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

Abstract

Gilles de la Tourette syndrome (GTS) is a potentially debilitating neuropsychiatric disorder defined by the presence of both vocal and motor tics. Despite evidence that this and a related phenotypic spectrum, including chronic tics (CT) and Obsessive Compulsive Disorder (OCD), are genetically mediated, no gene involved in disease etiology has been identified. Chromosomal abnormalities have long been proposed to play a causative role in isolated cases of GTS spectrum phenomena, but confirmation of this hypothesis has yet to be forthcoming. We describe an i(18q21.1-q22.2) inversion in a patient with CT and OCD. We have fine mapped the telomeric aspect of the rearrangement to within 1 Mb of a previously reported 18q22 breakpoint that cosegregated in a family with GTS and related phenotypes. A comprehensive characterization of this genomic interval led to the identification of two transcripts, neither of which was found to be structurally disrupted. Analysis of the epigenetic characteristics of the region demonstrated a significant increase in replication asynchrony in the patient compared to controls, with the inverted chromosome showing delayed replication timing across at least a 500-kb interval. These findings are consistent with long-range functional dysregulation of one or more genes in the region. Our data support a link between chromosomal aberrations and epigenetic mechanisms in GTS and suggest that the study of the functional consequences of balanced chromosomal rearrangements is warranted in patients with phenotypes of interest, irrespective of the findings regarding structurally disrupted transcripts.

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.…”

Candidate locus for Gilles de la Tourette syndrome/obsessive compulsive disorder/chronic tic disorder at 18q22

“…1B). Using additional mapping data from the two previously reported 18q22 rearrangements, our patient's breakpoint was found to map to a genomic position approximately 4.7 Mb centromeric to the 18q22 inversion breakpoint reported by State et al [2003] and approximately 5.5 Mb centromeric to the previously reported 18q22 translocation breakpoint described by Boghosian-Sell et al [1996].…”

“…Boghosian-Sell et al [1996] presented mapping data on a pedigree in which GTS, CTD, and OCD segregated with a t(7;18)(q22-31;q22) translocation. More recently, the fine mapping of a patient carrying an inv(18)(q21-q22) inversion with CTD and OCD was reported [State et al, 2003].…”

“…Among these, loci on chromosomes 7q, 8q, and 18q have been found to be rearranged in more than one unrelated patient [Boghosian-Sell et al, 1996;Brett et al, 1996;Matsumoto et al, 2000;Kroisel et al, 2001;State et al, 2003;Verkerk et al, 2003].…”

Replication Timing: Evolution, Nuclear Organization and Relevance for Human Disease

“…Epigenetic reprogramming in diseased cells is often observed to occur with changes in replication timing patterns, with changes in replication being observed with chromosomal rearrangements in cancer cell lines (D'Antoni et al, 2004;Gondor and Ohlsson, 2009;State et al, 2003). Better detection of prostate cancer may come in the form of measuring replication timing changes observed in peripheral blood lymphocytes undergoing aneuploidy (Dotan et al, 2004).…”