rss
J Med Genet 38:e12 doi:10.1136/jmg.38.4.e12
  • Electronic letters

New problems in testing for Huntington's disease: the issue of intermediate and reduced penetrance alleles

  1. ANNEKE MAAT-KIEVIT*,
  2. MONIQUE LOSEKOOT*,
  3. HANNEKE VAN DEN BOER-VAN DEN BERG*§,
  4. GERT-JAN VAN OMMEN,
  5. MARTINUS NIERMEIJER,
  6. MARTIJN BREUNING*,
  7. AAD TIBBEN**
  1. *Department of Clinical Genetics, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands
  2. †Department of Clinical Genetics, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands
  3. ‡Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  4. §Department of Philosophy, Medical Ethics, and History of Medicine, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands
  5. ¶Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
  6. **Department of Medical Psychology, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands
  1. Dr Maat-Kievit, J.A.Maat{at}KGC.AZL.NL

    Editor—Huntington's disease (HD) is an autosomal dominant, progressive, incurable neuropsychiatric disorder, characterised by chorea, changes in personality, mood, and behaviour, and dementia. Because the mean age at onset is 40 years (range 5 to 70 years), the risk for a healthy young adult with an affected parent will remain nearly 50%, making decisions about the future and family planning difficult.1 2 After the localisation of the gene to chromosome 4p16.3 in 1983, predictive testing by linkage analysis became available for subjects at risk for HD3 and was shown to have potential benefits.4 When the mutation in the HD gene was identified in 1993,5 predictive testing became technically simpler, reliable, and available for everyone at risk. HD, like other neurodegenerative disorders (for example, SCA1, 2, 3, 6, and 7, DRPLA, and SBMA), is caused by an expanded CAG repeat. The wild type allele has six to 35 copies but affected subjects have between 36 and 121 repeats.6 7 The HD and normal range have quite distinct peaks but the tails of both curves are close to each other. As in SCA1 and 2 (and as opposed to SCA3 and 6, SBMA, and DRPLA), there is no gap between normal and disease ranges in HD and reduced penetrance is found in the lower range of the disease repeat. The normal repeat segregates simply and stably as a polymorphic locus, but the disease repeat size tends to increase and occasionally decrease in successive generations.8 The limits of the CAG repeat size in the HD gene have been redefined,9 based on the total number of normal and symptomatic subjects assessed.

    A normal repeat, with less than 27 repeats, has never been associated with a HD phenotype, nor has it shown instability resulting in a HD …