Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing

Abstract

Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although there is a large genetic contribution, the genetic architecture of TS remains unclear. Exome sequencing has successfully revealed the contribution of de novo mutations in sporadic cases with neuropsychiatric disorders such as autism and schizophrenia. Here, using exome sequencing, we investigated de novo mutations in individuals with sporadic TS to identify novel risk loci and elucidate the genetic background of TS. Exome analysis was conducted for sporadic TS cases: nine trio families and one quartet family with concordant twins were investigated. Missense mutations were evaluated using functional prediction algorithms, and their population frequencies were calculated based on three public databases. Gene expression patterns in the brain were analyzed using the BrainSpan Developmental Transcriptome. Thirty de novo mutations, including four synonymous and four missense mutations, were identified. Among the missense mutations, one in the rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR)-coding gene (rs140964083: G > A, found in one proband) was predicted to be hazardous. In the three public databases analyzed, variants in the same SNP locus were absent, and variants in the same gene were either absent or present at an extremely low frequency (3/5,008), indicating the rarity of hazardous RICTOR mutations in the general population. The de novo variant of RICTOR may be implicated in the development of sporadic TS, and RICTOR is a novel candidate factor for TS etiology.

Progress in Genetic Studies of Tourette’s Syndrome

“…Willsey et al performed WES in two TS cohorts (325 trios from the Tourette International Collaborative Genetics cohort; 186 trios from the Tourette Syndrome Association International Consortium on Genetics), and suggested that de novo damaging variants found in approximately 400 genes may contribute to genetic risk in 12% of clinical cases of TS; and they particularly reported 4 likely risk genes for TS, i.e., WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1) [ 200 ]. Eriguchi et al identified 30 de novo mutations, including four missense mutations (RICTOR, STRIP2, NEK10, and TNRC6A genes) in WES of nine trio families and one quartet family of TS [ 201 ]. Sun et al identified a nonsense mutation through WES in the PNKD gene segregating with TS and Tic disorders in six out of nine members in a three-generation TD multiplex family [ 202 ].…”

<p>Family-Based Analysis Combined with Case–Controls Study Implicate Roles of PCNT in Tourette Syndrome</p>

“…TS is a complex neuropsychiatric disease possibly resulting from an interaction between genetic, biological, psychological, and environmental factors, 12,17 with onset ratio about 3-4:1 in male and female. 18 Children with TS often present a variety of comorbidity, such as attention ADHD, OCD, dyslexia, anxiety disorders, sleep abnormalities, depression, and other behavioral problems that can cause impairments including distress, social impact, and interference with activities.…”

European Multicentre Tics in Children Studies (EMTICS): protocol for two cohort studies to assess risk factors for tic onset and exacerbation in children and adolescents

“…NRXN1 deletions and CNTN6 duplications [16]. Like GWASs, WES studies in TS are also limited by their small sample sizes compared to other complex psychiatric traits; an association with de novo damaging variants has been reported for a dozen candidate genes [17–20] and needs to be confirmed by studies with larger sample sizes. There is also a striking paucity of gene expression studies in tic disorders.…”

“…There is also a striking paucity of gene expression studies in tic disorders. Studies in this area focused on biological pathways related to neurotransmitters and immune regulation [17, 21–23], but were based on small sample sizes, did not clarify whether the observed changes were causes or consequences of the behavioural phenotype, and were never adequately combined to genomic data. Finally, the exploration of epigenetic modifications associated with TS and other chronic tic disorders is still in its dawning [12, 24].…”