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Published on: December 10, 2021
Huntington disease reduced penetrance alleles occur at high frequency in the general population
Chris Kay1, Jennifer A Collins1, Zosia Miedzybrodzka1
1From the Centre for Molecular Medicine and Therapeutics (C.K., J.A.C., R.A.S., M.R.H.), University of British Columbia, Canada; Medical Genetics Group (Z.M., M.D.), School of Medicine and Dentistry, University of Aberdeen, UK; and Molecular Biology Group (S.J.M., E.S.G., N.G.), Coriell Institute for Medical Research, Camden, NJ.
Insights
Huntington disease (HD) alleles with 36-38 CAG repeats are common in the general population, but their low penetrance explains the infrequent diagnosis. Older individuals may also be underdiagnosed.
Area of Science:
- Genetics
- Neurodegenerative Diseases
- Population Health
Background:
- Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the HTT gene.
- Estimating the frequency and penetrance of these alleles in the general population is crucial for understanding disease prevalence.
Purpose of the Study:
- To directly estimate the frequency and penetrance of CAG repeat alleles associated with Huntington disease (HD) in the general population.
- To compare the penetrance of reduced penetrance alleles (36-39 CAG) in the general population versus clinically ascertained HD patients.
Main Methods:
- CAG repeat length was analyzed in 7,315 individuals across three population-based cohorts (British Columbia, US, Scotland).
- Frequency of ≥36 CAG alleles was assessed from 14,630 total alleles.
- Penetrance of 36-38 CAG repeat alleles was estimated in individuals ≥65 years and compared to prior clinical estimates.
Main Results:
- Approximately 1 in 400 individuals (0.246%) in the general population carry ≥36 CAG repeats associated with HD.
- The most common expanded alleles were CAG 36 (0.096%) and 37 (0.082%).
- General population penetrance rates for CAG 36-38 alleles were lower than those extrapolated from clinical cohorts.
Conclusions:
- CAG repeat lengths of 36-38 are frequent in the general population but exhibit low penetrance for Huntington disease.
- Low penetrance is the primary reason for the infrequent diagnosis of HD at these CAG lengths.
- Reduced ascertainment of HD in older individuals may also contribute to the observed prevalence.
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.
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