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1. PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis

Author

Yamaguchi, Junna, Isnard, Pierre, Robil, Noemie, de la Grange, Pierre, Hoguin, Clement, Schmitt, Alain, Hummel, Aurelie, Megret, Jerome, Goudin, Nicolas, Luka, Marine, Menager, Mickael M., Masson, Cecile, Zarhrate, Mohammed, Bole-Feysot, Christine, Janiszewska, Michalina, Polyak, Kornelia, Dairou, Julien, Baldassari, Sara, Baulac, Stephanie, Broissand, Christine, Legendre, Christophe, Terzi, Fabiola, and Canaud, Guillaume

Subjects
Glomerulonephritis -- Care and treatment -- Risk factors -- Development and progression, Health care industry
Abstract

Proliferative glomerulonephritis is a severe condition that often leads to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of- function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing, and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation, and inflammation. Additionally, we show that alpelisib, a PI3K[alpha] inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3K[alpha] affects B and T lymphocyte populations in lupus nephritis mouse models, with a decrease in the production of proinflammatory cytokines, autoantibodies, and glomerular complement deposition, which are all characteristic features of PI3KO inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3K[alpha] inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3K[alpha] in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system., Introduction PI3K[alpha] is a lipid kinase that is widely expressed in various tissues and plays a crucial role in controlling signaling pathways involved in cell proliferation, motility, survival, and metabolism [...]

Published
2024
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4. Treatment Responsiveness in KCNT1-Related Epilepsy

Author

Fitzgerald, Mark P., Fiannacca, Martina, Smith, Douglas M., Gertler, Tracy S., Gunning, Boudewijn, Syrbe, Steffen, Verbeek, Nienke, Stamberger, Hannah, Weckhuysen, Sarah, Ceulemans, Berten, Schoonjans, An-Sofie, Rossi, Massimiliano, Demarquay, Geneviève, Lesca, Gaetan, Olofsson, Kern, Koolen, D. A., Hornemann, Frauke, Baulac, Stephanie, Rubboli, Guido, Minks, Kelly Q., Lee, Bohoon, Helbig, Ingo, Dlugos, Dennis, Møller, Rikke S., and Bearden, David

Published
2019
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5. LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

Author

Seagar, Michael, Russier, Michael, Caillard, Olivier, Maulet, Yves, Fronzaroli-Molinieres, Laure, De San Feliciano, Marina, Boumedine-Guignon, Norah, Rodriguez, Léa, Zbili, Mickael, Usseglio, Fabrice, Formisano-Tréziny, Christine, Youssouf, Fahamoe, Sangiardi, Marion, Boillot, Morgane, Baulac, Stéphanie, Benitez, María José, Garrido, Juan-José, Debanne, Dominique, and El Far, Oussama

Published
2017

6. Second-hit mosaic mutation in mTORCI repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy

Author

Ribierre, Theo, Deleuze, Charlotte, Bacq, Alexandre, Baldassari, Sara, Marsan, Elise, Chipaux, Mathilde, Muraca, Giuseppe, Roussel, Delphine, Navarro, Vincent, Leguern, Eric, Miles, Richard, and Baulac, Stephanie

Subjects
Epilepsy -- Genetic aspects -- Risk factors -- Care and treatment -- Research, Gene mutation -- Research, Drug resistance -- Research, Focal dermal hypoplasia -- Genetic aspects -- Complications and side effects -- Research, Health care industry
Abstract

DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia. Here, using postoperative human tissue, we provide the proof of concept that a biallelic 2-hit--brain somatic and germline--mutational mechanism in DEPDC5 causes focal epilepsy with FCD. We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone. Furthermore, we demonstrate the causality of a Depdc5 brain mosaic inactivation using CRISPR-Cas9 editing and in utero electroporation in a mouse model recapitulating focal epilepsy with FCD and SUDEP-like events. We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons. This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1- targeting molecules., Introduction The human brain is genetically mosaic. Accumulation of somatic variants in postmitotic cells from healthy human cerebral tissues has recently been described, emphasizing that somatic mutational events are frequent [...]

Published
2018
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7. Alterations in the α2δ ligand, thrombospondin‐1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies

Author

Santolini, Ines, Celli, Roberta, Cannella, Milena, Imbriglio, Tiziana, Guiducci, Michela, Parisi, Pasquale, Schubert, Julian, Iacomino, Michele, Zara, Federico, Lerche, Holger, Moyanova, Slavianka, Ngomba, Richard Teke, van Luijtelaar, Gilles, Battaglia, Giuseppe, Bruno, Valeria, Striano, Pasquale, Nicoletti, Ferdinando, Palotie, Aarno, Folkhälsan, Anna‐Elina Lehesjoki, Ruppert, Ann‐Kathrin, Siren, Auli, Koeleman, Bobby, Lal, Dennis, Becker, Felicitas, Caglayan, Hande, Hjalgrim, Helle, Muhle, Hiltrud, Thiele, Holger, Helbig, Ingo, Altmuller, Janine, Jabbari, Kamel, Everett, Kate, May, Patrick, Nurnberg, Peter, Møller, Rikke, Nabbout, Rima, Krause, Roland, Balling, Rudi, Baulac, Stephanie, Sander, Thomas, Kunz, Wolfram, Weber, Yvonne, Bianchi, Amedeo, La Neve, Angela, Coppola, Antonietta, Striano, Salvatore, Capovilla, Giuseppe, Ferlazzo, Edoardo, Bagnasco, Irene, Ferretti, Alessandro, Di Bonaventura, Carlo, Vari, Maria Stella, Pinto, Francesca, Bisulli, Francesca, Tinuper, Paolo, Minetti, Carlo, Belcastro, Vincenzo, Giordano, Lucio, and Gambardella, Antonio

Published
2017
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8. Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.

Author

Ververi, Athina, Zagaglia, Sara, Menzies, Lara, Baptista, Julia, Caswell, Richard, Baulac, Stephanie, Ellard, Sian, Lynch, Sally, Consortium, Genomics England Research, Jacques, Thomas S, Chawla, Maninder Singh, Heier, Martin, Kulseth, Mari Ann, Mero, Inger-Lise, Våtevik, Anne Katrine, Kraoua, Ichraf, Rhouma, Hanene Ben, Younes, Thouraya Ben, Miladi, Zouhour, and Turki, Ilhem Ben Youssef

Published
2023
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9. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum

Author

Bonardi, Claudia M, primary, Heyne, Henrike O, additional, Fiannacca, Martina, additional, Fitzgerald, Mark P, additional, Gardella, Elena, additional, Gunning, Boudewijn, additional, Olofsson, Kern, additional, Lesca, Gaétan, additional, Verbeek, Nienke, additional, Stamberger, Hannah, additional, Striano, Pasquale, additional, Zara, Federico, additional, Mancardi, Maria M, additional, Nava, Caroline, additional, Syrbe, Steffen, additional, Buono, Salvatore, additional, Baulac, Stephanie, additional, Coppola, Antonietta, additional, Weckhuysen, Sarah, additional, Schoonjans, An-Sofie, additional, Ceulemans, Berten, additional, Sarret, Catherine, additional, Baumgartner, Tobias, additional, Muhle, Hiltrud, additional, Portes, Vincent des, additional, Toulouse, Joseph, additional, Nougues, Marie-Christine, additional, Rossi, Massimiliano, additional, Demarquay, Geneviève, additional, Ville, Dorothée, additional, Hirsch, Edouard, additional, Maurey, Hélène, additional, Willems, Marjolaine, additional, de Bellescize, Julitta, additional, Altuzarra, Cecilia Desmettre, additional, Villeneuve, Nathalie, additional, Bartolomei, Fabrice, additional, Picard, Fabienne, additional, Hornemann, Frauke, additional, Koolen, David A, additional, Kroes, Hester Y, additional, Reale, Chiara, additional, Fenger, Christina D, additional, Tan, Wen-Hann, additional, Dibbens, Leanne, additional, Bearden, David R, additional, Møller, Rikke S, additional, and Rubboli, Guido, additional

