Reduced Penetrance Alleles

HD Lighthouse Contributing Editor's Comment: Those at risk for Huntington's Disease who decide to undergo presymptomatic testing hope to answer whether or not they will develop Huntington's Disease if no treatment is forthcoming. Most of the time, their test results will answer that question.

However, those who test in the reduced penetrance range, 36 to 39 repeats, continue to be faced with uncertainty. Their risk has gone up from 50 percent of having the HD gene to 100 percent. The current thinking is that a gene with 36-39 is is the HD gene and that if people lived long enough, to extreme old age, they would develop the disease. But few people live that long and so the risk of actually developing the Huntington's Disease with a reduced penetrance CAG count has been unknown.

This new study provides us with some additional information.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 03-18-2007

Model of DNA: James J. Caras, National Science Foundation

Reduced penetrance alleles for Huntington’s disease: a multi-centre direct observational study

Oliver Quarrell, Alan Rigby, L Hutton, Y Crow, A Dalton, N Dennis, AE Fryer, F Haydon E Kinning, A Lashwood, M Loosekoot, L Margerison, S McConnell, PJ Morrison, A Norman, M Peterson, FL Raymond, S Simpson, E Thompson, J Warner

Objective:

To obtain penetrance data for Huntington’s disease when DNA results are in the range of 36–39 CAG repeats and assess the consistency of reporting the upper allele from two reference centres.

Method:

Data were collected anonymously on age of onset or age last known to be unaffected from a cohort of individuals with results in this range. DNA samples were re-analysed in two reference centres. Kaplan-Meier analysis was used to construct an age of onset curve and penetrance figures.

Results:

Clinical data and concordant DNA results from both reference centres were available for 176 samples; penetrance figures (and 95% confidence intervals) for this cohort, at age 65 and 75 years, were 63.9% (55.5% to 73.2%) and 74.2% (64.2% to 84.2%), respectively. Inclusion of 28 additional subjects for whom repeat DNA results were unavailable, obtained from only one reference centre, or discrepant by one repeat within this range, gave penetrance data (including 95% confidence intervals) at ages 65 and 75 years of 62.4% (54.4% to 70.4%) and 72.7.% (63.3% to 82.1%), respectively. 238 duplicate results were available from the reference centres; 10 (4.2%) differed by one CAG repeat in the reporting of the upper allele and in two (0.84%) of these cases the discrepancy was between 39 and 40 repeats.

Conclusion:

When DNA results are in this range, a conservative approach is to say that there is at least a 40% chance the person will be asymptomatic at age 65 years and at least a 30% chance the person will be asymptomatic at age 75 years.

Source: Journal of Medical Genetics 2007: Mar;44(3):e68.