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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1994 Oct;55(4):606–617.

Proceed with Care: Direct Predictive Testing for Huntington Disease

C M Benjamin, S Adam, S Wiggins, J L Theilmann, T T Copley, M Bloch, F Squitieri, W McKellin, S Cox, S A Brown, H P H Kremer, M Burgess, W Meshino, A Summers, D Macgregor, J Buchanan, C Greenberg, N Carson, E Ives, M Frecker, J P Welch, A Fuller, D Rosenblatt, S Miller, S Dufrasne, M Roy, E Andermann, C Prevost, M Khalifa, K Girard, S Taylor, A Hunter, C Goldsmith, D Whelan, D Eisenberg, H Soltan, J Kane, M H K Shokeir, A Gibson, S Cardwell, S Bamforth, S Grover, O Suchowersky, M Klimek, T Garber, H A Gardner, P MacLeod, M R Hayden
PMCID: PMC1918294  PMID: 7942838

Abstract

The cloning of the Huntington disease (HD) gene allows highly accurate predictive testing using direct analysis of the CAG repeat. This new test provides results with almost complete certainty but poses unique counseling issues related to direct testing for an adult-onset disease. These include testing individuals who are at 25% risk, without the need for blood from a 50% at risk relative; the assessment of symptomatic individuals; the need for ongoing counseling despite simplification of laboratory procedures; and counseling of persons from families who represent a new mutation for HD. This paper describes protocols for direct predictive testing for adult and prenatal assessment, on the basis of the experience of the Canadian Collaborative Study on Predictive Testing (CCSPT). Over the past 8 years, we have provided >400 results by using linked markers and, more recently, 416 results by using direct assessment of CAG expansion in the HD gene. The vast majority (86%) of requests for direct predictive testing have been from persons who have not previously received results by using linked markers. Despite the ability to now directly assess for the mutation associated with HD, we still recommend assessment of DNA from an affected relative, as this may significantly enhance the accuracy of information to be provided to the at-risk individual. Distance from a genetics center has previously limited the availability of testing, and therefore we have developed approaches to providing predictive testing in the patient's own community.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adam S., Wiggins S., Whyte P., Bloch M., Shokeir M. H., Soltan H., Meschino W., Summers A., Suchowersky O., Welch J. P. Five year study of prenatal testing for Huntington's disease: demand, attitudes, and psychological assessment. J Med Genet. 1993 Jul;30(7):549–556. doi: 10.1136/jmg.30.7.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andrew S. E., Goldberg Y. P., Kremer B., Squitieri F., Theilmann J., Zeisler J., Telenius H., Adam S., Almquist E., Anvret M. Huntington disease without CAG expansion: phenocopies or errors in assignment? Am J Hum Genet. 1994 May;54(5):852–863. [PMC free article] [PubMed] [Google Scholar]
  3. Andrew S. E., Goldberg Y. P., Kremer B., Telenius H., Theilmann J., Adam S., Starr E., Squitieri F., Lin B., Kalchman M. A. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993 Aug;4(4):398–403. doi: 10.1038/ng0893-398. [DOI] [PubMed] [Google Scholar]
  4. Andrew S. E., Goldberg Y. P., Theilmann J., Zeisler J., Hayden M. R. A CCG repeat polymorphism adjacent to the CAG repeat in the Huntington disease gene: implications for diagnostic accuracy and predictive testing. Hum Mol Genet. 1994 Jan;3(1):65–67. doi: 10.1093/hmg/3.1.65. [DOI] [PubMed] [Google Scholar]
  5. Babul R., Adam S., Kremer B., Dufrasne S., Wiggins S., Huggins M., Theilmann J., Bloch M., Hayden M. R. Attitudes toward direct predictive testing for the Huntington disease gene. Relevance for other adult-onset disorders. The Canadian Collaborative Group on Predictive Testing for Huntington Disease. JAMA. 1993 Nov 17;270(19):2321–2325. [PubMed] [Google Scholar]
  6. Billings P. R., Kohn M. A., de Cuevas M., Beckwith J., Alper J. S., Natowicz M. R. Discrimination as a consequence of genetic testing. Am J Hum Genet. 1992 Mar;50(3):476–482. [PMC free article] [PubMed] [Google Scholar]
