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This familial neurodegenerative disorder involves variable onset followed by consistent worsening of characteristic abnormal movements along with cognitive decline and psychiatric disturbances. HD was the first autosomal disease for which the genetic defect was assigned to a position on the human chromosomes using only genetic linkage analysis with common DNA polymorphisms. This discovery set off a multitude of similar studies in other diseases, while the HD gene, later renamed HTT, and its vicinity in chromosome 4p16.3 then acted as a proving ground for development of technologies to clone and sequence genes based upon their genomic location, with the growing momentum of such advances fueling the Human Genome Project. The identification of the HD gene has not yet led to an effective treatment, but continued human genetic analysis of genotype-phenotype relationships in large HD subject populations, first at the HTT locus and subsequently genome-wide, has provided insights into pathogenesis that divide the course of the disease into two sequential, mechanistically distinct components.<\/jats:p>","DOI":"10.3233\/jhd-200427","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T21:31:30Z","timestamp":1612906290000},"page":"35-51","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":110,"title":["Huntington\u2019s Disease Pathogenesis: Two Sequential Components"],"prefix":"10.1177","volume":"10","author":[{"given":"Eun Pyo","family":"Hong","sequence":"first","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department 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