A Genetic Linkage Study of GTS

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Investigator: Carol A. Mathews, MD
Sponsor: Tourette Syndrome Association, Inc.

Location(s): Canada

Description

We are continuing our systematic screening of the autosomal genome for strong evidence of a genetic linkage between a major locus for Gilles de la Tourette Syndrome (GTS) and the simple Mendelian polymorphic markers that we are typing. This work will involve both typing of additional markers and re-analysis of all existing marker data using revised/updated diagnoses and genetic models. We will continue to concentrate our typing efforts on the Oregon kindred (52 individuals being typed) and on branch C (66 individuals) of the larger Canadian kindred in order to cover the genome more rapidly with markers. We have sent DNA from the individuals in these two kindreds to other members of the TSA Collaborative Genetics Group–the Weber, Tsui, and Oostra labs–in order to assure that these families are as thoroughly covered with markers as possible. Data from these labs, our lab in genetics, and David Pauls' lab in the Child Study Center will be integrated for analysis. When we have a clear clue to a possible genetic map location for a GTS locus, then we can follow up by typing our other TS families and by typing additional marker loci in the vicinity of the promising finding.

Our choice of new markers to type is being guided by the exclusion maps we are helping generate through the TSA's Collaborative Genetics Group (e.g. Pakstis et al. (1991) Amer. J. Hum. Gen. 48: 281-294, and more recent updates). We are looking for markers that will fill the gaps in these combined exclusion maps as well as the less extensive exclusion maps of the individual kindreds.

Our clinical collaborators continue to seek out and interview important individuals in these kindreds that have not been interviewed previously as well as to have follow up interviews with individuals who still are at risk for developing the disorder. Roger Kurlan is also refining and updating diagnoses in the Canadian and Michigan kindreds. David Pauls will soon update diagnoses on the Oregon kindred and has just recently complete diagnoses in the Kansas family. (We have already phenotyped a large number of genetic markers on the Kansas kindred that will now become informative for mapping Tourette Syndrome.) Updated results from the segregation analyses that David Pauls has been pursuing on a large series of TS families will be considered for the purposes of revising our genetic models. Revisions might be made concerning the most appropriate penetrances to apply to the as yet unaffected individuals in the pedigree taking into account the sex of the individual. Changes might also be made in what constitutes the exact definitions of who will be considered affected with TS for the purpose of screening the families for a significant genetic linkage. Once these diagnostic and genetic model changes are incorporated, we will do a complete re-analysis of all marker data accumulated to date.