Published
2021
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10. Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Author

Blümcke, Ingmar, primary, Coras, Roland, additional, Busch, Robyn M., additional, Morita‐Sherman, Marcia, additional, Lal, Dennis, additional, Prayson, Richard, additional, Cendes, Fernando, additional, Lopes‐Cendes, Iscia, additional, Rogerio, Fabio, additional, Almeida, Vanessa S., additional, Rocha, Cristiane S., additional, Sim, Nam Suk, additional, Lee, Jeong Ho, additional, Kim, Se Hoon, additional, Baulac, Stephanie, additional, Baldassari, Sara, additional, Adle‐Biassette, Homa, additional, Walsh, Christopher A., additional, Bizzotto, Sara, additional, Doan, Ryan N., additional, Morillo, Katherine S., additional, Aronica, Eleonora, additional, Mühlebner, Angelika, additional, Becker, Albert, additional, Cienfuegos, Jesus, additional, Garbelli, Rita, additional, Giannini, Caterina, additional, Honavar, Mrinalini, additional, Jacques, Thomas S., additional, Thom, Maria, additional, Mahadevan, Anita, additional, Miyata, Hajime, additional, Niehusmann, Pitt, additional, Sarnat, Harvey B., additional, Söylemezoglu, Figen, additional, and Najm, Imad, additional

Published
2021
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11. KCNT1-related epilepsies and epileptic encephalopathies:phenotypic and mutational spectrum

Author

Bonardi, Claudia M., Heyne, Henrike O., Fiannacca, Martina, Fitzgerald, Mark P., Gardella, Elena, Gunning, Boudewijn, Olofsson, Kern, Lesca, Gaétan, Verbeek, Nienke, Stamberger, Hannah, Striano, Pasquale, Zara, Federico, Mancardi, Maria M., Nava, Caroline, Syrbe, Steffen, Buono, Salvatore, Baulac, Stephanie, Coppola, Antonietta, Weckhuysen, Sarah, Schoonjans, An Sofie, Ceulemans, Berten, Sarret, Catherine, Baumgartner, Tobias, Muhle, Hiltrud, Portes, Vincent des, Toulouse, Joseph, Nougues, Marie Christine, Rossi, Massimiliano, Demarquay, Geneviève, Ville, Doroth Crossed D.sign©e, Hirsch, Edouard, Maurey, HCrossed D.sign©lène, Willems, Marjolaine, De Bellescize, Julitta, Altuzarra, Cecilia Desmettre, Villeneuve, Nathalie, Bartolomei, Fabrice, Picard, Fabienne, Hornemann, Frauke, Koolen, David A., Kroes, Hester Y., Reale, Chiara, Fenger, Christina D., Tan, Wen Hann, Dibbens, Leanne, Bearden, David R., Møller, Rikke S., Rubboli, Guido, Bonardi, Claudia M., Heyne, Henrike O., Fiannacca, Martina, Fitzgerald, Mark P., Gardella, Elena, Gunning, Boudewijn, Olofsson, Kern, Lesca, Gaétan, Verbeek, Nienke, Stamberger, Hannah, Striano, Pasquale, Zara, Federico, Mancardi, Maria M., Nava, Caroline, Syrbe, Steffen, Buono, Salvatore, Baulac, Stephanie, Coppola, Antonietta, Weckhuysen, Sarah, Schoonjans, An Sofie, Ceulemans, Berten, Sarret, Catherine, Baumgartner, Tobias, Muhle, Hiltrud, Portes, Vincent des, Toulouse, Joseph, Nougues, Marie Christine, Rossi, Massimiliano, Demarquay, Geneviève, Ville, Doroth Crossed D.sign©e, Hirsch, Edouard, Maurey, HCrossed D.sign©lène, Willems, Marjolaine, De Bellescize, Julitta, Altuzarra, Cecilia Desmettre, Villeneuve, Nathalie, Bartolomei, Fabrice, Picard, Fabienne, Hornemann, Frauke, Koolen, David A., Kroes, Hester Y., Reale, Chiara, Fenger, Christina D., Tan, Wen Hann, Dibbens, Leanne, Bearden, David R., Møller, Rikke S., and Rubboli, Guido

Abstract

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy

Published
2021

12. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum

Author

Genetica Klinische Genetica, Child Health, Bonardi, Claudia M, Heyne, Henrike O, Fiannacca, Martina, Fitzgerald, Mark P, Gardella, Elena, Gunning, Boudewijn, Olofsson, Kern, Lesca, Gaétan, Verbeek, Nienke, Stamberger, Hannah, Striano, Pasquale, Zara, Federico, Mancardi, Maria M, Nava, Caroline, Syrbe, Steffen, Buono, Salvatore, Baulac, Stephanie, Coppola, Antonietta, Weckhuysen, Sarah, Schoonjans, An-Sofie, Ceulemans, Berten, Sarret, Catherine, Baumgartner, Tobias, Muhle, Hiltrud, Portes, Vincent des, Toulouse, Joseph, Nougues, Marie-Christine, Rossi, Massimiliano, Demarquay, Geneviève, Ville, Dorothée, Hirsch, Edouard, Maurey, Hélène, Willems, Marjolaine, de Bellescize, Julitta, Altuzarra, Cecilia Desmettre, Villeneuve, Nathalie, Bartolomei, Fabrice, Picard, Fabienne, Hornemann, Frauke, Koolen, David A, Kroes, Hester Y, Reale, Chiara, Fenger, Christina D, Tan, Wen-Hann, Dibbens, Leanne, Bearden, David R, Møller, Rikke S, Rubboli, Guido, Genetica Klinische Genetica, Child Health, Bonardi, Claudia M, Heyne, Henrike O, Fiannacca, Martina, Fitzgerald, Mark P, Gardella, Elena, Gunning, Boudewijn, Olofsson, Kern, Lesca, Gaétan, Verbeek, Nienke, Stamberger, Hannah, Striano, Pasquale, Zara, Federico, Mancardi, Maria M, Nava, Caroline, Syrbe, Steffen, Buono, Salvatore, Baulac, Stephanie, Coppola, Antonietta, Weckhuysen, Sarah, Schoonjans, An-Sofie, Ceulemans, Berten, Sarret, Catherine, Baumgartner, Tobias, Muhle, Hiltrud, Portes, Vincent des, Toulouse, Joseph, Nougues, Marie-Christine, Rossi, Massimiliano, Demarquay, Geneviève, Ville, Dorothée, Hirsch, Edouard, Maurey, Hélène, Willems, Marjolaine, de Bellescize, Julitta, Altuzarra, Cecilia Desmettre, Villeneuve, Nathalie, Bartolomei, Fabrice, Picard, Fabienne, Hornemann, Frauke, Koolen, David A, Kroes, Hester Y, Reale, Chiara, Fenger, Christina D, Tan, Wen-Hann, Dibbens, Leanne, Bearden, David R, Møller, Rikke S, and Rubboli, Guido

