Abstract
Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder characterised by motor and vocal tics. Despite decades of research, the aetiology of TS has remained elusive. Recent successes in gene discovery backed by rapidly advancing genomic technologies have given us new insights into the genetic basis of the disorder, but the growing collection of rare and disparate findings have added confusion and complexity to the attempts to translate these findings into neurobiological mechanisms resulting in symptom genesis. In this review, we explore a previously unrecognised genetic link between TS and a competing series of trans-synaptic complexes (neurexins (NRXNs), neuroligins (NLGNs), leucine-rich repeat transmembrane proteins (LRRTMs), leucine rich repeat neuronals (LRRNs) and cerebellin precursor 2 (CBLN2)) that links it with autism spectrum disorder through neurodevelopmental pathways. The emergent neuropathogenetic model integrates all five genes so far found to be uniquely disrupted in TS into a single pathogenetic chain of events described in context with clinical and research implications.
Highlights
Tourette syndrome (TS) is characterised by motor and vocal tics, with a pre-pubertal age of onset, a waxing and waning course, and improvement in symptoms in adulthood.[1]
Genomic rearrangements and copy number variations (CNVs) are the most common DNA lesions associated with TS and the most commonly rearranged locus in TS is chromosome 18q22. 2.6,11,24–47 Recent reviews and reports on the genetics of TS3,45,48 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]
Five genes have been directly disrupted in TS by independent genomic rearrangements and CNVs with unique breakpoints, namely IMMP2L, NRNX1, CTNNA3, NLGN4X and CNTNAP2.36,39–40,45–46 Viewed in isolation, each of these novel genomic rearrangements can be difficult to interpret in relation to a complex disorder like TS, even when a gene has been disrupted
Summary
Tourette syndrome (TS) is characterised by motor and vocal tics, with a pre-pubertal age of onset, a waxing and waning course, and improvement in symptoms in adulthood.[1]. There is emerging evidence to suggest an overlap between TS and ASD from phenomenological, epidemiological and pathogenetic perspectives.[8] TS and ASD are both conditions that begin during childhood and mostly affect males. Symptoms such as obsessions, compulsive behaviours, involuntary movements (tics in TS and stereotypies in ASD), poor speech control and echolalia are common in both conditions. There has been little progress in understanding the pathogenetic basis of TS except that linkage and candidate gene analyses have virtually ruled out any likelihood of common dominant mutations of large effect
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