Kay C, Collins JA, Miedzybrodzka Z, Madore SJ, Gordon ES,
Gerry N, Davidson M,
Slama RA, Hayden MR. Huntington disease reduced penetrance
alleles occur at high
frequency in the general population. Neurology. 2016 Jul
19;87(3):282-8.
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.
Semaka A, Kay C, Doty CN, Collins JA, Tam N, Hayden MR. High frequency of intermediate alleles on Huntington disease-associated haplotypes in British Columbia's general population. Am J Med Genet B Neuropsychiatr Genet. 2013 Dec;162B(8):864-71.
ReplyDeleteAbstract
Intermediate alleles (27-35 CAG, IAs) for Huntington disease (HD) usually do not confer the disease phenotype but are prone to CAG repeat instability. Consequently, offspring are at-risk of inheriting an expanded allele in the HD range (≥36 CAG). IAs that expand into a new mutation have been hypothesized to be more susceptible to instability compared to IAs identified on the non-HD side of a family from the general population. Frequency estimates for IAs are limited and have largely been determined using clinical samples of HD or related disorders, which may result in an ascertainment bias. This study aimed to establish the frequency of IAs in a sample of a British Columbia's (B.C.) general population with no known association to HD and examine the haplotype of new mutation and general population IAs. CAG sizing was performed on 1,600 DNA samples from B.C.'s general population. Haplotypes were determined using 22 tagging SNPs across the HTT gene. 5.8% of individuals were found to have an IA, of which 60% were on HD-associated haplotypes. There was no difference in the haplotype distribution of new mutation and general population IAs. These findings suggest that IAs are relatively frequent in the general population and are often found on haplotypes associated with expanded CAG lengths. There is likely no difference in the propensity of new mutation and general population IAs to expand into the disease range given that they are both found on disease-associated haplotypes. These findings have important implications for clinical practice.