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Am J Med Genet B Neuropsychiatr Genet. 2018 Apr;177(3):346-357. doi: 10.1002/ajmg.b.32618. Epub 2018 Feb 20.

The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population.

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Centre for Molecular Medicine Therapeutics, University of British Columbia, Vancouver, BC, Canada.
Division of Human Genetics, Department of Pathology, University of Cape Town, South Africa.
Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Medical Genetics Group, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Singapore.
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
Molecular Biology Group, Coriell Institute for Medical Research, Camden, New Jersey.
Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
IRCCS Casa Sollievo della Sofferenza Hospital, Huntington and Rare Diseases Unit (CSS-Mendel Rome), San Giovanni Rotondo, Italy.
Department of Genetics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.


Huntington disease (HD) is the most common monogenic neurodegenerative disorder in populations of European ancestry, but occurs at lower prevalence in populations of East Asian or black African descent. New mutations for HD result from CAG repeat expansions of intermediate alleles (IAs), usually of paternal origin. The differing prevalence of HD may be related to the rate of new mutations in a population, but no comparative estimates of IA frequency or the HD new mutation rate are available. In this study, we characterize IA frequency and the CAG repeat distribution in fifteen populations of diverse ethnic origin. We estimate the HD new mutation rate in a series of populations using molecular IA expansion rates. The frequency of IAs was highest in Hispanic Americans and Northern Europeans, and lowest in black Africans and East Asians. The prevalence of HD correlated with the frequency of IAs by population and with the proportion of IAs found on the HD-associated A1 haplotype. The HD new mutation rate was estimated to be highest in populations with the highest frequency of IAs. In European ancestry populations, one in 5,372 individuals from the general population and 7.1% of individuals with an expanded CAG repeat in the HD range are estimated to have a molecular new mutation. Our data suggest that the new mutation rate for HD varies substantially between populations, and that IA frequency and haplotype are closely linked to observed epidemiological differences in the prevalence of HD across major ancestry groups in different countries.


Huntington disease; genetic epidemiology; haplotypes; molecular epidemiology; trinucleotide repeat disorders


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