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Lal, Dennis ; Ruppert, Ann-Kathrin ; Trucks, Holger ; Schulz, Herbert ; Kovel, Carolien G. de ; Kasteleijn-Nolst Trenité, Dorothée G. ; Sonsma, Anja C. M. ; Koeleman, Bobby P. ; Lindhout, Dick ; Weber, Yvonne G. ; Lerche, Holger ; Kapser, Claudia ; Schankin, Christoph Josef ; Kunz, Wolfram S. ; Surges, Rainer ; Elger, Christian Erich ; Gaus, Verena ; Schmitz, Bettina ; Helbig, Ingo ; Muhle, Hiltrud ; Stephani, Ulrich ; Klein, Karl Martin ; Rosenow, Felix ; Neubauer, Bernd Axel ; Reinthaler, Eva Maria ; Zimprich, Fritz ; Feucht, Martha ; Møller, Rikke S. ; Hjalgrim, Helle ; Jonghe, Peter De ; Suls, Arvid ; Lieb, Wolfgang ; Franke, Andre ; Strauch, Konstantin ; Gieger, Christian ; Schurmann, Claudia ; Schminke, Ulf ; Nürnberg, Peter ; Sander, Thomas
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
Adler, Clemens ; Ahammed, Zubayer ; Allgower, C. ; Amonett, J. ; Anderson, B.D. ; Anderson, M. ; Averichev, Georgy S. ; Balewski, J. ; Barannikova, O. ; Barnby, L.S. ; Baudot, J. ; Bekele, S. ; Belaga, V.V. ; Bellwied, Rene ; Berger, J. ; Bichsel, H. ; Billmeier, A. ; Bland, L.C. ; Blyth, C.O. ; Bonner, B.E. ; Boucham, A. ; Brandin, A. ; Bravar, A. ; Cadman, R.V. ; Caines, Helen Louise ; Calderón de la Barca Sánchez, Manuel ; Cardenas, A. ; Carroll, J. ; Castillo Castellanos, Javier Ernesto ; Castro, M. ; Cebra, D. ; Chaloupka, Petr ; Chattopadhyay, S. ; Chen, Y. ; Chernenko, S.P. ; Cherney, M. ; Chikanian, A. ; Choi, B. ; Christie, William ; Coffin, J.P. ; Cormier, T.M. ; Cramer, J.G. ; Crawford, H.J. ; Deng, W.S. ; Derevschikov, A.A. ; Didenko, L. ; Dietel, Thomas ; Draper, J.E. ; Dunin, V.B. ; Dunlop, J.C. ; Eckardt, V. ; Efimov, L.G. ; Emelianov, V. ; Engelage, J. ; Eppley, G. ; Erazmus, B. ; Fachini, P. ; Faine, V. ; Filimonov, K. ; Finch, E. ; Fisyak, Y. ; Flierl, D. ; Foley, K.J. ; Fu, J. ; Gagliardi, Carl A. ; Gagunashvili, N. ; Gans, J. ; Gaudichet, L. ; Germain, M. ; Geurts, F. ; Ghazikhanian, V. ; Grachov, O. ; Grigoriev, Vladislav A. ; Guedon, M. ; Gushin, E. ; Hallman, T.J. ; Hardtke, D. ; Harris, J.W. ; Henry, T.W. ; Heppelmann, S. ; Herston, T. ; Hippolyte, Boris ; Hirsch, A. ; Hjort, E. ; Hoffmann, Gerald W. ; Horsley, M. ; Huang, H.Z. ; Humanic, Thomas J. ; Igo, G. ; Ishihara, A. ; Ivanshin, Yu.I. ; Jacobs, P. ; Jacobs, W.W. ; Janik, M. ; Johnson, I. ; Jones, Peter Graham ; Judd, Eleanor G. ; Kaneta, M. ; Kaplan, M. ; Keane, Declan ; Kiryluk, J. ; Kisiel, A. ; Klay, J. ; Klein, S.R. ; Klyachko, A. ; Konstantinov, A.S. ; Kopytine, M. ; Kotchenda, L. ; Kovalenko, A.D. ; Kramer, M. ; Kravtsov, P. ; Krueger, Keith William ; Kuhn, C. ; Kulikov, A.I. ; Kunde, G.J. ; Kunz, C.L. ; Kutuev, R.Kh. ; Kuznetsov, A.A. ; Lakehal-Ayat, L. ; Lamont, Matthew A. C. ; Landgraf, J.M. ; Lange, S. ; Lansdell, C.P. ; Lasiuk, B. ; Laue, F. ; Lebedev, A. ; Lednický, R. ; Leontiev, V.M. ; LeVine, M.J. ; Li, Q. ; Lindenbaum, S.J. ; Lisa, Michael A. ; Liu, F. ; Liu, L. ; Liu, Z. ; Liu, Q.J. ; Ljubicic, T. ; Llope, W.J. ; LoCurto, G. ; Long, H. ; Longacre, R.S. ; Lopez-Noriega, M. ; Love, W.A. ; Ludlam, T. ; Lynn, D. ; Ma, J. ; Majka, R. ; Margetis, Spyridon ; Markert, Christina ; Martin, L. ; Marx, J. ; Matis, Howard S. ; Matulenko, Yu.A. ; McShane, T.S. ; Meissner, F. ; Melnick, Yu. ; Meschanin, A. ; Messer, M. ; Miller, M.L. ; Milosevich, Z. ; Minaev, N.G. ; Mitchell, J. ; Moiseenko, V.A. ; Moore, C.F. ; Morozov, V. ; de Moura, M.M. ; Munhoz, M.G. ; Nelson, J.M. ; Nevski, P. ; Nikitin, V.A. ; Nogach, L.V. ; Norman, B. ; Nurushev, S.B. ; Odyniec, G. ; Ogawa, A. ; Okorokov, Vitaly A. ; Oldenburg, M. ; Olson, D. ; Paic, Guy ; Pandey, S.U. ; Panebratsev, Y. ; Panitkin, S.Y. ; Pavlinov, A.I. ; Pawlak, T. ; Perevoztchikov, V. ; Peryt, W. ; Petrov, V.A. ; Planinic, M. ; Pluta, J. ; Porile, N. ; Porter, J. ; Poskanzer, A.M. ; Potrebenikova, E. ; Prindle, D. ; Pruneau, C. ; Putschke, Jörn H. ; Rai, G. ; Rakness, G. ; Ravel, O. ; Ray, R.L. ; Razin, S.V. ; Reichhold, D. ; Reid, Jeffrey G. ; Retiere, F. ; Ridiger, A. ; Ritter, H.G. ; Roberts, J.B. ; Rogachevski, O.V. ; Romero, J.L. ; Rose, A. ; Roy, C. ; Rykov, V. ; Sakrejda, I. ; Salur, Sevil ; Sandweiss, J. ; Saulys, A.C. ; Savin, I. ; Schambach, Joachim ; Scharenberg, R.P. ; Schmitz, N. ; Schroeder, L.S. ; Schüttauf, A. ; Schweda, Kai ; Seger, J. ; Seliverstov, D. ; Seyboth, P. ; Shahaliev, E. ; Shestermanov, K.E. ; Shimanskii, S.S. ; Shvetcov, V.S. ; Skoro, G. ; Smirnov, Nikolai ; Snellings, Raimond ; Sorensen, P. ; Sowinski, J. ; Spinka, Harold. M. ; Srivastava, B. ; Stephenson, E.J. ; Stock, Reinhard ; Stolpovsky, A. ; Strikhanov, M. ; Stringfellow, B. ; Struck, C. ; Suaide, Alexandre Alarcon do Passo ; Sugarbaker, E. ; Suire, Christophe Pierre ; Šumbera, Michal ; Surrow, Bernd ; Symons, T.J.M. ; Szanto de Toledo, A. ; Szarwas, P. ; Tai, A. ; Takahashi, Jun ; Tang, A.H. ; Thomas, James H. ; Thompson, M. ; Tikhomirov, V. ; Tokarev, M. ; Tonjes, M.B. ; Trainor, T.A. ; Trentalange, Stephen ; Tribble, Robert E. ; Trofimov, V. ; Tsai, Oleg D. ; Ullrich, Thomas ; Underwood, D.G. ; Van Buren, G. ; VanderMolen, A.M. ; Vasilevski, I.M. ; Vasiliev, A.N. ; Vigdor, S.E. ; Voloshin, S.A. ; Wang, Fuqiang ; Ward, H. ; Watson, J.W. ; Wells, R. ; Westfall, Gary D. ; Whitten, C. ; Wieman, H. ; Willson, R. ; Wissink, S.W. ; Witt, Richard ; Wood, J. ; Xu, N. ; Xu, Z. ; Yakutin, A.E. ; Yamamoto, E. ; Yang, J. ; Yepes, P. ; Yurevich, V.I. ; Zanevski, Y.V. ; Zborovský, I. ; Zhang, H. ; Zhang, W.M. ; Zoulkarneev, R. ; Zubarev, A.N.
Mid-rapidity transverse mass spectra and multiplicity densities of charged and neutral kaons are reported for Au + Au collisions at √sNN = 130 GeV at RHIC. The spectra are exponential in transverse mass, with an inverse slope of about 280 MeV in central collisions. The multiplicity densities for these particles scale with the negative hadron pseudo-rapidity density. The charged kaon to pion ratios are K+/π− = 0.161± 0.002(stat) ± 0.024(syst) and K−/π− = 0.146± 0.002(stat) ± 0.022(syst) for the most central collisions. The K+/π− ratio is lower than the same ratio observed at the SPS while the K−/π− is higher than the SPS result. The ratios are enhanced by about 50% relative to p + p and p¯ + p collision data at similar energies.