title: 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 ∼400 kb 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.
authors.affiliation: UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Nag
authors.forename: Elena G
authors.initials: EG
authors.lastname: Bochukova
authors.forename: Barbara
authors.initials: B
authors.lastname: Kremeyer
authors.forename: Desmond D
authors.initials: DD
authors.lastname: Campbell
authors.forename: Heike
authors.initials: H
authors.lastname: Muller
authors.forename: Ana V
authors.initials: AV
authors.lastname: Valencia-Duarte
authors.forename: Julio
authors.initials: J
authors.lastname: Cardona
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Rivas
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Mesa
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cuartas
authors.forename: Jharley
authors.initials: J
authors.lastname: Garcia
authors.forename: Gabriel
authors.initials: G
authors.lastname: Bedoya
authors.forename: William
authors.initials: W
authors.lastname: Cornejo
authors.forename: Luis D
authors.initials: LD
authors.lastname: Herrera
authors.forename: Roxana
authors.initials: R
authors.lastname: Romero
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fournier
authors.forename: Victor I
authors.initials: VI
authors.lastname: Reus
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Lowe
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Carol A
authors.initials: CA
authors.lastname: Mathews
authors.forename: Lauren M
authors.initials: LM
authors.lastname: McGrath
authors.forename: Dongmei
authors.initials: D
authors.lastname: Yu
authors.forename: Ed
authors.initials: E
authors.lastname: Cook
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Jeremiah M
authors.initials: JM
authors.lastname: Scharf
authors.forename: David L
authors.initials: DL
authors.lastname: Pauls
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Freimer
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Andrés
authors.initials: A
authors.lastname: Ruiz-Linares
mesh_terms: D000293:Adolescent; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002648:Child; D024081:Collagen Type IX / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D005879:Tourette Syndrome / Q000209:etiology / Q000235:genetics*
chemical_list: C439970:COL9A1 protein, human; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D024081:Collagen Type IX; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules