Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy

Rikke S. Møller, Yvonne G. Weber, Laura L. Klitten, Holger Trucks, Hiltrud Muhle, Wolfram S. Kunz, Heather C. Mefford, Andre Franke, Monika Kautza, Peter Wolf, Dieter Dennig, Stefan Schreiber, Ina Maria Rückert, H. Erich Wichmann, Jan P. Ernst, Claudia Schurmann, Hans J. Grabe, Niels Tommerup, Ulrich Stephani, Holger LercheHelle Hjalgrim, Ingo Helbig, Thomas Sander, Fritz Zimprich, Martina Mörzinger, Martha Feucht, Arvid Suls, Sarah Weckhuysen, Lieve Claes, Liesbet Deprez, Katrien Smets, Tine Van Dyck, Tine Deconinck, Peter De Jonghe, Reana Velizarova, Petya Dimova, Melania Radionova, Ivaylo Tournev, Dahlia Kancheva, Radka Kaneva, Albena Jordanova, Ditte B. Kjelgaard, Anna Elina Lehesjoki, Auli Siren, Stéphanie Baulac, Eric Leguern, Sarah Von Spiczak, Philipp Ostertag, Markus Leber, Costin Leu, Mohammad R. Toliat, Peter Nürnberg, Anne Hempelmann, Franz Rüschendorf, Christian E. Elger, Ailing A. Kleefuß-Lie, Rainer Surges, Verena Gaus, Dieter Janz, Bettina Schmitz, Karl Martin Klein, Philipp S. Reif, Wolfgang H. Oertel, Hajo M. Hamer, Felix Rosenow, Felicitas Becker, Carla Marini, Reno Guerrini, Davide Mei, Vanessa Norci, Federico Zara, Pasquale Striano, Angela Robbiano, Marianna Pezzella, Amedo Bianchi, Antonio Gambardella, Paolo Tinuper, Angela La Neve, Giuseppe Capovilla, Piernanda Vigliano, Giovanni Crichiutti, Francesca Vanadia, Aglaia Vignoli, Antonietta Coppola, Salvatore Striano, Maria Teresa Giallonardo, Silvana Franceschetti, Vincenzo Belcastro, Paolo Benna, Giangennaro Coppola, Alessia De Palo, Edoardo Ferlazzo, Marilena Vecchi, Vittorio Martinelli, Francesca Bisulli, Francesca Beccaria, Ennio Del Giudice, Margherita Mancardi, Giuseppe Stranci, Aldo Scabar, Giuseppe Gobbi, Ivan Giordano, Bobby P C Koeleman, Carolien De Kovel, Dick Lindhout, Gerrit Jan De Haan, Ugur Ozbeck, Nerses Bebek, Betul Baykan, Ozkan Ozdemir, Sibel Ugur, Elif Kocasoy-Orhan, Emrah Yücesan, Naci Cine, Aysen Gokyigit, Candan Gurses, Gunay Gul, Zuhal Yapici, Cigdem Ozkara, Hande Caglayan, Ozlem Yalcin, Destina Yalcin, Dilsad Turkdogan, Gulsen Dizdarer, Kadriye Agan

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods: We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings: We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance: We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Original languageEnglish
Pages (from-to)256-264
Number of pages9
JournalEpilepsia
Volume54
Issue number2
DOIs
Publication statusPublished - Feb 1 2013

Keywords

  • 1q21.1 microdeletion
  • Idiopathic generalized epilepsy
  • NRXN1
  • Two-hit hypothesis

ASJC Scopus subject areas

  • Medicine(all)
  • Neurology
  • Clinical Neurology

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