Published
2021

13. Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Author

Pathologie, Pathologie Pathologen staf, Cancer, Blümcke, Ingmar, Coras, Roland, Busch, Robyn M, Morita-Sherman, Marcia, Lal, Dennis, Prayson, Richard, Cendes, Fernando, Lopes-Cendes, Iscia, Rogerio, Fabio, Almeida, Vanessa S, Rocha, Cristiane S, Sim, Nam Suk, Lee, Jeong Ho, Kim, Se Hoon, Baulac, Stephanie, Baldassari, Sara, Adle-Biassette, Homa, Walsh, Christopher A, Bizzotto, Sara, Doan, Ryan N, Morillo, Katherine S, Aronica, Eleonora, Mühlebner, Angelika, Becker, Albert, Cienfuegos, Jesus, Garbelli, Rita, Giannini, Caterina, Honavar, Mrinalini, Jacques, Thomas S, Thom, Maria, Mahadevan, Anita, Miyata, Hajime, Niehusmann, Pitt, Sarnat, Harvey B, Söylemezoglu, Figen, Najm, Imad, Pathologie, Pathologie Pathologen staf, Cancer, Blümcke, Ingmar, Coras, Roland, Busch, Robyn M, Morita-Sherman, Marcia, Lal, Dennis, Prayson, Richard, Cendes, Fernando, Lopes-Cendes, Iscia, Rogerio, Fabio, Almeida, Vanessa S, Rocha, Cristiane S, Sim, Nam Suk, Lee, Jeong Ho, Kim, Se Hoon, Baulac, Stephanie, Baldassari, Sara, Adle-Biassette, Homa, Walsh, Christopher A, Bizzotto, Sara, Doan, Ryan N, Morillo, Katherine S, Aronica, Eleonora, Mühlebner, Angelika, Becker, Albert, Cienfuegos, Jesus, Garbelli, Rita, Giannini, Caterina, Honavar, Mrinalini, Jacques, Thomas S, Thom, Maria, Mahadevan, Anita, Miyata, Hajime, Niehusmann, Pitt, Sarnat, Harvey B, Söylemezoglu, Figen, and Najm, Imad

Published
2021

14. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Author

Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Federico, Striano, Pasquale, Robbiano, Angela, Capovilla, Giuseppe, Tinuper, Paolo, Gambardella, Antonio, Bianchi, Amedeo, La Neve, Angela, Crichiutti, Giovanni, de Kovel, Carolien G.F., Kasteleijn-Nolst Trenité, Dorothée, de Haan, Gerrit-Jan, Lindhout, Dick, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Steinhoff, Bernhard J., Kleefu-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Elger, Christian E., Muhle, Hiltrud, von Spiczak, Sarah, Ostertag, Philipp, Helbig, Ingo, Stephani, Ulrich, Møller, Rikke S., Hjalgrim, Helle, Dibbens, Leanne M., Bellows, Susannah, Oliver, Karen, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo, Lehesjoki, Anna-Elina, Siren, Auli, Guipponi, Michel, Malafosse, Alain, Thomas, Pierre, Nabbout, Rima, Baulac, Stephanie, Leguern, Eric, Guerrero, Rosa, Serratosa, Jose M., Reif, Philipp S., Rosenow, Felix, Mörzinger, Martina, Feucht, Martha, Zimprich, Fritz, Kapser, Claudia, Schankin, Christoph J., Suls, Arvid, Smets, Katrin, De Jonghe, Peter, Jordanova, Albena, Caglayan, Hande, Yapici, Zuhal, Yalcin, Destina A., Baykan, Betul, Bebek, Nerses, Ozbek, Ugur, Gieger, Christian, Wichmann, Heinz-Erich, Balschun, Tobias, Ellinghaus, David, Franke, Andre, Meesters, Christian, Becker, Tim, Wienker, Thomas F., Hempelmann, Anne, Schulz, Herbert, Rüschendorf, Franz, Leber, Markus, Pauck, Steffen M., Trucks, Holger, Toliat, Mohammad R., Nürnberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P.C., and Sander, Thomas

Published
2012
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15. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Author

Leu, Costin, de Kovel, Carolien G.F., Zara, Federico, Striano, Pasquale, Pezzella, Marianna, Robbiano, Angela, Bianchi, Amedeo, Bisulli, Francesca, Coppola, Antonietta, Giallonardo, Anna Teresa, Beccaria, Francesca, Trenité, Dorothée Kasteleijn-Nolst, Lindhout, Dick, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Kleefu-Lie, Ailing A., Hallman, Kerstin, Kunz, Wolfram S., Elger, Christian E., Muhle, Hiltrud, Stephani, Ulrich, Mller, Rikke S., Hjalgrim, Helle, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo, Lehesjoki, Anna-Elina, Siren, Auli, Nabbout, Rima, Baulac, Stephanie, Leguern, Eric, Serratosa, Jose M., Rosenow, Felix, Feucht, Martha, Unterberger, Iris, Covanis, Athanasios, Suls, Arvid, Weckhuysen, Sarah, Kaneva, Radka, Caglayan, Hande, Turkdogan, Dilsad, Baykan, Betul, Bebek, Nerses, Ozbek, Ugur, Hempelmann, Anne, Schulz, Herbert, Rüschendorf, Franz, Trucks, Holger, Nürnberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P.C., and Sander, Thomas

Published
2012
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17. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome

Author

Depienne, Christel, Trouillard, Oriane, Gourfinkel-An, Isabelle, Saint-Martin, Cecile, Bouteiller, Delphine, Graber, Denis, Barthez-Carpentier, Marie-Anne, Gautier, Agnes, Villeneuve, Nathalie, Dravet, Charlotte, Livet, Marie-Odile, Rivier-Ringenbach, Clothilde, Adam, Claude, Dupont, Sophie, Baulac, Stephanie, Heron, Delphine, Nabbout, Rima, and LeGuern, Eric

Subjects
Epilepsy -- Research, Epilepsy -- Genetic aspects, Gene mutations -- Research, Gene mutations -- Physiological aspects, Mosaicism -- Research, Health
Published
2010

18. Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Author

Siekierska, Aleksandra, Stamberger, Hannah, Deconinck, Tine, Oprescu, Stephanie N., Partoens, Michèle, Zhang, Yifan, Sourbron, Jo, Adriaenssens, Elias, Mullen, Patrick, Wiencek, Patrick, Hardies, Katia, Lee, Jeong-Soo, Giong, Hoi-Khoanh, Distelmaier, Felix, Elpeleg, Orly, Helbig, Katherine L., Hersh, Joseph, Isikay, Sedat, Jordan, Elizabeth, Karaca, Ender, Kecskes, Angela, Lupski, James R., Kovacs-Nagy, Reka, May, Patrick, Narayanan, Vinodh, Pendziwiat, Manuela, Ramsey, Keri, Rangasamy, Sampathkumar, Shinde, Deepali N., Spiegel, Ronen, Timmerman, Vincent, von Spiczak, Sarah, Helbig, Ingo, Weckhuysen, Sarah, Francklyn, Christopher, Antonellis, Anthony, de Witte, Peter, Partoens, Michele, Balak, Chris, Belnap, Newell, Claasen, Ana, Courtright, Amanda, de Both, Matt, Huentelman, Matthew J., Naymik, Marcus, Richholt, Ryan, Siniard, Ashley L., Szelinger, Szabolcs, Craig, David W., Schrauwen, Isabelle, Afawi, Zaid, Balling, Rudi, Baulac, Stephanie, Barisic, Nina, Caglayan, Hande S., Craiu, Dana, Guerrero-Lopez, Rosa, Guerrini, Renzo, Hjalgrim, Helle, Jahn, Johanna, Klein, Karl Martin, Leguern, Eric, Lemke, Johannes R., Lerche, Holger, Marini, Carla, Moller, Rikke S., Muhle, Hiltrud, Rosenow, Felix, Serratosa, Jose, Suls, Arvid, Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Zara, Federico, De Jonghe, Peter, C4RCD Research Group, AR working group of the EuroEPINOMICS RES Consortium, and HKÜ, Sağlık Bilimleri Yüksekokulu, Fizyoterapi ve Rehabilitasyon Bölümü

