Evidence from family studies conducted over the last several years (by us and others) has convinced us that the vast majority of cases of Tourette Syndrome (TS) may well be caused by a genetic predisposition determined by a single gene. Locating that gene on the genetic map of a chromosome will greatly enhance our ability to diagnose TS and identify vulnerable individuals, those at risk to develop the. Syndrome. Mapping that presumed gene is also an important initial step in the scientific process leading to understanding what biological abnormality leads to the many problems affecting individuals with TS. Eventually, by cloning the gene, by characterizing the gene and its product, and by determining how they cause a vulnerability to TS, it will be possible to develop much more effective treatments for TS and related disorders. Therefore, with the help of a grant from the TSA, we are now accelerating our efforts to find a gene that can cause TS. Our project is designed around the concept of genetic linkage— genes close together on a chromosome tend to be inherited together. The TS gene cannot be seen directly, but we can infer how it has been transmitted from affected parents to specific children in large families. If we can find, in a very large family, some normal genetic trait (a genetic marker) that is inherited in the same pattern by the same individuals, we will know that the TS gene is located near that genetic marker. This is the same research strategy that has been used to find the location of the genes for Huntington disease and cystic fibrosis. All such studies use the newly discovered class of genetic markers called RFLPs, a convenient short acronym for the technical description of these markers that are studied directly in-the DNA of individuals. There are now” hundreds of these genetic markers distributed throughout the human genome, so success in a genetic linkage study is primarily dependent on having suitable families and rigorous, valid diagnoses. Since 1982 we have been .pursuing genetic linkage studies of TS. Large numbers of cell lines have been established on over 300 individuals in four large kind-reds, each having several cases of TS. Diagnostic evaluations were made on those individuals, and large numbers of probes for DNA markers were assembled. One of those families is the large Mennonite kindred in Canada being studied by Dr. Roger Kurlan and his associates. Dr. Kurlan’s studies have been supported for several years by the TSA. He sent blood samples to Yale, where we established the cell lines to collect DNA in the laboratory. We now have the necessary DNA samples on over 130 individuals from that large kind red. Two other large kindreds have been studied by our group at Yale and the fourth has been studied jointly with Dr. Kurlan. This new TSA grant is now allowing the Yale collaborative team, which includes James Leckman and Judith Kidd, to use the resources accumulated to speed up a focused, systematic search for a gene causing TS. A new laboratory technician who is working exclusively on the TS project has been hired to work along with several other technicians, statistical analysts, students, and postdoctoral fellows who are all working on the TS project at least part of the time. Concurrently, With the increased laboratory effort, this TSA grant will allow us to study a fifth large family. We have retained a research assistant to coordinate this effort. We have chosen to study five large kindreds for two reasons. First, it is possible that in different families there may be different genes responsible for TS. Therefore, each kindred must be large enough to allow us to find the gene in that particular family. If there are two or more common forms, with five large kindreds of different ancestry we should identify more than one gene causing TS. The second reason is that, if all five families have the same abnormal gene, we will have the large sample necessary to speed up the next phase: going from knowing the location of TS gene to finding out what it is and what it does. Kenneth K. Kidd, Ph.D, Yale School of Medicine, New Haven, CT David L Pauls, Ph.D., Yale Child Study Center New Haven, CT Award: $113,00 Tourette Association of America Inc. – Research Grant Award 1988