Predictive Genetic Testing: The Huntington Disease Model

Aad Tibben, Leiden University Medical Centre, Leiden, The Netherlands
Emilia Bijlsma, Leiden University Medical Centre, Leiden, The Netherlands

Published online: December 2009

DOI: 10.1002/9780470015902.a0005617.pub2

Predictive or presymptomatic genetic testing enables individuals at risk for a hereditary late-onset disease to learn about their genetic status before symptoms have appeared. The predictive testing protocol for Huntington disease (HD) safeguards the interests of test candidates and has served as a model for other diseases. Most people seen for genetic counselling regarding HD are the asymptomatic children of an affected parent. Predictive testing provides the opportunity to get relief from the anguish of being at risk, to have prenatal tests or preimplantation genetic testing, to have children free from the disorder and to make informed plans for the future regarding marriage, education, professional career and finances. The common experience has been that tested individuals found relief from their prior psychological distress and that they benefited psychologically from testing. Having children proved to be an additional stress factor for partners.

Key concepts:

  • Predictive testing provides the opportunity to get relief from uncertainty and prepare better for the future.
  • Preimplantation genetic testing enables couples to have a pregnancy without the burden of termination after an unfavourable prenatal test result.
  • At 55 years of age and being not symptomatic, there is still a 25% empirical chance of being a carrier of the Huntington's gene.
  • The Huntington disease CAG repeat length accounts for roughly 50–77% of the variation in the age of onset.
  • Predictive testing requires informed consent by the individual at risk and the provision of psychological support.
  • Predictive testing for adult-onset disorders without treatment options should not be offered to children and adolescents.
  • Exclusion testing is an important option for an individual at 25% risk because the genetic status of his at-risk parent does not need to be revealed.
  • Counselling test candidates at 25% risk to get Huntington disease requires a family system approach.
  • The predictive test candidate's beliefs about causation and emotional, social and cultural issues may affect the perception of the information that is given in genetic counselling.

Keywords: predictive; presymptomatic; prenatal; Huntington disease

Figure 1. Exclusion testing in Huntington disease (HD). In this family, the HD gene is associated with marker genotype A. Thus, if a person (or pregnancy) at 25% risk has also inherited genotype A (left), he/she will be at high risk of developing HD (50%, the same as for the intervening parent), whereas if a person has inherited genotype B (right), derived from the unaffected grandparent, the risk will be low. Figure reproduced with permission from Harper (1996).
close
 References
    Almqvist EW, Elterman DS, MacLeod PM and Hayden MR (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.
    Andresen JM, Gayan J, Djousse L et al. (2007) The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset. Annals of Human Genetics 71(Pt 3): 295–301.
    Aziz NA, van der Burg JM, Landwehrmeyer GB et al. (2008) Weight loss in Huntington disease increases with higher CAG repeat number. Neurology 71(19): 1506–1513.
    Brinkman RR, Mezei MM, Theilmann J, Almqvist E and Hayden MR (1997) The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. American Journal of Human Genetics 60(5): 1202–1210.
    book Clarke A (ed.) (1998) The Genetic Testing of Children. Oxford, UK: Bios Scientific Publishers.
    Duisterhof GMD, Trijsburg RW, Niermeijer MF, Roos RAC and Tibben A (2001) Psychological studies on Huntington disease: making up the balance. Journal of Medical Genetics 38: 852–861.
    book Evers-Kiebooms G, Zoeteweij M and Harper P (2002) Prenatal Testing for Late-Onset Neurogenetic Diseases. Oxford: BIOS Scientific Publishers Limited.
    book Geraedts JP and Liebaers I (2002) "Preimplantation genetic diagnosis for Huntington's disease" In: Evers-Kiebooms G, Zoeteweij M and Harper P (eds) Prenatal Testing for Late-Onset Neurogenetic Diseases, pp. 107–118. Oxford: BIOS Scientific Publishers Limited.
    book Harper PS (1996) Huntington Disease. London, UK: Saunders.
    Harper PS and Newcombe RG (1992) Age at onset and life table risks in genetic counselling for Huntington disease. Journal of Medical Genetics 29(4): 239–242.
    Huntington Disease Collaborative Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington disease chromosomes. Cell 72: 971–983.
    International Huntington Association and the World Federation of Neurology (IHA/WFN) Research Group on Huntington's Chorea (1994) Guidelines for the molecular genetics predictive test in Huntington disease. Journal of Medical Genetics 31(7): 555–559.
    Langbehn DR, Brinkman RR, Falush D, Paulsen JS and Hayden MR (2004) A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clinical Genetics 65(4): 267–277.
    other Maat-Kievit A (2001) Predictive Testing for Huntington Disease. PhD thesis, Leiden University, Leiden.
    Maat-Kievit A, Losekoot M, vdBoer-vdBerg H et al. (2001) New problems in testing for Huntington disease: the issue of intermediate and reduced penetrance alleles. Journal of Medical Genetics 38: E12.
    Meiser B and Dunn S (2000) Psychological impact of genetic testing for Huntington's disease: an update of the literature. Journal of Neurology, Neurosurgery and Psychiatry 69: 574–578.
    Quarrell OW, Rigby AS, Barron L et al. (2007) Reduced penetrance alleles for Huntington's disease: a multi-centre direct observational study. Journal of Medical Genetics 44(3): e68.
    Semaka A, Creighton S, Warby S and Hayden MR (2006) Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. Clinical Genetics 70(4): 283–294.
    Tibben A (2007) Predictive testing for Huntington's disease. Brain Research Bulletin 72(2–3): 165–171.
 Further Reading
    Almqvist EW, Bloch M, Brinkman R, Craufurd D and Hayden MR (1999) A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease. American Journal of Human Genetics 64(5): 1293–1304.
    Andrew SE, Goldberg YP, Kremer B et al. (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington disease. Nature Genetics 4(4): 398–403.
    book Baker DL, Schuette JL and Uhlmann WR (eds) (1998) A Guide to Genetic Counseling. New York: Wiley-Liss.
    book Folstein SE (1991) Huntington Disease. A Disorder of Families. Baltimore, MD: The Johns Hopkins University Press.
    Kremer BP, Goldberg YP, Andrew SE 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.
    Lerman C, Hughes C, Croyle RT et al. (2000) Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing. Preventive Medicine 31: 75–80.
    Lucotte GJC, Turpin JC, Riess O et al. (1995) Confidence intervals for predicted age of onset, given the size of (CAG)n repeat, in Huntington's disease. Human Genetics 95(2): 231–232.
    book Marteau T and Richards M (eds) (1996) The Troubled Helix: Social and Psychological Implications of the New Human Genetics. Cambridge, UK: Cambridge University Press.
    Meijers-Heijboer EJ, Verhoog LC, Brekelmans CT et al. (2000) Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355: 2015–2020.
    Rubinsztein DC, Leggo J, Coles R et al. (1996) Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. American Journal of Human Genetics 59(1): 16–22.
 Web Links
    ePath Huntingtin (HTT); LocusID: 3064. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3064
    ePath Huntingtin (HTT); OMIM number: 143100. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?143100

Related Sub-Topics:

Techniques and Tools in Clinical Genetics | Linkage Analysis | Genetic Counseling | Health Care | Bioethics
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Predictive Genetic Testing: The Huntington Disease Model
 
How to Cite close
Tibben, Aad, and Bijlsma, Emilia(Dec 2009) Predictive Genetic Testing: The Huntington Disease Model. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005617.pub2]