Breakpoint sequences of an 1;8 translocation in a family with Gilles de la Tourette syndrome

Abstract

Gilles de la Tourette syndrome (GTS) is a common, heritable neurological disorder manifested by chronic motor and vocal tics with childhood onset. Previous extensive linkage analysis failed to identify a GTS gene based on an autosomal dominant pattern of inheritance. Recently, a family was reported with a balanced chromosomal translocation t(1;8)(q21.1;q22.1) in family members with GTS or tics. Chromosome 8q22.1 was previously implicated in GTS by both association and linkage results. We therefore cloned and sequenced both translocation breakpoints from this family. The CBFA2T1 gene was identified 11 kb distal to the 8q22.1 breakpoint. Sequencing of CBFA2TI exons within 37 unrelated GTS patients failed to identify any mutations. However, it is possible that the translocation altered the expression of this gene or another nearby gene. Examination of the breakpoint sequences revealed a duplication of six nucleotides from chromosome 8 but no change in the chromosome 1 sequence. The sequences immediately flanking the breakpoints on the two chromosomes were modestly similar, but the breakpoints did not occur within known interspersed repeats. Our results add to our knowledge of the genetics of GTS and the mechanisms of balanced chromosomal translocations.

Epigenetic abnormalities associated with a chromosome 18(q21-q22) inversion and a Gilles de la Tourette syndrome phenotype

“…In addition to linkage and association strategies, multiple investigators have studied chromosomal abnormalities in individuals and families with GTS in the hopes of identifying a gene or genes of major effect disrupted by the rearrangement (14)(15)(16). This strategy is predicated on the notion that such patients, although unusual, may help to identify genes that are of consequence for a subgroup of patients with GTS, OCD, and CT, and provide important insights into physiologic pathways that more commonly contribute to trait development.…”

“…A review of all published cases of chromosomal translocations or inversions identified in patients with GTS reveals that three segments of the genome, on chromosomes 18q, 7q, and 8q, have been reported to be rearranged in more than one unrelated individual (14)(15)(16)(17). Nonetheless, only one report to date has identified a structurally disrupted transcript (16), and its relevance to GTS has yet to be confirmed.…”

Genetic and clinical analysis of a large Dutch Gilles de la Tourette family

“…These yielded several candidate regions, however none of the involved breakpoints has yet led to a final breakthrough. Candidate regions or genes that have been indicated by chromosomal aberrations include chromosomes 9p, 16 7q22, 18q22, 17 8q22, 18 a de novo duplication indicating the IMMP2L gene at 7q31, 19 disruption of the CNTNAP2 gene at chromosome 7q35-36 in three affected individuals in one family, 20 a chromosome 18q21-22 inversion, 21 and a translocation breakpoint at 8q. 22 Finally, a very recent study in a child with GTS has identified a de novo chromosome 13q inversion, indicating the Slit and Trk-like family member 1 (SLITRK1) geneinvolved in dendritic growth -to be a candidate gene.…”

Neurobiology and neuroimmunology of Tourette?s syndrome: an update

“…To date the candidate gene studies have been negative. Related studies have chosen candidate regions based on identified chromosomal abnormalities in individual patients; however, involvement of the candidate region could either not be confirmed [74,75], or still awaits confirmation (a novel gene by a breakpoint in 7q31 [76]; and the contactin-associated protein 2 gene by the breakpoint at 7q35-7q36 [77]). A recent study described a TS patient with a 18q21-q22 inversion, whereby the rearrangement was fine-mapped to within 1 Mb of a 7;18 translocation (breakpoint at 18q22) present in a previously independently described TS pedigree [78] in which that translocation cosegregated with TS and related problems in that individual's family.…”