CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1

Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.

De Novo Coding Variants Are Strongly Associated with Tourette Disorder

“…Our group and others have reported on copy number variations (CNVs) in TD (Fernandez et al, 2012; McGrath et al, 2014; Nag et al, 2013; Sundaram et al, 2010), confirming a role for rare structural variants and showing a trend toward enrichment of de novo events. These findings also provide additional support for the involvement of histaminergic neurotransmission, as well as dopaminergic neurotransmission, in the pathogenesis of TD (Ercan-Sencicek et al, 2010; Fernandez et al, 2012) and suggest a potential overlap with CNVs contributing to other neurodevelopmental syndromes (Malhotra and Sebat, 2012).…”

Gilles de la Tourette syndrome

“…The largest reported GTS CNV study to date (2,285 GTS cases and 3,791 controls) identified two genome-wide significant loci (NRXN1, OR=20.2, p=7.6x10 -5 and CNTN6, OR=6.0, p=1.7x10 -4 ) 66 . Rare NRXN1 deletions were also implicated in GTS pathogenesis in two previous studies of 111 and 210 GTS cases each 67,68 . In addition, recurrent exon-affecting microdeletions of the arylacetamide deacetylase (AADAC) were also observed in one of these early studies 67 and recently identified in a larger meta-analysis, including a total of 1181 patients with GTS and 118,730 controls from six European countries (p=4.4×10 -4 ) 69 .…”

Copy Number Variation in Obsessive-Compulsive Disorder and Tourette Syndrome: A Cross-Disorder Study

“…15,17 We detected one 600kb NRXN1 deletion in a patient with OCD (TS status unknown) (chr2:50185814–50799877, hg18) that was called by iPattern and qPCR-validated, although it did not pass initial QC because <50% of the region was called by PennCNV. We also observed 3 22q11 duplications, all patients with OCD (2 OCD only, 1 OCD+CT), 1 de novo deletion (OCD only), and 1 control duplication (Figure S4, available online).…”

“…In TS, the three previous genome-wide surveys of CNVs have been limited by small sample sizes (<500 cases), and results differ with regard to whether there is an increased CNV burden in TS compared to controls. 15–17 No specific CNV region has received strong statistical support across studies, although exonic NRXN1 deletions have been identified in two studies. 15,17 …”

“…15–17 No specific CNV region has received strong statistical support across studies, although exonic NRXN1 deletions have been identified in two studies. 15,17 …”