Journal of Genetic Counseling

, Volume 22, Issue 2, pp 200–217

“Grasping the Grey”: Patient Understanding and Interpretation of an Intermediate Allele Predictive Test Result for Huntington Disease

Original Research

Abstract

Since the discovery of the genetic mutation underlying Huntington disease (HD) and the development of predictive testing, the genetics of HD has generally been described as straightforward; an individual receives either mutation-positive or negative predictive test results. However, in actuality, the genetics of HD is complex and a small proportion of individuals receive an unusual predictive test result called an intermediate allele (IA). Unlike mutation-positive or negative results, IAs confer uncertain clinical implications. While individuals with an IA will usually not develop HD, there remains an unknown risk for their children and future generations to develop the disorder. The purpose of this study was to explore how individuals understood and interpreted their IA result. Interviews were conducted with 29 individuals who received an IA result and 8 medical genetics service providers. Interviews were analyzed using the constant comparative method and the coding procedures of grounded theory. Many participants had difficulty “Grasping the Grey” (i.e. understanding and interpreting their IA results) and their family experience, beliefs, expectations, and genetic counseling influenced the degree of this struggle. The theoretical model developed informs clinical practice regarding IAs, ensuring that this unique subset of patients received appropriate education, support, and counseling.

Keywords

Huntington disease Predictive testing Intermediate alleles Uncertainty Understanding Beliefs Expectations Genetic counseling 

