Huntington disease reduced penetrance alleles occur at high frequency in the general population

Abstract

Objective: To directly estimate the frequency and penetrance of CAG repeat alleles associated with Huntington disease (HD) in the general population.

Methods: CAG repeat length was evaluated in 7,315 individuals from 3 population-based cohorts from British Columbia, the United States, and Scotland. The frequency of ≥36 CAG alleles was assessed out of a total of 14,630 alleles. The general population frequency of reduced penetrance alleles (36-39 CAG) was compared to the prevalence of patients with HD with genetically confirmed 36-39 CAG from a multisource clinical ascertainment in British Columbia, Canada. The penetrance of 36-38 CAG repeat alleles for HD was estimated for individuals ≥65 years of age and compared against previously reported clinical penetrance estimates.

Results: A total of 18 of 7,315 individuals had ≥36 CAG, revealing that approximately 1 in 400 individuals from the general population have an expanded CAG repeat associated with HD (0.246%). Individuals with CAG 36-37 genotypes are the most common (36, 0.096%; 37, 0.082%; 38, 0.027%; 39, 0.000%; ≥40, 0.041%). General population CAG 36-38 penetrance rates are lower than penetrance rates extrapolated from clinical cohorts.

Conclusion: HD alleles with a CAG repeat length of 36-38 occur at high frequency in the general population. The infrequent diagnosis of HD at this CAG length is likely due to low penetrance. Another important contributing factor may be reduced ascertainment of HD in those of older age.

Figure 1. Distribution and haplotype of general population CAG repeat alleles in the Huntington disease (HD) range (≥36 CAG)

(A) HD CAG repeat distribution and frequency out of 14,630 total general population alleles. (B) Haplotypes of HD alleles in the general population conform to risk haplotypes (A1, A2, or A3a) of clinically ascertained, disease-causing HD mutations in patients of European ancestry.

Figure 2. Estimated penetrance of CAG repeats in the CAG 36–39 range at ≥65 years of age

(A) Frequency of alleles with reduced penetrance for Huntington disease in a multisource ascertainment of patients from British Columbia (BC), Canada. Proportions of patients ≥65 years of age are shown in black. (B) Estimated age-dependent penetrance rates of CAG 36–38 alleles in the general population as compared to clinical penetrance rates. Extrapolated clinical penetrance rates by 65 years of age derive from previously reported survival analysis of clinical onset data. Direct penetrance rates are calculated as the number of symptomatic patients ≥65 years of age in BC in 2012 with each CAG repeat genotype divided by the number of individuals ≥65 years of age in BC expected to have each expanded CAG repeat genotype.