The recent localization of the Huntington's disease (HD) gene to the short arm of chromosome 4 was made possible through the study of a unique HD kindred living in the State of Zulia, Venezuela. For the past four years, the P.I. and others listed have conducted field work in Venezuela with the primary goal of locating the HD gene. The community has many special features: 1. All HD patients have inherited their gene from a common ancestor. 2. The pedigree numbers 3,539 with superb large families for studying HD and genetic linkage in general. 3. The potential for discovering a homozygote exists in several families in which both parents either have or are at risk for HD. 4. The HD genotype and environmental factors are controlled, facilitating the study of modifying genes in accounting for the wide phenotypic variation observed. 5. Patients take no medications usually prescribed for HD, permitting longitudinal and prospective observation of the natural history of the illness. 6. Families are geographically contained within a state. 7. The presence of large sibships and multiple living generations makes portions of this pedigree ideal as a """"""""reference pedigree"""""""" for mapping all genes on the human genome. The current study proposes to: 1. Better define the distance between G8 and the HD gene by searching for """"""""recombinants,"""""""" those with the disease but with a different HD form of the marker. This will be done by testing additional patients not yet collected and by the diagnosis, when appropriate, of at-risk individuals already collected. 2. Study intensively those shown genetically to be homozygous. 3. Investigate the natural history of the illness in unmedicated patients and particularly in its earliest and asymptomatic phase in genetically confirmed but presymptomatic individuals. 4. Explore modifying factors accounting for phenotypic variation. 5. Complete collection of the reference pedigree for general gene mapping. 6. Coordinate the use of the reference pidigree among many investigators to maximize its value.
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