Subjects
0301 basic medicine, Male, Models, Molecular, Microcephaly, TRANSFER-RNA-SYNTHETASE, ILAE COMMISSION, MUTATIONS CAUSE, ONSET, GENES, HYPOMYELINATION, BIOGENESIS, PHENOTYPE, TRNA(VAL), MECHANISM, General Physics and Astronomy, 02 engineering and technology, chemistry.chemical_compound, Gene Knockout Techniques, Loss of Function Mutation, lcsh:Science, Zebrafish, Genetics, Brain Diseases, Multidisciplinary, biology, 021001 nanoscience & nanotechnology, Phenotype, 3. Good health, Pedigree, ddc, Complementation, Female, 0210 nano-technology, Engineering sciences. Technology, Valine-tRNA Ligase, In silico, Science, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, Prosencephalon, medicine, Animals, Humans, Genetic Predisposition to Disease, Allele, Gene, Biology, Alleles, AR working group of the EuroEPINOMICS RES Consortium, Epilepsy, Aminoacyl tRNA synthetase, fungi, General Chemistry, Fibroblasts, biology.organism_classification, medicine.disease, Disease Models, Animal, 030104 developmental biology, chemistry, C4RCD Research Group, Neurodevelopmental Disorders, lcsh:Q, Human medicine
Abstract

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies., tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.

Published
2018

19. Treatment Responsiveness in KCNT1-Related Epilepsy

Author

Genetica, Genetica Klinische Genetica, Fitzgerald, Mark P., Fiannacca, Martina, Smith, Douglas M., Gertler, Tracy S., Gunning, Boudewijn, Syrbe, Steffen, Verbeek, Nienke, Stamberger, Hannah, Weckhuysen, Sarah, Ceulemans, Berten, Schoonjans, An Sofie, Rossi, Massimiliano, Demarquay, Geneviève, Lesca, Gaetan, Olofsson, Kern, Koolen, D. A., Hornemann, Frauke, Baulac, Stephanie, Rubboli, Guido, Minks, Kelly Q., Lee, Bohoon, Helbig, Ingo, Dlugos, Dennis, Møller, Rikke S., Bearden, David, Genetica, Genetica Klinische Genetica, Fitzgerald, Mark P., Fiannacca, Martina, Smith, Douglas M., Gertler, Tracy S., Gunning, Boudewijn, Syrbe, Steffen, Verbeek, Nienke, Stamberger, Hannah, Weckhuysen, Sarah, Ceulemans, Berten, Schoonjans, An Sofie, Rossi, Massimiliano, Demarquay, Geneviève, Lesca, Gaetan, Olofsson, Kern, Koolen, D. A., Hornemann, Frauke, Baulac, Stephanie, Rubboli, Guido, Minks, Kelly Q., Lee, Bohoon, Helbig, Ingo, Dlugos, Dennis, Møller, Rikke S., and Bearden, David

Published
2019

20. Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies: an exome-based case-control study

Author

May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R., Schubert, Julian, Wolking, Stefan, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E., Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-Lopez, Rosa, Baulac, Stephanie, Marini, Carla, Thiele, Holger, Altmueller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Dennis, Rusconi, Raffaella, Cestele, Sandrine, Terragni, Benedetta, Coombs, Ian D., Reid, Christopher A., Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Moller, Rikke S., Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S., Weber, Yvonne G., Weckhuysen, Sarah, De Jonghe, Peter, Sisodiya, Sanjay M., Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S., Trenite, Dorothee Kasteleijn-Nolst, Baykan, Betul, Ozbek, Ugur, Bebek, Nerses, Klein, Karl M., Rosenow, Felix, Nguyen, Dang K., Dubeau, Francois, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clement, Jean-Francois, Cieuta-Walti, Cecile, Sills, Graeme J., Auce, Pauls, Francis, Ben, Johnson, Michael R., Marson, Anthony G., Berghuis, Bianca, Sander, Josemir W., Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M. Arfan, Uitterlinden, Andre G., Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thomas, LeGuern, Eric, Serratosa, Jose M., Koeleman, Bobby P. C., Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nuernberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R., Schubert, Julian, Wolking, Stefan, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E., Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-Lopez, Rosa, Baulac, Stephanie, Marini, Carla, Thiele, Holger, Altmueller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Dennis, Rusconi, Raffaella, Cestele, Sandrine, Terragni, Benedetta, Coombs, Ian D., Reid, Christopher A., Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Moller, Rikke S., Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S., Weber, Yvonne G., Weckhuysen, Sarah, De Jonghe, Peter, Sisodiya, Sanjay M., Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S., Trenite, Dorothee Kasteleijn-Nolst, Baykan, Betul, Ozbek, Ugur, Bebek, Nerses, Klein, Karl M., Rosenow, Felix, Nguyen, Dang K., Dubeau, Francois, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clement, Jean-Francois, Cieuta-Walti, Cecile, Sills, Graeme J., Auce, Pauls, Francis, Ben, Johnson, Michael R., Marson, Anthony G., Berghuis, Bianca, Sander, Josemir W., Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M. Arfan, Uitterlinden, Andre G., Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thomas, LeGuern, Eric, Serratosa, Jose M., Koeleman, Bobby P. C., Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nuernberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, and Lerche, Holger

Abstract

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA(A) receptors and was compared to the respective GABA(A) receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA(A) receptors in cases (odds ratio [OR] 2.40 [95% CI 1.41-4.10]; p(Nonsyn)=0.0014, adjusted p(Nonsyn)=0.019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1.46 [95% CI 1.05-2.03]; p(Nonsyn)=0.0081, adjusted p(Nonsyn)=0.016). Comparison of genes encoding GABA(A) receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABA(A) receptor genes in cases compare

Published
2018

21. Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

Author

Allen, Andrew S, Berkovic, Samuel F, Bridgers, Joshua, Cossette, Patrick, Dlugos, Dennis, Epstein, Michael P, Glauser, Tracy, Goldstein, David B, Heinzen, Erin L, Jiang, Yu, Johnson, Michael R, Kuzniecky, Ruben, Lowenstein, Daniel H, Marson, Anthony G, Mefford, Heather C, O'Brien, Terence J, Ottman, Ruth, Petrou, Steven, Petrovski, Slave, Poduri, Annapurna, Ren, Zhong, Scheffer, Ingrid E, Sherr, Elliott, Wang, Quanli, Balling, Rudi, Barisic, Nina, Baulac, Stephanie, Caglayan, Hande, Craiu, Dana, De Jonghe, Peter, Depienne, Christel, Guerrini, Renzo, Helbig, Ingo, Hjalgrim, Helle, Hoffman-Zacharska, Dorota, Jaehn, Johanna, Klein, Karl Martin, Koeleman, Bobby, Komarek, Vladimir, Krause, Roland, Leguern, Eric, Lehesjoki, Anna-Elina, Lemke, Johannes R, Lerche, Holger, Linnankivi, Tarja, Marini, Carla, May, Patrick, Moller, Rikke S, Muhle, Hiltrud, Pal, Deb, Palotie, Aarno, Rosenow, Felix, Selmer, Kaja, Serratosa, Jose M, Sisodiya, Sanjay, Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Suls, Arvid, Talvik, Tiina, von Spiczak, Sarah, Weber, Yvonne, Weckhuysen, Sarah, Zara, Federico, Abou-Khalil, Bassel, Alldredge, Brian K, Amrom, Dina, Andermann, Eva, Andermann, Frederick, Bautista, Jocelyn F, Bluvstein, Judith, Cascino, Gregory D, Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Fiol, Miguel E, Fountain, Nathan B, French, Jacqueline, Friedman, Daniel, Haas, Kevin, Haut, Sheryl R, Hayward, Jean, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E, Kossoff, Eric H, Kuperman, Rachel, McGuire, Shannon M, Motika, Paul V, Novotny, Edward J, Paolicchi, Juliann M, Parent, Jack, Park, Kristen, Shellhaas, Renee A, Sirven, Joseph, Smith, Michael C, Sullivan, Joseph, Thio, Liu Lin, Venkat, Anu, Vining, Eileen PG, Von Allmen, Gretchen K, Weisenberg, Judith L, Widdess-Walsh, Peter, Winawer, Melodie R, Consortium, Epi4K, Consortium, EuroEPINOMICS-RES, Project, Epilepsy Phenome Genome, Epi4K Consortium, EuroEPINOMICS- RES Consortium, and Epilepsy Phenome Genome Project

