Whole Exome and Targeted Sequencing in Tourette Syndrome Multiplex Families

This study consists of 771 individuals from 15 extended, multi-generational Tourette Syndrome (TS) pedigrees collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG), 213 of whom are affected either with TS or its broader, genetically related phenotype, chronic tic disorder (CT). Prior microsatellite linkage analysis, including 624 individuals from these families, has identified a genome-wide significant TS/CT susceptibility locus on chromosome 2p21-24 with two additional loci meeting criteria for suggestive linkage on chromosomes 6p12-21 and 17p11-q11. Subsequent joint linkage and association analysis, incorporating genome-wide SNP genotyping on the Illumina Hap610 platform from 221 individuals, has strengthened the evidence for a major TS/CT locus on chromosome 2p but did not refine the locus further. In addition, haplotype analyses suggest that multiple TS/CT loci may exist on the short arm of chromosome 2. The goal of the current sequencing study is to use exon-focused sequencing, supplemented with targeted sequencing of additional known functional elements on chromosome 2p, to identify susceptibility variants contributing to the highly penetrant TS/CT phenotype in these families.]]>
Each pedigree was selected based on the presence of multiple affected individuals either with TS or CT across at least two generations. Both affected individuals and unaffected relatives were recruited and assessed for the presence of TS and CT using a standardized, semi-structured interview, which has high clinical validity and reliability for the diagnosis of TS (κ=1.0) (TSAICG, Am J Hum Genet, 2007). For the current sequencing study, pedigrees with the strongest evidence for linkage on chromosome 2 were prioritized. Within pedigrees, individuals were chosen for sequencing based on the following criteria: a) affected individuals as distantly related as possible with the common haplotype(s) segregating in that pedigree; b) individuals with key recombination events. For branches of chromosome 2-linked families, where the chromosome 2 risk haplotype was not transmitted to an affected offspring, complete trios were selected with the goal of identifying TS causal variants elsewhere in the exome. For the large pedigrees with little-or-no evidence for linkage on chromosome 2, complete trios with an affected parent were selected, as well as multi-generational lineages with a chain of affected individuals.]]>
1980s-1990s: Samples collected 2004-2006: Microsatellite linkage analyses performed on 624 individuals 2009-2010: High-density SNP genotyping performed on 221 individuals 2011: Current study with whole genome genotyping data. ]]>