The search for tourette syndrome genes : a conceptual and experimental approach

[摘要] ENGLISH SUMMARY: Tourette syndrome has been reported in most populations throughout the world.Overall, there appears to be similar clinical phenomenology and psychopathology,which may serve as an indication of the biological nature for the condition.The diagnosis of Tourette syndrome represents a challenge for physicians because ofclinical heterogeneity and often-present comorbidity with other knownneurobehavioural conditions. Due to these clinical overlaps Tourette syndrome mayserve as a model disorder for investigating the relationship between variousneurological and behavioral domains of childhood reflecting either the expression of acommon biological pathway or a common genetic background. The understanding ofthe genetic basis of Tourette syndrome is therefore of special importance, because itmay provide useful insights for the study of other developmental disorders. However,the lack of objective biological markers of clinical manifestation together with apossible high phenocopy rate, unclear mode of inheritance, incomplete penetrance,and frequent bilinear transmission of predisposing genes represent major obstacles forthose attempting to elucidate the genetic basis of Tourette syndrome.The research presented in this document is a result of six years' effort of the authorand her collaborators to generate cytogenetic and molecular genetic data contributingto a better understanding of genetic and environmental factors affecting thephenotypic expression of Tourette syndrome. Theoretical and experimental results ofthis collaborative effort are assembled in seven articles (four published, threecurrently submitted for a publication) and a general introductory section relating tothe problems, methods and methodology described and utilized in data collection forthe individual papers.Taken as a whole, while the study of chromosome fragile site expression in Tourettesyndrome probands yielded equivocal results leading to a number of rather speculative but interesting interpretations, the results of subsequent molecular geneticstudies are far clearer.The three most valuable outcomes of these studies for future genetic investigations inTourette syndrome gene-mapping efforts in the Afrikaner population, and complexgenetic traits in general, are:I. The evidence for association/linkage of at least three genomic regions withTourette syndrome in the Afrikaner population, with two of the regions (11q23and 8q22) being suggestively linked to Tourette syndrome by others in differentpopulations and employing different analytical methods.2. The evidence for extended background linkage disequilibrium in the generalAfrikaner population (> 5 cM) which further strengthens existing experimentaldata demonstrating the suitability of this population for gene-mapping effortsinvolving complex traits.3. The proof based on real rather than computer-simulated data that sequential andsemiparametric methods of analysis could be sufficiently powerful to generatecumulative evidence for positive linkage with the trait in the regions whichrepeatedly yielded both highly significant as well as suggestively significantdisease-marker associations in the initial set of samples.

[发布机构] Stellenbosch University