Subjects
0301 basic medicine, Linkage disequilibrium, medicine.medical_specialty, genetic structures, Population, Disequilibrium, Short Report, Genome-wide association study, Biology, Bioinformatics, Linkage Disequilibrium, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Epilepsy Phenome/Genome Project, medicine, Genetics, Journal Article, Humans, Genetics(clinical), Genetic Predisposition to Disease, education, Genetics (clinical), education.field_of_study, Polymorphism, Genetic, Lennox Gastaut Syndrome, Infant, Transmission disequilibrium test, medicine.disease, Multicenter Study, Chemistry, 030104 developmental biology, Medical genetics, Human medicine, medicine.symptom, Spasms, Infantile, 030217 neurology & neurosurgery, Lennox–Gastaut syndrome, Genome-Wide Association Study
Abstract

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox-Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient-parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population.

Published
2017

23. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Author

Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Federico, Striano, Pasquale, Robbiano, Angela, Capovilla, Giuseppe, Tinuper, Paolo, Gambardella, Antonio, Bianchi, Amedeo, La Neve, Angela, Crichiutti, Giovanni, de Kovel, Carolien G.F., Kasteleijn-Nolst Trenité, Dorothée, de Haan, Gerrit-Jan, Lindhout, Dick, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Steinhoff, Bernhard J., Kleefuß-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Elger, Christian E., Muhle, Hiltrud, von Spiczak, Sarah, Ostertag, Philipp, Helbig, Ingo, Stephani, Ulrich, Møller, Rikke S., Hjalgrim, Helle, Dibbens, Leanne M., Bellows, Susannah, Oliver, Karen, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo, Lehesjoki, Anna-Elina, Siren, Auli, Guipponi, Michel, Malafosse, Alain, Thomas, Pierre, Nabbout, Rima, Baulac, Stephanie, Leguern, Eric, Guerrero, Rosa, Serratosa, Jose M., Reif, Philipp S., Rosenow, Felix, Mörzinger, Martina, Feucht, Martha, Zimprich, Fritz, Kapser, Claudia, Schankin, Christoph J., Suls, Arvid, Smets, Katrin, De Jonghe, Peter, Jordanova, Albena, Caglayan, Hande, Yapici, Zuhal, Yalcin, Destina A., Baykan, Betul, Bebek, Nerses, Ozbek, Ugur, Gieger, Christian, Wichmann, Heinz-Erich, Balschun, Tobias, Ellinghaus, David, Franke, Andre, Meesters, Christian, Becker, Tim, Wienker, Thomas F., Hempelmann, Anne, Schulz, Herbert, Rüschendorf, Franz, Leber, Markus, Pauck, Steffen M., Trucks, Holger, Toliat, Mohammad R., Nürnberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P.C., Sander, Thomas, Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Federico, Striano, Pasquale, Robbiano, Angela, Capovilla, Giuseppe, Tinuper, Paolo, Gambardella, Antonio, Bianchi, Amedeo, La Neve, Angela, Crichiutti, Giovanni, de Kovel, Carolien G.F., Kasteleijn-Nolst Trenité, Dorothée, de Haan, Gerrit-Jan, Lindhout, Dick, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Steinhoff, Bernhard J., Kleefuß-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Elger, Christian E., Muhle, Hiltrud, von Spiczak, Sarah, Ostertag, Philipp, Helbig, Ingo, Stephani, Ulrich, Møller, Rikke S., Hjalgrim, Helle, Dibbens, Leanne M., Bellows, Susannah, Oliver, Karen, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo, Lehesjoki, Anna-Elina, Siren, Auli, Guipponi, Michel, Malafosse, Alain, Thomas, Pierre, Nabbout, Rima, Baulac, Stephanie, Leguern, Eric, Guerrero, Rosa, Serratosa, Jose M., Reif, Philipp S., Rosenow, Felix, Mörzinger, Martina, Feucht, Martha, Zimprich, Fritz, Kapser, Claudia, Schankin, Christoph J., Suls, Arvid, Smets, Katrin, De Jonghe, Peter, Jordanova, Albena, Caglayan, Hande, Yapici, Zuhal, Yalcin, Destina A., Baykan, Betul, Bebek, Nerses, Ozbek, Ugur, Gieger, Christian, Wichmann, Heinz-Erich, Balschun, Tobias, Ellinghaus, David, Franke, Andre, Meesters, Christian, Becker, Tim, Wienker, Thomas F., Hempelmann, Anne, Schulz, Herbert, Rüschendorf, Franz, Leber, Markus, Pauck, Steffen M., Trucks, Holger, Toliat, Mohammad R., Nürnberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P.C., and Sander, Thomas

Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes

Published
2017

24. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Author

Schubert, Julian, Siekierska, Aleksandra, Langlois, Melanie, May, Patrick, Huneau, Clement, Becker, Felicitas, Muhle, Hiltrud, Suls, Arvid, Lemke, Johannes R., de Kovel, Carolien G. F., Thiele, Holger, Konrad, Kathryn, Kawalia, Amit, Toliat, Mohammad R., Sander, Thomas, Rueschendorf, Franz, Caliebe, Almuth, Nagel, Inga, Kohl, Bernard, Kecskes, Angela, Jacmin, Maxime, Hardies, Katia, Weckhuysen, Sarah, Riesch, Erik, Dorn, Thomas, Brilstra, Eva H., Baulac, Stephanie, Moller, Rikke S., Hjalgrim, Helle, Koeleman, Bobby P. C., Jurkat-Rott, Karin, Lehman-Horn, Frank, Roach, Jared C., Glusman, Gustavo, Hood, Leroy, Galas, David J., Martin, Benoit, de Witte, Peter A. M., Biskup, Saskia, De Jonghe, Peter, Helbig, Ingo, Balling, Rudi, Nuernberg, Peter, Crawford, Alexander D., Esguerra, Camila V., Weber, Yvonne G., Lerche, Holger, Schubert, Julian, Siekierska, Aleksandra, Langlois, Melanie, May, Patrick, Huneau, Clement, Becker, Felicitas, Muhle, Hiltrud, Suls, Arvid, Lemke, Johannes R., de Kovel, Carolien G. F., Thiele, Holger, Konrad, Kathryn, Kawalia, Amit, Toliat, Mohammad R., Sander, Thomas, Rueschendorf, Franz, Caliebe, Almuth, Nagel, Inga, Kohl, Bernard, Kecskes, Angela, Jacmin, Maxime, Hardies, Katia, Weckhuysen, Sarah, Riesch, Erik, Dorn, Thomas, Brilstra, Eva H., Baulac, Stephanie, Moller, Rikke S., Hjalgrim, Helle, Koeleman, Bobby P. C., Jurkat-Rott, Karin, Lehman-Horn, Frank, Roach, Jared C., Glusman, Gustavo, Hood, Leroy, Galas, David J., Martin, Benoit, de Witte, Peter A. M., Biskup, Saskia, De Jonghe, Peter, Helbig, Ingo, Balling, Rudi, Nuernberg, Peter, Crawford, Alexander D., Esguerra, Camila V., Weber, Yvonne G., and Lerche, Holger

