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

E ditor -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 HD 3 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. In our series, we could discern five categories of subjects with intermediate or reduced penetrance alleles (table 1 ), depending on the family structure, test results, test indication, and status of the test applicant, each with its own counselling issues, as shown in the selected case descriptions (fig 1 ).\n Other problems concern the difficulty in coping with the uncertainty about the risk of expansion and penetrance, the difference of an intermediate test result for daughters and sons, and turmoil induced by informing relatives, unaware of a risk, about the uncertain consequences of intermediate and reduced penetrance alleles. Besides this, it is important to realise that it is difficult for most of these applicants, who are unexpectedly confronted with a risk for themselves, their offspring, and relatives to live with this uncertainty.