Molecular Cytogenetics and Tourette Disorder

Yale University, New Haven CT

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Abstract

The goal of this proposal is to use molecular cytogenetic and molecular genetic tools to identify genes involved in Tourette syndrome (TS) and related phenotypes. TS is a neuropsychiatric disorder defined by the combination of persistent vocal and motor tics. Despite strong evidence for a genetic etiology, linkage studies undertaken over several decades have not yet identified a single gene clearly implicated in TS- spectrum disorders, which include chronic tics (CT) and tic- related Obsessive Compulsive Disorder (OCD). We have undertaken an alternative strategy for disease-gene identification based on the hypothesis that a small subset of patients presenting with this genetically heterogeneous disorder have their symptoms as the result of a structural or functional disruption of a gene of major effect due to a cytogenetic abnormality. We further propose that the identification of such a gene may illuminate biological pathways involved in more common forms of TS. Our lab has identified two patients with TS-related phenotypes: (1) a patient with CT and OCD and an inversion inv(18)(q21q22); and, (2) a patient with OCD and a balanced translocation t(18;2)(q22;p25). These abnormalities map approximately 500 kilobases (kb) and 4 megabases (Mb) respectively from a chromosome 18q22 breakpoint that segregates with TS, CT and OCD in a previously-described family (Bhogosian-Sell et al. 1996). We have obtained cell lines from this pedigree as well and have initiated an exhaustive molecular characterization of the 4.5 Mb interval defined by the three 18q22 breakpoints. Our preliminary data also demonstrates that the 18q22 inversion is altering the replication timing at this locus. This change in the epigenetic properties of the patient's inverted chromosome 18 suggests that the rearrangement is influencing the regulation of gene expression across this region. The data has prompted two associated avenues of investigation: (1) an assessment of the extent of epigenetic changes in all three 18q22 rearrangements; and, (2) an evaluation of the epigenetic properties of the 18q22 region in cytogenetically-normal subjects with TS-spectrum phenotypes. We now propose: (1) to complete the fine-mapping of the three chromosome 18q22 breakpoints at the nucleotide level; (2) to identify known and novel transcripts within the interval defined by these abnormalities; (3) to prioritize genes based on functional and structural data and to conduct mutation screening on selected candidates; (4) to investigate epigenetic phenomena in the region in cytogenetically-affected cases as well as in cytogenetically-normal TS, OCD and CT patients; and, (5) to perform screening karyotypes on well-characterized TS spectrum patients from the Yale Child Study Center and Genetics Clinic as the basis for future mapping experiments.