More people than previously thought may be at risk of developing Huntington disease (HD), a large cohort study from three Western countries showed.
A total of 18 of 7,315 individuals (14,630 alleles) from the general adult population in the U.S., Canada, and Scotland had a cytosine-adenine-guanine (CAG) repeat of ≥36, Michael R. Hayden, MBChB, PhD, of the University of British Columbia in Vancouver, and colleagues reported online in Neurology.
This indicates that about one in 400 individuals (0.246%, 95% CI 0.151%-0.380%) had HD-associated alleles in the reduced penetrance range of 36-39 CAG repeats within the huntingtin protein gene -- an unexpectedly high frequency, the researchers said.
About one in 2,500 people from all three countries had an HD allele in the full penetrance range, the researchers said. Earlier estimates of the condition's prevalence have clustered under 10 per 100,000 population.
"Our direct estimates show that the heterozygote frequency of ≥36 CAG in the general population is up to 10-fold higher than indirect estimates, but that the majority of these are HD alleles of reduced penetrance (CAG 36-39)," the study authors wrote. "The frequency of reduced penetrance alleles in the general population thus appears to be underestimated by clinical ascertainment, and individuals at risk of developing HD may be more numerous than previously believed."
Low penetrance may be the reason behind infrequent diagnosis of HD at this CAG length, Hayden and colleagues said. "Another important contributing factor may be reduced ascertainment of HD in those of older age," they said.
For the study, the researchers used current genetic diagnostic standards for HD to assess HTT CAG length in 3,906 individuals from the U.S., 1,815 individuals from Scotland, and 1,594 previously reported individuals from British Columbia.
Exome or whole-genome sequencing has been used in the past to assess control cohorts, they pointed out, adding that these short-read technologies can't accurately assess HTT CAG repeat lengths.
When researchers estimated the penetrance of 36-38 CAG repeat alleles for HD for individuals ≥65 years of age and compared this against previously reported clinical penetrance estimates, they found that CAG 36-38 penetrance rates in this general population were lower than penetrance rates extrapolated from clinical cohorts.
"In this study, we estimate that 0.2% of individuals with CAG 37 and 2.0% of individuals with CAG 38 are symptomatic for HD among individuals ≥65 years of age," Hayden and colleagues said. "It is crucial to note that the number of individuals who manifest HD with a reduced penetrance allele will change with age structure, both within the ≥65 years of age category and in the population as a whole."
Although this study is "impressive in its scale" and "intriguing in its results" providing "important data" for counseling patients at risk of HD, the penetrance levels it identified should not be used in clinical practice, Martin B. Delatycki, MBBS, PhD, and Oliver Bandmann, MD, PhD, warned in an accompanying editorial.
Delatycki is with the Murdoch Children's Research Institute in Parkville, Victoria, Australia, and Bandmann is at the Sheffield Institute for Translational Neuroscience at the University of Sheffield in England.
"Clinicians who identify individuals with reduced penetrance alleles in families with manifest HD should not use the low penetrance figures identified in this study, but rather should use penetrance figures identified from studies of families where there is clinical HD present," they said.
Previously, they noted, HD prevalence was taken from studies based on individuals with relatives with symptomatic HD.
"If these results were to hold up in larger studies, then one would need to assume that the prevalence of HD may be an order of magnitude greater than the reported prevalence of between 2.17 and 7.33 per 100,000 in largely Caucasian populations."
One possible explanation for the stark contrast between data from previous epidemiological studies and this one, they added, is the possibility of non-penetrance in some individuals who carry ≥40 CAG repeats. In the study, three individuals were identified who had fully penetrant alleles: two had 42 CAG repeats; and one had 44 CAG repeats. "However, the absolute number of individuals identified with ≥40 repeats is clearly too small to draw any firm conclusions," they said.
The study design also leaves some answered questions, the editorialists pointed out. The fact that the DNA samples came from unidentified individuals meant that those with CAG repeats of ≥36 could not be examined for subtle, early manifestations of HD. Similarly, family history could not be taken into account.
In addition, the age of the individuals was not included. "If the cohort is young," Delatycki and Bandmann said, "it would require a longer period of follow-up to answer questions of penetrance."
Efforts to sequence the entire genome in much larger cohorts such as the 100,000 Genomes Project will "likely supercede" this study, they predicted.
Funding for this study was provided by the Canadian Institutes of Health Research. Hayden disclosed that he is president of Global R&D and chief scientific officer of TEVA with financial interests in Teva Pharmaceuticals.
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