Abstract

Febrile seizures affect 2-4% of all children(1) and have a strong genetic component(2). Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)(3-5) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B(6), that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees(7,8) identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

Published
2014

25. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Appenzeller, Silke, Balling, Rudi, Barisic, Nina, Baulac, Stephanie, Caglayan, Hande, Craiu, Dana, De Jonghe, Peter, Depienne, Christel, Dimova, Petia, Djemie, Tania, Gormly, Padhraig, Guerrini, Renzo, Helbig, Ingo, Hjalgrim, Helle, Hoffman-Zacharska, Dorota, Jähn, Klein, Karl Martin, Koeleman, Bobby, Komarek, Vladimir, Krause, Roland, Kuhlenbäumer, Gregor, Leguern, Eric, Lehesjoki, Anna-Elina, Lemke, Johannes R., Lerche, Holger, Linnankivi, Tarja, Marini, Carla, May, Patrick, Møller, Rikke S., Muhle, Hiltrud, Pal, Deb, Palotie, Aarno, Pendziwitat, Manuela, Robbiano, Angela, Roelens, Filip, Rosenow, Felix, Selmer, Kaja, Serratosa, Jose M., Sisodiya, Sanjay, Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Suls, Arvid, Talvik, Tiina, von Spizak, Sarah, Weber, Yvonne, Weckhuysen, Sarah, Zara, Frederico, Epilepsy Phenome/Genome Project, Epi4K Consortium, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Appenzeller, Silke, Balling, Rudi, Barisic, Nina, Baulac, Stephanie, Caglayan, Hande, Craiu, Dana, De Jonghe, Peter, Depienne, Christel, Dimova, Petia, Djemie, Tania, Gormly, Padhraig, Guerrini, Renzo, Helbig, Ingo, Hjalgrim, Helle, Hoffman-Zacharska, Dorota, Jähn, Klein, Karl Martin, Koeleman, Bobby, Komarek, Vladimir, Krause, Roland, Kuhlenbäumer, Gregor, Leguern, Eric, Lehesjoki, Anna-Elina, Lemke, Johannes R., Lerche, Holger, Linnankivi, Tarja, Marini, Carla, May, Patrick, Møller, Rikke S., Muhle, Hiltrud, Pal, Deb, Palotie, Aarno, Pendziwitat, Manuela, Robbiano, Angela, Roelens, Filip, Rosenow, Felix, Selmer, Kaja, Serratosa, Jose M., Sisodiya, Sanjay, Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Suls, Arvid, Talvik, Tiina, von Spizak, Sarah, Weber, Yvonne, Weckhuysen, Sarah, Zara, Frederico, Epilepsy Phenome/Genome Project, and Epi4K Consortium

Abstract

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the “classical” epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10−4), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

Published
2014

26. De novo mutations in HCN1 cause early infantile epileptic encephalopathy

Author

May, Patrick [collaborator], Balling, Rudi [collaborator], Barisic, Nina [collaborator], Baulac, Stéphanie [collaborator], Caglayan, Hande S. [collaborator], Craiu, Dana C. [collaborator], De Jonghe, Peter [collaborator], Depienne, Christel [collaborator], Gormley, Padhraig [collaborator], Guerrini, Renzo [collaborator], Helbig, Ingo [collaborator], Hjalgrim, Helle [collaborator], Hoffman-Zacharska, Dorota [collaborator], Jähn, Johanna [collaborator], Klein, Karl Martin [collaborator], Koeleman, Bobby P. C. [collaborator], Komarek, Vladimir [collaborator], Krause, Roland [collaborator], LeGuern, Eric [collaborator], Lehesjoki, Anna-Elina [collaborator], Lemke, Johannes R. [collaborator], Lerche, Holger [collaborator], Marini, Carla [collaborator], Møller, Rikke S. [collaborator], Muhle, Hiltrud [collaborator], Palotie, Aarno [collaborator], Pal, Deb [collaborator], Rosenow, Felix [collaborator], Selmer, Kaja [collaborator], Serratosa, José M. [collaborator], Sisodiya, Sanjay [collaborator], Stephani, Ulrich [collaborator], Sterbova, Katalin [collaborator], Striano, Pasquale [collaborator], Suls, Arvid [collaborator], Talvik, Tiina [collaborator], von Spiczak, Sarah [collaborator], Weber, Yvonne [collaborator], Weckhuysen, Sarah [collaborator], Zara, Federico [collaborator], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Nava, Caroline, Dalle, Carine, Rastetter, Agnès, Striano, Pasquale, de Kovel, Carolien G. F., Nabbout, Rima, Cancès, Claude, Ville, Dorothée, Brilstra, Eva H., Gobbi, Giuseppe, Raffo, Emmanuel, Bouteiller, Delphine, Marie, Yannick, Trouillard, Oriane, Robbiano, Angela, Keren, Boris, Agher, Dahbia, Roze, Emmanuel, Lesage, Suzanne, Nicolas, Aude, Brice, Alexis, Baulac, Michel, Vogt, Cornelia, El Hajj, Nady, Schneider, Eberhard, Suls, Arvid, Weckhuysen, Sarah, Gormley, Padhraig, Lehesjoki, Anna-Elina, De Jonghe, Peter, Helbig, Ingo, Baulac, Stephanie, Zara, Federico, Koeleman, Bobby P. C., Consortium, Euroepinomics R. E. S., Haaf, Thomas, LeGuern, Eric, Depienne, Christel, May, Patrick [collaborator], Balling, Rudi [collaborator], Barisic, Nina [collaborator], Baulac, Stéphanie [collaborator], Caglayan, Hande S. [collaborator], Craiu, Dana C. [collaborator], De Jonghe, Peter [collaborator], Depienne, Christel [collaborator], Gormley, Padhraig [collaborator], Guerrini, Renzo [collaborator], Helbig, Ingo [collaborator], Hjalgrim, Helle [collaborator], Hoffman-Zacharska, Dorota [collaborator], Jähn, Johanna [collaborator], Klein, Karl Martin [collaborator], Koeleman, Bobby P. C. [collaborator], Komarek, Vladimir [collaborator], Krause, Roland [collaborator], LeGuern, Eric [collaborator], Lehesjoki, Anna-Elina [collaborator], Lemke, Johannes R. [collaborator], Lerche, Holger [collaborator], Marini, Carla [collaborator], Møller, Rikke S. [collaborator], Muhle, Hiltrud [collaborator], Palotie, Aarno [collaborator], Pal, Deb [collaborator], Rosenow, Felix [collaborator], Selmer, Kaja [collaborator], Serratosa, José M. [collaborator], Sisodiya, Sanjay [collaborator], Stephani, Ulrich [collaborator], Sterbova, Katalin [collaborator], Striano, Pasquale [collaborator], Suls, Arvid [collaborator], Talvik, Tiina [collaborator], von Spiczak, Sarah [collaborator], Weber, Yvonne [collaborator], Weckhuysen, Sarah [collaborator], Zara, Federico [collaborator], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Nava, Caroline, Dalle, Carine, Rastetter, Agnès, Striano, Pasquale, de Kovel, Carolien G. F., Nabbout, Rima, Cancès, Claude, Ville, Dorothée, Brilstra, Eva H., Gobbi, Giuseppe, Raffo, Emmanuel, Bouteiller, Delphine, Marie, Yannick, Trouillard, Oriane, Robbiano, Angela, Keren, Boris, Agher, Dahbia, Roze, Emmanuel, Lesage, Suzanne, Nicolas, Aude, Brice, Alexis, Baulac, Michel, Vogt, Cornelia, El Hajj, Nady, Schneider, Eberhard, Suls, Arvid, Weckhuysen, Sarah, Gormley, Padhraig, Lehesjoki, Anna-Elina, De Jonghe, Peter, Helbig, Ingo, Baulac, Stephanie, Zara, Federico, Koeleman, Bobby P. C., Consortium, Euroepinomics R. E. S., Haaf, Thomas, LeGuern, Eric, and Depienne, Christel

