Huntington’s disease-associated alleles were identified at a greater frequency than expected in a general population cohort, suggesting that the neurodegenerative disease is more common than thought.
The Huntington’s disease (HD) phenotype is linked to 35 or more CAG repeats at exon 1 of the Huntington’s gene. However, 36 to 39 CAG repeats are associated with a reduced penetrance of the dominant condition. In a study published in Neurology, Chris Kay, BSc, of the Centre for Molecular Medicine and Therapeutics at the University of British Columbia in Vancouver, Canada, and colleagues sought to estimate the penetrance and frequency of the HD-associated CAG repeats in the general population.
Using data from 3 population-based cohorts, the CAG repeat length was assessed in 7315 patients. The frequency of reduced penetrance alleles was then compared to the actual prevalence of HD in British Columbia, Canada.
The HD-associated CAG repeat with 36 or more repeats was found in 18 individuals (0.246%, 95% CI: 0.151-0.38%, P=.485, x2). The investigators found that the CAG 36-37 genotype was the most commonly identified HD-associated alleles. Intermediate alleles with 27–35 CAG repeats were found in 3.13% of the study population (95% CI: 2.86-3.42%, P=.080, x2).
The authors estimate that 1 in 400 individuals in the general population carry the reduced penetrance HD-associated 36-39 CAG repeats. Further, 1 in 2500 may carry the full penetrance HD-associated allele. Late-onset HD is tied to 36 to 41 CAG repeats and may have slower progression and milder signs. “It is therefore possible that some individuals with reduced penetrance alleles escape diagnosis or do not seek medical services for early signs of HD,” the authors wrote. “Given the high frequency of reduced penetrance alleles in our study, genetic testing for HD should be considered in those who present with suggestive but mild clinical features, particularly among the elderly.”
The age at which symptoms develop in patients with HD varies. If the frequency of reduced penetrance alleles is as high as this study suggests, the authors hypothesize that environmental and other genetic factors may impact the expression of the disease.
In an accompanying editorial, Martin Delatycki, MBBS, FRACP, PhD, of the Bruce Lefroy Centre in Heidelberg, Australia, commented that the results suggest “that considerably more individuals have mutations that could lead to symptomatic HD than was previously suspected.”
However, the study was limited because the data was anonymous and there was no further personal or family history available on the 18 participants identified with 36 or more CAG repeats.
Future research, such as data from the 100 000 Genomes Project in the United Kingdom that plans to sequence the entire genome, may provide more answers.
- Kay C, Collins JA, Miedzybrodzka Z. Huntington disease reduced penetrance alleles occur at high frequency in the general population. Neurology. 2016; doi: 10.1212/WNL.0000000000002858.
- Delatycki MB and Bandmann O. Huntington disease: More common than you think? Neurology. 2016; doi: 10.1212/WNL.0000000000002874