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Haplotype-based stratification of Huntington's disease

Chao, Michael J., Gillis, Tammy, Atwal, Ranjit S., Srinidhi Mysore, Jayalakshmi, Arjomand, Jamshid, Harold, Denise, Holmans, Peter Alan ORCID:, Jones, Lesley ORCID:, Orth, Michael, Myers, Richard H., Kwak, Seung, Wheeler, Vanessa C., MacDonald, Marcy E., Gusella, James F. and Lee, Jong-Min 2017. Haplotype-based stratification of Huntington's disease. European Journal of Human Genetics 25 , pp. 1202-1209. 10.1038/ejhg.2017.125

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT, resulting in an extended polyglutamine tract in huntingtin. We and others have previously determined that the HD-causing expansion occurs on multiple different haplotype backbones, reflecting more than one ancestral origin of the same type of mutation. In view of the therapeutic potential of mutant allele-specific gene silencing, we have compared and integrated two major systems of HTT haplotype definition, combining data from 74 sequence variants to identify the most frequent disease-associated and control chromosome backbones and revealing that there is potential for additional resolution of HD haplotypes. We have used the large collection of 4078 heterozygous HD subjects analyzed in our recent genome-wide association study of HD age at onset to estimate the frequency of these haplotypes in European subjects, finding that common genetic variation at HTT can distinguish the normal and CAG-expanded chromosomes for more than 95% of European HD individuals. As a resource for the HD research community, we have also determined the haplotypes present in a series of publicly available HD subject-derived fibroblasts, induced pluripotent cells, and embryonic stem cells in order to facilitate efforts to develop inclusive methods of allele-specific HTT silencing applicable to most HD patients. Our data providing genetic guidance for therapeutic gene-based targeting will significantly contribute to the developments of rational treatments and implementation of precision medicine in HD.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher: Nature Publishing Group
ISSN: 1018-4813
Date of First Compliant Deposit: 7 July 2017
Date of Acceptance: 13 June 2017
Last Modified: 05 Mar 2023 17:50

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