Published
2014

27. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Schubert, Julian, Siekierska, Aleksandra, Langlois, Melanie, May, Patrick, Huneau, Clement, Becker, Felicitas, Muhle, Hiltrud, Suls, Arvid, Lemke, Johannes R., de Kovel, Carolien G. F., Thiele, Holger, Konrad, Kathryn, Kawalia, Amit, Toliat, Mohammad R., Sander, Thomas, Ruschendorf, Franz, Caliebe, Almuth, Nagel, Inga, Kohl, Bernard, Kecskes, Angela, Jacmin, Maxime, Hardies, Katia, Weckhuysen, Sarah, Riesch, Erik, Dorn, Thomas, Brilstra, Eva H., Baulac, Stephanie, Moller, Rikke S., Hjalgrim, Helle, Koeleman, Bobby P. C., EuroEPINOMICS RES Consortium, Krause, Roland, Jurkat-Rott, Karin, Lehman-Horn, Frank, Roach, Jared C., Glusman, Gustavo, Hood, Leroy, Galas, David J., Martin, Benoit, de Witte, Peter A. M., Biskup, Saskia, De Jonghe, Peter, Helbig, Ingo, Balling, Rudi, Nurnberg, Peter, Crawford, Alexander Dettmar, Esguerra, Camila V., Weber, Yvonne G., Lerche, Holger, Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Schubert, Julian, Siekierska, Aleksandra, Langlois, Melanie, May, Patrick, Huneau, Clement, Becker, Felicitas, Muhle, Hiltrud, Suls, Arvid, Lemke, Johannes R., de Kovel, Carolien G. F., Thiele, Holger, Konrad, Kathryn, Kawalia, Amit, Toliat, Mohammad R., Sander, Thomas, Ruschendorf, Franz, Caliebe, Almuth, Nagel, Inga, Kohl, Bernard, Kecskes, Angela, Jacmin, Maxime, Hardies, Katia, Weckhuysen, Sarah, Riesch, Erik, Dorn, Thomas, Brilstra, Eva H., Baulac, Stephanie, Moller, Rikke S., Hjalgrim, Helle, Koeleman, Bobby P. C., EuroEPINOMICS RES Consortium, Krause, Roland, Jurkat-Rott, Karin, Lehman-Horn, Frank, Roach, Jared C., Glusman, Gustavo, Hood, Leroy, Galas, David J., Martin, Benoit, de Witte, Peter A. M., Biskup, Saskia, De Jonghe, Peter, Helbig, Ingo, Balling, Rudi, Nurnberg, Peter, Crawford, Alexander Dettmar, Esguerra, Camila V., Weber, Yvonne G., and Lerche, Holger

Abstract

Febrile seizures affect 2–4% of all children1 and have a strong genetic component2. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)3, 4, 5 have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B6, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees7, 8 identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

Published
2014

28. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Author

EPICURE Consortium, EMINet Consortium, Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Federico, Striano, Pasquale, Robbiano, Angela, Capovilla, Giuseppe, Tinuper, Paolo, Gambardella, Antonio, Bianchi, Amedeo, La Neve, Angela, Crichiutti, Giovanni, de Kovel, Carolien G.F., Kasteleijn-Nolst Trenité, Dorothee, de Haan, Gerrit-Jan, Lindhout, Dick, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Steinhoff, Bernhard J., Kleefuß-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Elger, Christian E., Muhle, Hiltrud, von Spiczak, Sarah, Ostertag, Philipp, Helbig, Ingo, Stephani, Ulrich, Møller, Rikke S., Hjalgrim, Helle, Dibbens, Leanne M., Bellows, Susannah, Oliver, Karen, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo, Lehesjoki, Anna-Elina, Siren, Auli, Guipponi, Michel, Malafosse, Alain, Thomas, Pierre, Nabbout, Rima, Baulac, Stephanie, Leguern, Eric, Guerrero, Rosa, Serratosa, Jose M., Reif, Philipp S., Rosenow, Felix, Mörzinger, Martina, Feucht, Martha, Zimprich, Fritz, Kapser, Claudia, Schankin, Christoph J., Suls, Arvid, Smets, Katrin, De Jonghe, Peter, Jordanova, Albena, Caglayan, Hande, Yapici, Zuhal, Yalcin, Destina A., Baykan, Betul, Bebek, Nerses, Ozbek, Ugur, Gieger, Christian, Wichmann, Heinz-Erich, Balschun, Tobias, Ellinghaus, David, Franke, Andre, Meesters, Christian, Becker, Tim, Wienker, Thomas F., Hempelmann, Anne, Schulz, Herbert, Rüschendorf, Franz, Leber, Markus, Pauck, Steffen M., Trucks, Holger, Toliat, Mohammad R., Nürnberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P.C., Sander, Thomas, EPICURE Consortium, EMINet Consortium, Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Federico, Striano, Pasquale, Robbiano, Angela, Capovilla, Giuseppe, Tinuper, Paolo, Gambardella, Antonio, Bianchi, Amedeo, La Neve, Angela, Crichiutti, Giovanni, de Kovel, Carolien G.F., Kasteleijn-Nolst Trenité, Dorothee, de Haan, Gerrit-Jan, Lindhout, Dick, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Steinhoff, Bernhard J., Kleefuß-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Elger, Christian E., Muhle, Hiltrud, von Spiczak, Sarah, Ostertag, Philipp, Helbig, Ingo, Stephani, Ulrich, Møller, Rikke S., Hjalgrim, Helle, Dibbens, Leanne M., Bellows, Susannah, Oliver, Karen, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo, Lehesjoki, Anna-Elina, Siren, Auli, Guipponi, Michel, Malafosse, Alain, Thomas, Pierre, Nabbout, Rima, Baulac, Stephanie, Leguern, Eric, Guerrero, Rosa, Serratosa, Jose M., Reif, Philipp S., Rosenow, Felix, Mörzinger, Martina, Feucht, Martha, Zimprich, Fritz, Kapser, Claudia, Schankin, Christoph J., Suls, Arvid, Smets, Katrin, De Jonghe, Peter, Jordanova, Albena, Caglayan, Hande, Yapici, Zuhal, Yalcin, Destina A., Baykan, Betul, Bebek, Nerses, Ozbek, Ugur, Gieger, Christian, Wichmann, Heinz-Erich, Balschun, Tobias, Ellinghaus, David, Franke, Andre, Meesters, Christian, Becker, Tim, Wienker, Thomas F., Hempelmann, Anne, Schulz, Herbert, Rüschendorf, Franz, Leber, Markus, Pauck, Steffen M., Trucks, Holger, Toliat, Mohammad R., Nürnberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P.C., and Sander, Thomas

Published
2012

29. A Second Locus for Familial Generalized Epilepsy with Febrile Seizures Plus Maps to Chromosome 2q21-q33.

Author

Baulac, Stephanie, Gourfinkel-An, Isabelle, Picard, Fabienne, Rosenberg-Bourgin, Myriam, Prud'homme, Jean-Francois, Baulac, Michel, Brice, Alexis, and LeGuern, Eric

Subjects
*GENETICS of epilepsy, *FEBRILE seizures, *GENES, *ANALYTICAL chemistry
Abstract

Presents a clinical and genetic study on a family with a phenotype resembling generalized epilepsy with febrile seizures plus (GEFS+). Linkage analysis on the genes; Identification of a locus on chromosome 2q21-q33; Recognition of four genes coding as possible source of the disease.