  7. Bloch M., Adam S., Fuller A., Kremer B., Welch J. P., Wiggins S., Whyte P., Huggins M., Theilmann J., Hayden M. R. Diagnosis of Huntington disease: a model for the stages of psychological response based on experience of a predictive testing program. Am J Med Genet. 1993 Sep 1;47(3):368–374. doi: 10.1002/ajmg.1320470314. [DOI] [PubMed] [Google Scholar]
  8. Bloch M., Adam S., Wiggins S., Huggins M., Hayden M. R. Predictive testing for Huntington disease in Canada: the experience of those receiving an increased risk. Am J Med Genet. 1992 Feb 15;42(4):499–507. doi: 10.1002/ajmg.1320420416. [DOI] [PubMed] [Google Scholar]
  9. Bloch M., Fahy M., Fox S., Hayden M. R. Predictive testing for Huntington disease: II. Demographic characteristics, life-style patterns, attitudes, and psychosocial assessments of the first fifty-one test candidates. Am J Med Genet. 1989 Feb;32(2):217–224. doi: 10.1002/ajmg.1320320215. [DOI] [PubMed] [Google Scholar]
  10. Bloch M., Hayden M. R. Opinion: predictive testing for Huntington disease in childhood: challenges and implications. Am J Hum Genet. 1990 Jan;46(1):1–4. [PMC free article] [PubMed] [Google Scholar]
  11. Brandt J., Quaid K. A., Folstein S. E., Garber P., Maestri N. E., Abbott M. H., Slavney P. R., Franz M. L., Kasch L., Kazazian H. H., Jr Presymptomatic diagnosis of delayed-onset disease with linked DNA markers. The experience in Huntington's disease. JAMA. 1989 Jun 2;261(21):3108–3114. [PubMed] [Google Scholar]
  12. Chapman M. A. Predictive testing for adult-onset genetic disease: ethical and legal implications of the use of linkage analysis for Huntington disease. Am J Hum Genet. 1990 Jul;47(1):1–3. [PMC free article] [PubMed] [Google Scholar]
  13. Craufurd D., Tyler A. Predictive testing for Huntington's disease: protocol of the UK Huntington's Prediction Consortium. J Med Genet. 1992 Dec;29(12):915–918. doi: 10.1136/jmg.29.12.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Duyao M., Ambrose C., Myers R., Novelletto A., Persichetti F., Frontali M., Folstein S., Ross C., Franz M., Abbott M. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet. 1993 Aug;4(4):387–392. doi: 10.1038/ng0893-387. [DOI] [PubMed] [Google Scholar]
  15. Fox S., Bloch M., Fahy M., Hayden M. R. Predictive testing for Huntington disease: I. Description of a pilot project in British Columbia. Am J Med Genet. 1989 Feb;32(2):211–216. doi: 10.1002/ajmg.1320320214. [DOI] [PubMed] [Google Scholar]
  16. Goldberg Y. P., Andrew S. E., Theilmann J., Kremer B., Squitieri F., Telenius H., Brown J. D., Hayden M. R. Familial predisposition to recurrent mutations causing Huntington's disease: genetic risk to sibs of sporadic cases. J Med Genet. 1993 Dec;30(12):987–990. doi: 10.1136/jmg.30.12.987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Goldberg Y. P., Kremer B., Andrew S. E., Theilmann J., Graham R. K., Squitieri F., Telenius H., Adam S., Sajoo A., Starr E. Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects. Nat Genet. 1993 Oct;5(2):174–179. doi: 10.1038/ng1093-174. [DOI] [PubMed] [Google Scholar]
  18. Gusella J. F., Wexler N. S., Conneally P. M., Naylor S. L., Anderson M. A., Tanzi R. E., Watkins P. C., Ottina K., Wallace M. R., Sakaguchi A. Y. A polymorphic DNA marker genetically linked to Huntington's disease. Nature. 1983 Nov 17;306(5940):234–238. doi: 10.1038/306234a0. [DOI] [PubMed] [Google Scholar]
  19. Huggins M., Bloch M., Kanani S., Quarrell O. W., Theilman J., Hedrick A., Dickens B., Lynch A., Hayden M. Ethical and legal dilemmas arising during predictive testing for adult-onset disease: the experience of Huntington disease. Am J Hum Genet. 1990 Jul;47(1):4–12. [PMC free article] [PubMed] [Google Scholar]
  20. Huggins M., Bloch M., Wiggins S., Adam S., Suchowersky O., Trew M., Klimek M., Greenberg C. R., Eleff M., Thompson L. P. Predictive testing for Huntington disease in Canada: adverse effects and unexpected results in those receiving a decreased risk. Am J Med Genet. 1992 Feb 15;42(4):508–515. doi: 10.1002/ajmg.1320420417. [DOI] [PubMed] [Google Scholar]
  21. Kessler S. Psychiatric implications of presymptomatic testing for Huntington's disease. Am J Orthopsychiatry. 1987 Apr;57(2):212–219. doi: 10.1111/j.1939-0025.1987.tb03531.x. [DOI] [PubMed] [Google Scholar]