References

  1. Almqvist, E. W., Elterman, D. S., MacLeod, P. M., & Hayden, M. R. (2001). High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia. Clinical Genetics, 60(3), 198–205.PubMedCrossRefGoogle Scholar
  2. Andrich, J., Arning, L., Wieczorek, S., Kraus, P. H., Gold, R., & Saft, C. (2008). Huntington’s disease as caused by 34 CAG repeats. Movement Disorders, 23(6), 879–881.PubMedCrossRefGoogle Scholar
  3. Aubeeluck, A., & Moskowitz, C. (2008). Huntington’s disease. Part 3: family aspects of HD. British Journal of Nursing, 17(5), 328.PubMedGoogle Scholar
  4. Balneaves, L. G., Truant, T. L. O., Kelly, M., Verhoef, M. J., & Davison, B. J. (2007). Bridging the gap: decision-making processes of women with breast cancer using complementary and alternative medicine. Support Care Cancer, 15(8), 973–983.PubMedCrossRefGoogle Scholar
  5. Beeson, D. (1997). Nuance, complexity, and context: qualitative methods in genetic counseling research. Journal of Genetic Counseling, 6(1), 21–43.PubMedCrossRefGoogle Scholar
  6. Bish, A., Sutton, S., Jacobs, C., Levene, S., Ramirez, A., & Hodgson, S. (2002). No news is (not necessarily) good news: impact of preliminary results for BRCA1 mutation searches. Genetics in Medicine, 4(5), 353–358.CrossRefGoogle Scholar
  7. Chong, S. S., Almqvist, E., Telenius, H., LaTray, L., Nichol, K., Bourdelat-Parks, B., et al. (1997). Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses. Human Molecular Genetics, 6(2), 301–309.PubMedCrossRefGoogle Scholar
  8. Corbin, J., & Strauss, A. (1990). Grounded theory research: procedures, canons, and evaluative criteria. Qualitative Sociology, 13(1), 3–21.CrossRefGoogle Scholar
  9. Cox, S. (2003). Stories in decisions: how at-risk individuals decide to request predictive testing for Huntington disease. Qualitative Sociology, 26(2), 257–280.CrossRefGoogle Scholar
  10. Cox, S., & McKellin, W. (2001). ‘There’s this thing in our family’: predictive testing and the construction of risk for Huntington Disease. Sociology of Health & Illness, 21(5), 622–646.CrossRefGoogle Scholar
  11. Creighton, S., Almqvist, E. W., MacGregor, D., Fernandez, B., Hogg, H., Beis, J., et al. (2003). Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000. Clinical Genetics, 63(6), 462–475.PubMedCrossRefGoogle Scholar
  12. Etchegary, H. (2006). Discovering the family history of Huntington Disease (HD). Journal of Genetic Counseling, 15(2), 105–117.PubMedCrossRefGoogle Scholar
  13. Falush, D., Almqvist, E. W., Brinkmann, R. R., Iwasa, Y., & Hayden, M. R. (2001). Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial underascertainment of late-onset cases. American Journal of Human Genetics, 68(2), 373–385.PubMedCrossRefGoogle Scholar
  14. Festinger, L. (1964). Conflict, decision and dissonance. Stanford: Stanford University Press.Google Scholar
  15. Forrest Keenan, K. (2009). How young people find out about their family history of Huntington’s disease. Social Science & Medicine, 68(10), 1892–1900.CrossRefGoogle Scholar
  16. Forrest Keenan, K., Miedzybrodzka, Z., Van Teijlingen, E., Mckee, L., & Simpson, S. (2007). Young people’s experiences of growing up in a family affected by Huntington’s disease. Clinical Genetics, 71(2), 120–129.PubMedCrossRefGoogle Scholar
  17. Goldberg, Y. P., Kremer, B., Andrew, S. E., Theilmann, J., Graham, R. K., Squitieri, F., et al. (1993). Molecular analysis of new mutations for Huntington’s disease: intermediate alleles and sex of origin effects. Nature Genetics, 5(2), 174–179.PubMedCrossRefGoogle Scholar
  18. Goldberg, Y. P., McMurray, C. T., Zeisler, J., Almqvist, E., Sillence, D., Richards, R., et al. (1995). Increased instability of intermediate alleles in families with sporadic Huntington disease compared to similar sized intermediate alleles in the general population. Human Molecular Genetics, 4(10), 1911–8.PubMedCrossRefGoogle Scholar
  19. Groen, J. L., de Bie, R. M. A., Foncke, E. M. J., Roos, R. A. C., Leenders, K. L., & Tijssen, M. A. J. (2010). Late-onset Huntington disease with intermediate CAG repeats: true or false? Journal of Neurology, Neurosurgery, and Psychiatry, 81(2), 228–230.PubMedCrossRefGoogle Scholar
  20. Grover, S. (2003). The psychological dimension of informed consent: dissonance processes in genetic testing. Journal of Genetic Counseling, 12(5), 389–403.PubMedCrossRefGoogle Scholar
  21. Grubs, R., & Piantanida, M. (2010). Grounded theory in genetic counseling research: an interpretive perspective. Journal of Genetic Counseling, 19(2), 99–111.PubMedCrossRefGoogle Scholar
  22. Hallowell, N., Foster, C., Ardern-Jones, A., Eeles, R., Murday, V., & Watson, M. (2002). Genetic testing for women previously diagnosed with breast/ovarian cancer: examining the impact of BRCA1 and BRCA2 mutation searching. Genetic Testing, 6(2), 79–87.PubMedCrossRefGoogle Scholar
  23. Hamilton, R., & Bowers, B. (2007). The theory of genetic vulnerability: a Roy model exemplar. Nursing Science Quarterly, 20(3), 254–264.PubMedCrossRefGoogle Scholar
  24. Harper, P. S. (1991). Huntington disease. London: WB Saunders.Google Scholar
  25. Hayden, M. R. (1981). Huntington’s Chorea. Berlin: Springer.CrossRefGoogle Scholar
  26. Herishanu, Y. O., Parvari, R., Pollack, Y., Shelef, I., Marom, B., Martino, T., et al. (2009). Huntington disease in subjects from an Israeli Karaite community carrying alleles of intermediate and expanded CAG repeats in the HTT gene: Huntington disease or phenocopy? Journal of the Neurological Sciences, 277(1–2), 143–146.PubMedCrossRefGoogle Scholar
