CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder Annemieke J.M.H. Verkerk, a Carol A. Mathews, b Marijke Joosse, a Bert H.J. Eussen, a Peter Heutink, a Ben A. Oostra, a, * and the Tourette Syndrome Association International Consortium for Genetics 1 a Department of Clinical Genetics, Erasmus MC, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands b Neuropsychiatric Genetics Group, Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093-0810, USA Received 19 September 2002; accepted 26 March 2003 Abstract Gilles de la Tourette syndrome (GTS) is a sporadic or inherited complex neuropsychiatric disorder characterized by involuntary motor and vocal tics. There is comorbidity with disorders like obsessive compulsive disorder and attention deficit hyperactivity disorder. Until now linkage analysis has pointed to a number of chromosomal locations, but has failed to identify a clear candidate gene(s). We have investigated a GTS family with a complex chromosomal insertion/translocation involving chromosomes 2 and 7. The affected father [46,XY,inv(2) (p23q22),ins(7;2) (q35– q36;p21p23)] and two affected children [46,XX,der(7)ins(7;2)(q35– q36;p21p23) and 46,XY,der(7)ins(7;2)(q35– q36;p213p23)] share a chromosome 2p21–p23 insertion on chromosome 7q35– q36, thereby interrupting the contactin-associated protein 2 gene (CNTNAP2). This gene encodes a membrane protein located in a specific compartment at the nodes of Ranvier of axons. We hypothesize that disruption or decreased expression of CNTNAP2 could lead to a disturbed distribution of the K + channels in the nervous system, thereby influencing conduction and/or repolarization of action potentials, causing unwanted actions or movements in GTS. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Gilles de la Tourette syndrome; Contactin-associated protein; Potassium channel; Node of Ranvier; Translocation breakpoint; Chromosome 7; Chromosome 2 Gilles de la Tourette syndrome (GTS) (OMIM 137580) is an inherited neuropsychiatric disorder characterized by repeated simple or complex involuntary motor and vocal tics that begin in childhood and follow a waxing and waning course [1– 4]. GTS is also often accompanied by features associated with obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), poor impulse control, and other behavioral problems [1,2]. However, the relationships between both ADHD and GTS and OCD and GTS are complex and not yet clear [5]. Evidence is accumulating that an association exists between OCD and GTS [6,7]. Specific symptoms of obsessive– compulsive disorder are found to be similar in GTS with and without OCD and differ from tic-free OCD [8]. These studies suggest that GTS with OCD constitutes a form of GTS, and not of OCD, and reinforce the ideas that at least some forms of OCD are etiologically related to GTS and that GTS + OCD represents a variant phenotype or maybe a more severe form of GTS. At the same time OCD alone in individuals of GTS families might be considered an alternative phenotype or could be due to reduced penetrance of the autosomal dominant mode of inheritance of the disease [9]. Although the cause of GTS is unknown, there is evidence that genetic factors are involved [10,11]. An obvious first approach to search for responsible genes is linkage studies, but due to the complexity of the disorder, until now, results have remained elusive [12]. Several genomic regions have been identified using linkage and association studies point- * Corresponding author. Fax: +31 10 4089489. E-mail address: b.oostra@erasmusmc.nl (B.A. Oostra). 1 A complete list of members can be found under Acknowledgments in Am. J. Hum. Genet. 65 (1999) 1428 –1436. R Available online at www.sciencedirect.com Genomics 82 (2003) 1–9 www.elsevier.com/locate/ygeno 0888-7543/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0888-7543(03)00097-1