  22. Kremer B., Goldberg P., Andrew S. E., Theilmann J., Telenius H., Zeisler J., Squitieri F., Lin B., Bassett A., Almqvist E. A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med. 1994 May 19;330(20):1401–1406. doi: 10.1056/NEJM199405193302001. [DOI] [PubMed] [Google Scholar]
  23. Lam R. W., Bloch M., Jones B. D., Marcus A. M., Fox S., Amman W., Hayden M. R. Psychiatric morbidity associated with early clinical diagnosis of Huntington disease in a predictive testing program. J Clin Psychiatry. 1988 Nov;49(11):444–447. [PubMed] [Google Scholar]
  24. MacMillan J. C., Quinn N. P. 15th International World Federation of Neurology Workshop on Huntington's Disease, 31 August-3 September 1993, Boston, Massachusetts, USA. J Med Genet. 1993 Dec;30(12):1039–1041. doi: 10.1136/jmg.30.12.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mastromauro C., Myers R. H., Berkman B. Attitudes toward presymptomatic testing in Huntington disease. Am J Med Genet. 1987 Feb;26(2):271–282. doi: 10.1002/ajmg.1320260205. [DOI] [PubMed] [Google Scholar]
  26. Meissen G. J., Berchek R. L. Intended use of predictive testing by those at risk for Huntington disease. Am J Med Genet. 1987 Feb;26(2):283–293. doi: 10.1002/ajmg.1320260206. [DOI] [PubMed] [Google Scholar]
  27. Mennie M. E., Holloway S. M., Brock D. J. Attitudes of general practitioners to presymptomatic testing for Huntington's disease. J Med Genet. 1990 Apr;27(4):224–227. doi: 10.1136/jmg.27.4.224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Myers R. H., MacDonald M. E., Koroshetz W. J., Duyao M. P., Ambrose C. M., Taylor S. A., Barnes G., Srinidhi J., Lin C. S., Whaley W. L. De novo expansion of a (CAG)n repeat in sporadic Huntington's disease. Nat Genet. 1993 Oct;5(2):168–173. doi: 10.1038/ng1093-168. [DOI] [PubMed] [Google Scholar]
  29. Quaid K. A., Morris M. Reluctance to undergo predictive testing: the case of Huntington disease. Am J Med Genet. 1993 Jan 1;45(1):41–45. doi: 10.1002/ajmg.1320450112. [DOI] [PubMed] [Google Scholar]
  30. Quarrell O. W., Bloch M., Hayden M. R. Insurance and the presymptomatic diagnosis of delayed-onset disease. JAMA. 1989 Nov 3;262(17):2384–2385. [PubMed] [Google Scholar]
  31. Rubinsztein D. C., Barton D. E., Davison B. C., Ferguson-Smith M. A. Analysis of the huntingtin gene reveals a trinucleotide-length polymorphism in the region of the gene that contains two CCG-rich stretches and a correlation between decreased age of onset of Huntington's disease and CAG repeat number. Hum Mol Genet. 1993 Oct;2(10):1713–1715. doi: 10.1093/hmg/2.10.1713. [DOI] [PubMed] [Google Scholar]
  32. Simpson S. A., Harding A. E. Predictive testing for Huntington's disease: after the gene. The United Kingdom Huntington's Disease Prediction Consortium. J Med Genet. 1993 Dec;30(12):1036–1038. doi: 10.1136/jmg.30.12.1036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Snell R. G., MacMillan J. C., Cheadle J. P., Fenton I., Lazarou L. P., Davies P., MacDonald M. E., Gusella J. F., Harper P. S., Shaw D. J. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet. 1993 Aug;4(4):393–397. doi: 10.1038/ng0893-393. [DOI] [PubMed] [Google Scholar]
  34. Tyler A., Ball D., Craufurd D. Presymptomatic testing for Huntington's disease in the United Kingdom. The United Kingdom Huntington's Disease Prediction Consortium. BMJ. 1992 Jun 20;304(6842):1593–1596. doi: 10.1136/bmj.304.6842.1593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wasmuth J. J., Hewitt J., Smith B., Allard D., Haines J. L., Skarecky D., Partlow E., Hayden M. R. A highly polymorphic locus very tightly linked to the Huntington's disease gene. Nature. 1988 Apr 21;332(6166):734–736. doi: 10.1038/332734a0. [DOI] [PubMed] [Google Scholar]
  36. Wiggins S., Whyte P., Huggins M., Adam S., Theilmann J., Bloch M., Sheps S. B., Schechter M. T., Hayden M. R. The psychological consequences of predictive testing for Huntington's disease. Canadian Collaborative Study of Predictive Testing. N Engl J Med. 1992 Nov 12;327(20):1401–1405. doi: 10.1056/NEJM199211123272001. [DOI] [PubMed] [Google Scholar]

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