  27. Huntington, G. (1872). On chorea. The Medical and Surgical Reporter: A Weekly Journal, 26(15), 317–321.Google Scholar
  28. International Huntington disease Association & World Federation of Neurology Research Group on Huntington’s Chorea. (1994). Guidelines for the molecular genetics predictive test in Huntington’s disease. Neurology, 44(8), 1533–1536.CrossRefGoogle Scholar
  29. Kenney, C., Powell, S., & Jankovic, J. (2007). Autopsy-proven Huntington’s disease with 29 trinucleotide repeats. Movement Disorders, 22(1), 127–130.PubMedCrossRefGoogle Scholar
  30. Kremer, B., Goldberg, P., Andrew, S. E., Theilmann, J., Telenius, H., Zeisler, J., et al. (1994). A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. New England Journal of Medicine, 330(20), 1401–1406.PubMedCrossRefGoogle Scholar
  31. Laccone, F., Engel, U., Holinski-Feder, E., Weigell-Weber, M., Marczinek, K., Nolte, D., et al. (1999). DNA analysis of Huntington’s disease: five years of experience in Germany, Austria, and Switzerland. Neurology, 53(4), 801–806.PubMedCrossRefGoogle Scholar
  32. Maat-Kievit, A., Vegter-van der Vlis, M., Zoeteweij, M., Losekoot, M., van Haeringen, A., & Roos, R. (2000). Paradox of a better test for Huntington’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 69(5), 579–583.PubMedCrossRefGoogle Scholar
  33. Maat-Kievit, A., Losekoot, M., Van Den Boer-Van Den Berg, H., Van Ommen, G. J., Niermeijer, M., Breuning, M., et al. (2001). New problems in testing for Huntington’s disease: the issue of intermediate and reduced penetrance alleles. Journal of Medical Genetics, 38(4), E12.PubMedCrossRefGoogle Scholar
  34. Maheu, C., & Thorne, S. (2008). Receiving inconclusive genetic test results: an interpretive description of the BRCA1/2 experience. Research in Nursing & Health, 31(6), 553–562.CrossRefGoogle Scholar
  35. McAllister, M. (2001). Grounded theory in genetic counseling research. Journal of Genetic Counseling, 10(3), 233–250.CrossRefGoogle Scholar
  36. McCusker, E. A., Casse, R. F., Graham, S. J., Williams, D. B., & Lazarus, R. (2000). Prevalence of Huntington disease in New South Wales in 1996. Medical Journal of Australia, 173(4), 187–190.PubMedGoogle Scholar
  37. Potter, N. T., Spector, E. B., & Prior, T. W. (2004). Technical standards and guidelines for Huntington disease testing. Genetics in Medicine, 6(1), 61–65.PubMedCrossRefGoogle Scholar
  38. Ramos-Arroyo, M. A., Moreno, S., & Valiente, A. (2005). Incidence and mutation rates of Huntington’s disease in Spain: experience of 9 years of direct genetic testing. Journal of Neurology, Neurosurgery, and Psychiatry, 76(3), 337–42.PubMedCrossRefGoogle Scholar
  39. Semaka, A., Creighton, S., Warby, S., & Hayden, M. R. (2006). Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. Clinical Genetics, 70(4), 283–294.PubMedCrossRefGoogle Scholar
  40. Sequeiros, J., Ramos, E. M., Cerqueira, J., Costa, M. C., Sousa, A., Pinto-Basto, J., et al. (2010). Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population. Clinical Genetics, 78(4), 381–387.PubMedCrossRefGoogle Scholar
  41. Strauss, A., & Corbin, J. (1998). Basics of qualitative research: Grounded theory procedures and techniques. Thousand Oaks: Sage Publications.Google Scholar
  42. Tassicker, R. J., Marshall, P. K., Liebeck, T. A., Keville, M. A., Singaram, B. M., & Richards, F. H. (2006). Predictive and pre-natal testing for Huntington Disease in Australia: results and challenges encountered during a 10-year period (1994-2003). Clinical Genetics, 70(6), 480–489.PubMedCrossRefGoogle Scholar
  43. Telenius, H., Kremer, H. P., Theilmann, J., Andrew, S. E., Almqvist, E., Anvret, M., et al. (1993). Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Human Molecular Genetics, 2(10), 1535–1540.PubMedCrossRefGoogle Scholar
  44. The Huntington Society of Canada. What is Huntington disease? http://www.huntingtonsociety.ca/english/uploads/What_is_HD_brochure_(English).pdf. Accessed July 2011.
  45. The Huntington’s Disease Collaborative Research Group. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 72(6), 971–983.CrossRefGoogle Scholar
  46. van den Boer-van den Berg, H. M., & Maat-Kievit, A. A. (2001). The whole truth and nothing but the truth, but what is the truth? Journal of Medical Genetics, 38(1), 39–42.PubMedCrossRefGoogle Scholar
  47. van Dijk, S., Otten, W., Timmermans, D. R. M., van Asperen, C. J., Meijers-Heijboer, H., Tibben, A., et al. (2005). What’s the message? Interpretation of an uninformative BRCA1/2 test result for women at risk of familial breast cancer. Genetics in Medicine, 7(4), 239–245.PubMedCrossRefGoogle Scholar
  48. van Dijk, S., Timmermans, D. R. M., Meijers-Heijboer, H., Tibben, A., van Asperen, C. J., & Otten, W. (2006). Clinical characteristics affect the impact of an uninformative DNA test result: the course of worry and distress experienced by women who apply for genetic testing for breast cancer. Journal of Clinical Oncology, 24(22), 3672–3677.PubMedCrossRefGoogle Scholar
  49. van Dijk, S., Otten, W., Tollenaar, R. A. E. M., van Asperen, C. J., & Tibben, A. (2008). Putting it all behind: long-term psychological impact of an inconclusive DNA test result for breast cancer. Genetics in Medicine, 10(10), 745–750.PubMedCrossRefGoogle Scholar

Copyright information

© National Society of Genetic Counselors, Inc. 2012

Authors and Affiliations

  1. 1.Department of Medical Genetics, Centre for Molecular Medicine & TherapeuticsUniversity of British ColumbiaVancouverCanada
  2. 2.School of NursingUniversity of British ColumbiaVancouverCanada

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