

    Fu, Y.H. 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).

    CAS  Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

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

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 15

    Redman, J.B., Fenwick, R.G. Jr., Fu, Y.H., Pizzuti, A. & Caskey, C.T. Relationship between parental trinucleotide CTG repeat length and severity of myotonic dystrophy in offspring. J. Am. med. Assoc. 269, 1960–1965 (1993).

    CAS  Article  Google Scholar 

  16. 16

    Tsilfidis, C., MacKenzie, A.E., Mettler, G., Barcelo, J. & Korneluk, R.G. Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy. Nature Genet. 1, 192–195 (1992).

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

    La Spada, A.R. 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).

    CAS  Article  Google Scholar 

  19. 19

    Merritt, A.D., Conneally, P.M., Rahman, N.F. & Drew, A.L., Huntington's chorea. In Progress in neurogenetics (eds Barbeau, A. & Brunnett, J.R.) 645–650 (Excerpta Medica, Amsterdam, 1969).

    Google Scholar 

  20. 20

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

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Myers, R.H., Madden, J.J., Teague, J.L. & Falek, A. Factors related to onset age in Huntington's disease. Am. J. hum. Genet. 34, 481–488 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

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

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Hayden, M.R., Soles, J.A. & Ward, R.H. Age of onset in siblings of persons with juvenile onset Huntington disease. Clin. Genet 28, 100–105 (1985).

    CAS  Article  Google Scholar 

  24. 24

    Stevens, D.L. 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

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

    CAS  Article  Google Scholar 

  26. 26

    Goldberg, Y.P., Andrew, S.E., Clarke, L.A. & Hayden, M.R. A PCR method for accurate assessment of trinucleotide repeat expansion in Huntington disease. Hum. molec. Genet. 6, 635–636 (1993).

    Article  Google Scholar 

  27. 27

    Draper, N. & Smith, H. Applied regression analysis 2nd edn (Wiley, New York, 1981).

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Andrew, S., Paul Goldberg, Y., Kremer, B. et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet 4, 398–403 (1993). https://doi.org/10.1038/ng0893-398

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