Gilles de la Tourette Syndrome (TS) is a genetic, neurobehavioral disorder characterized by chronic, intermittent motor and vocal tics. In addition to tics, affected individuals frequently display symptoms such as attention-deficit hyperactivity disorder and/or obsessive compulsive disorder. Genetic analyses of family data have suggested that susceptibility to the disorder is most likely due to a single genetic locus with a dominant mode of transmission and reduced penetrance. In the search for genetic linkage to TS, we have collected well-characterized pedigrees with multiple affected individuals on whom extensive diagnostic evaluations have been done. Our power analyses indicate that collectively the families collected from the Toronto area and the Tourette Syndrome Association genetic consortium families are sufficient to detect linkage assuming genetic homogeneity among the families. In addition, many of the families could independently provide evidence for linkage given that a closely linked, sufficiently informative marker is used. Our plan is to systematically scan the genome using a panel of well mapped, uniformly spaced, highly polymorphic, microsatellite markers on 5 families segregating for TS. We have selected 400 markers evenly spaced at approximately 10 centimorgans (cM) intervals for linkage analysis. Because of the availability of these mapping panels and new methods for typing these markers, we predict that the scan of the entire genome will be complete in the next year. To date, 360 markers have been typed and 3,660 non-overlapping cM of the genome have been excluded (-95%) summed over all the families tested under the assumption of genetic homogeneity (the disorder is caused by the same single gene in every family studied). This may not be a correct assumption as there exists the possibility that there are several genes each in a different chromosomal location. Although this makes the search more complex, we and the other members of the TSA sponsored genetic Consortium are currently concentrating on completing the genome scan on a single well-studied family. If significant linkage is found, our efforts will shift to fine structure genetic mapping followed by physical mapping and cloning of the region. An understanding of genetic factors that contribute to the predisposition to TS could contribute to the development of more effective treatments for individuals with TS and possibly a subgroup of individuals with obsessive compulsive disorder, obsessive compulsive symptoms and attention-deficit disorder. Lap-Chee Tsui, Ph.D. The Hospital for Sick Children, Toronto, Ontario, Canada Award $50,000 Tourette Association of America Inc. – Research Grant Award 1994