The application proposes to continue an ongoing investigation of a newly identified autosomal dominant (AD) epilepsy syndrome with auditory features (ADPEAF). A susceptibility gene for this syndrome was recently localized to a 10 centimorgan region of chromosome 10q. The current plan is to ascertain and clinically characterize 5-10 additional extended pedigrees with ADPEAF, comprising approximately 100 living subjects (35 affected), and to confirm and refine the localization of the susceptibility gene by performing linkage analysis in these families. Families will be ascertained through four methods: 1) screening of the computerized database of epilepsy patients at the applicant institution; 2) yearly mailings to the membership of the American Epilepsy Society; 3) publication of an article in Epilepsy USA, the newspaper of the Epilepsy Foundation of America; and 4) requests for referrals in presentations given by the applicant. Families will be included in the analysis only if they contain 3 or more individuals with partial epilepsy with auditory features, similar to those in the original pedigree of this study. The applicants will test each family for linkage with the same markers on chromosome 10q and the same genetic model as in the previous analysis. If evidence for linkage is found, they will search for recombination events that further narrow the region containing the locus. Local heterogeneity will be assessed by determining the proportion of families with evidence for linkage to chromosome 10q and localizing susceptibility genes for ADPEAF to other regions in families that do not show evidence for linkage. In families with evidence for linkage to chromosome 10q, the applicants will test the hypothesis that the susceptibility gene raises risk for other seizure disorders in addition to ADPEAF (e.g., generalized epilepsies, isolated unprovoked seizures, febrile convulsions, and/or alcohol-related seizures), by comparing the proportion affected with these disorders among individuals likely, and not likely, to be gene carriers.
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