Translocation breakpoint in two unrelated Tourette syndrome cases, within a region previously linked to the disorder

Abstract

Tourette syndrome (TS) is a complex neuropsychiatric disorder characterized by both motor and vocal tics. The etiology of TS is poorly understood; however, evidence of genetic transmission arises from family and twin studies. A complex mode of inheritance has been suggested, likely involving contributions of several genes with different effect size. We describe here two unrelated families wherein balanced t(6;8) chromosomal translocations occur in individuals diagnosed with TS. In one of these families, the transmission of the translocation is associated with learning and behavioral difficulties; in the other family, one parent is unaffected and the other cannot be traced, thus transmission cannot be demonstrated and it is possible that the translocation may have occurred de novo. The breakpoint on chromosome 8 occurs within the q13 band in both families, suggesting that a gene or genes in this region might contribute to the TS phenotype. Existing linkage and cytogenetic data, suggesting involvement of chromosome 8 in TS families and individuals, further support this hypothesis. We have identified two YAC clones mapping distal and proximal to the chromosome 8 translocation site, as determined by fluorescent in situ hybridization (FISH). PCR amplification of genetic markers in this region, using isolated chromosomes from one of the patients, followed by BAC screening with the closest flanking genetic markers, has identified a 200-kb BAC, which, by FISH, we have demonstrated encompasses the chromosome 8 breakpoint in both families. The fact that the chromosomal breaks in the TS cases from both families occur within such a small region of chromosome 8 further supports the hypothesis that disruption of a gene or genes in this part of chromosome 8 contributes to the clinical phenotype.

Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism

“…6, 11, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 Recent reviews and reports on the genetics of TS 3, 45, 48 have identified at least 28 large independent genomic rearrangements and CNVs with unique breakpoints including deletions, insertions, duplications, inversions and inter-chromosomal translocations. 6, 11, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 Of the rearrangements that have been characterised, approximately one third have directly disrupted genes (Table 1), whereas the remainder have breakpoints within intergenic regions (Table 2). 24, 25, 26, 28, 29, 31, 32, 37, 44, 45 Intergenic breakpoints are of great interest as they can lead to the dysregulation of a neighbouring gene(s) even when separated by very long distances.…”

“…6, 11, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 Of the rearrangements that have been characterised, approximately one third have directly disrupted genes (Table 1), whereas the remainder have breakpoints within intergenic regions (Table 2). 24, 25, 26, 28, 29, 31, 32, 37, 44, 45 Intergenic breakpoints are of great interest as they can lead to the dysregulation of a neighbouring gene(s) even when separated by very long distances. 49 Candidate genes (Table 2) located near TS intergenic translocation breakpoints may be similarly affected by long-range dysregulation.…”

“…We searched other TS intergenic breakpoint loci 24, 26, 27, 28, 29, 31, 32, 33, 35, 37, 41, 42, 43, 45 for genes that are structurally or functionally related to those within the model (Figure 2). Other LRR -coding genes LRRTM1 , LRTM1 and SLITRK1 are located near breakpoints at 2p12, 3p21 and 13q31, respectively (Table 2).…”

Indications of Linkage and Association of Gilles de la Tourette Syndrome in Two Independent Family Samples: 17q25 Is a Putative Susceptibility Region

“…Positive association was also found between the monoamine oxidase A gene (MAOA [MIM 309850]) and GTS (Gade et al 1998;Díaz-Anzaldú a et al 2004). Chromosomal abnormalities in individuals and families with GTS have also been studied in the hope of identifying a gene or genes of major effect that would be disrupted by the rearrangement (Brett et al 1996;Kroisel et al 2001;Petek et al 2001;Crawford et al 2003;and State et al. 2003, among others).…”

Genome-wide sequencing for the identification of rearrangements associated with Tourette syndrome and obsessive-compulsive disorder

“…Notable examples are the combination of cytogenetic and molecular approaches that led to the identification of the SLIT and NTRK-like family member 1 SLITRK1 [12], inner mitochondrial membrane peptidase 2 like ( IMMP2L ) [13] and contactin associated protein-like 2 (CNTNAP2) [14] genes. To date, of seven independent balanced reciprocal translocations reported to be associated with TS, two involve chromosome 6 [15,16]. The latter work describes a 6q21 translocation, while the location of the former is not known.…”