Published
1999
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30. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Author

Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Federico, Striano, Pasquale, Robbiano, Angela, Capovilla, Giuseppe, Tinuper, Paolo, Gambardella, Antonio, Bianchi, Amedeo, La Neve, Angela, Crichiutti, Giovanni, de Kovel, Carolien G.F., Kasteleijn-Nolst Trenité, Dorothée, de Haan, Gerrit-Jan, Lindhout, Dick, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Steinhoff, Bernhard J., Kleefuß-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Elger, Christian E., Muhle, Hiltrud, von Spiczak, Sarah, Ostertag, Philipp, Helbig, Ingo, Stephani, Ulrich, Møller, Rikke S., Hjalgrim, Helle, Dibbens, Leanne M., Bellows, Susannah, Oliver, Karen, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo, Lehesjoki, Anna-Elina, Siren, Auli, Guipponi, Michel, Malafosse, Alain, Thomas, Pierre, Nabbout, Rima, Baulac, Stephanie, Leguern, Eric, Guerrero, Rosa, Serratosa, Jose M., Reif, Philipp S., Rosenow, Felix, Mörzinger, Martina, Feucht, Martha, Zimprich, Fritz, Kapser, Claudia, Schankin, Christoph J., Suls, Arvid, Smets, Katrin, De Jonghe, Peter, Jordanova, Albena, Caglayan, Hande, Yapici, Zuhal, Yalcin, Destina A., Baykan, Betul, Bebek, Nerses, Ozbek, Ugur, Gieger, Christian, Wichmann, Heinz-Erich, Balschun, Tobias, Ellinghaus, David, Franke, Andre, Meesters, Christian, Becker, Tim, Wienker, Thomas F., Hempelmann, Anne, Schulz, Herbert, Rüschendorf, Franz, Leber, Markus, Pauck, Steffen M., Trucks, Holger, Toliat, Mohammad R., Nürnberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P.C., Sander, Thomas, Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Federico, Striano, Pasquale, Robbiano, Angela, Capovilla, Giuseppe, Tinuper, Paolo, Gambardella, Antonio, Bianchi, Amedeo, La Neve, Angela, Crichiutti, Giovanni, de Kovel, Carolien G.F., Kasteleijn-Nolst Trenité, Dorothée, de Haan, Gerrit-Jan, Lindhout, Dick, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Steinhoff, Bernhard J., Kleefuß-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Elger, Christian E., Muhle, Hiltrud, von Spiczak, Sarah, Ostertag, Philipp, Helbig, Ingo, Stephani, Ulrich, Møller, Rikke S., Hjalgrim, Helle, Dibbens, Leanne M., Bellows, Susannah, Oliver, Karen, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo, Lehesjoki, Anna-Elina, Siren, Auli, Guipponi, Michel, Malafosse, Alain, Thomas, Pierre, Nabbout, Rima, Baulac, Stephanie, Leguern, Eric, Guerrero, Rosa, Serratosa, Jose M., Reif, Philipp S., Rosenow, Felix, Mörzinger, Martina, Feucht, Martha, Zimprich, Fritz, Kapser, Claudia, Schankin, Christoph J., Suls, Arvid, Smets, Katrin, De Jonghe, Peter, Jordanova, Albena, Caglayan, Hande, Yapici, Zuhal, Yalcin, Destina A., Baykan, Betul, Bebek, Nerses, Ozbek, Ugur, Gieger, Christian, Wichmann, Heinz-Erich, Balschun, Tobias, Ellinghaus, David, Franke, Andre, Meesters, Christian, Becker, Tim, Wienker, Thomas F., Hempelmann, Anne, Schulz, Herbert, Rüschendorf, Franz, Leber, Markus, Pauck, Steffen M., Trucks, Holger, Toliat, Mohammad R., Nürnberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P.C., and Sander, Thomas

Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes

31. Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations

Author

Rikke S. Møller, Giuseppe Plazzi, Fabienne Picard, Edouard Hirsch, Elena Gardella, Jamel Chelly, Lino Nobili, Manuela Bramerio, Richard A. Prayson, Jean Boutonnat, Guido Rubboli, Philippe Kahane, Leanne M. Dibbens, Stéphanie Baulac, The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], University of Copenhagen = Københavns Universitet (UCPH), University of Bologna/Università di Bologna, Institute of Neurological Sciences (CNR), National Research Council [Italy] (CNR), Geneva University Hospitals and Geneva University, Niguarda Hospital [Milan, Italy], Hôpital de Hautepierre [Strasbourg], Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nouvel Hôpital Civil de Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Cleveland Clinic, Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Université Grenoble Alpes (UGA), CHU Grenoble, University of South Australia [Adelaide], University of Southern Denmark (SDU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), univOAK, Archive ouverte, Rubboli G., Plazzi G., Picard F., Nobili L., Hirsch E., Chelly J., Prayson R.A., Boutonnat J., Bramerio M., Kahane P., Dibbens L.M., Gardella E., Baulac S., Moller R.S., Rubboli, Guido, Plazzi, Giuseppe, Picard, Fabienne, Nobili, Lino, Hirsch, Edouard, Chelly, Jamel, Prayson, Richard A, Boutonnat, Jean, Bramerio, Manuela, Kahane, Philippe, Dibbens, Leanne M, Gardella, Elena, Baulac, Stephanie, and Moller, Rikke S

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, KCNT1, [SDV.GEN] Life Sciences [q-bio]/Genetics, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, medicine, Epilepsy surgery, gene mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, sleep-related hypermotor epilepsy, business.industry, General Neuroscience, Periventricular Nodular Heterotopia, Cortical dysplasia, medicine.disease, Malformation of cortical development, Sleep in non-human animals, 3. Good health, ddc:616.8, 030104 developmental biology, epilepsy, Neurology (clinical), business, cortical dysplasia, electroencephalography, 030217 neurology & neurosurgery
Abstract

Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. Mutations in the sodium-activated potassium channel gene KCNT1 have been associated with nonlesional sleep-related hypermotor epilepsy (SHE). We report the co-occurrence of mild malformation of cortical development (mMCD) and KCNT1 mutations in four patients with SHE. Focal cortical dysplasia type I was neuropathologically diagnosed after epilepsy surgery in three unrelated MRI-negative patients, periventricular nodular heterotopia was detected in one patient by MRI. Our findings suggest that KCNT1 epileptogenicity may result not only from dysregulated excitability by controlling Na+K+ transport, but also from mMCD. Therefore, pathogenic variants in KCNT1 may encompass both lesional and nonlesional epilepsies. Refereed/Peer-reviewed

Published
2018

32. Genetic Insights Into Hypothalamic Hamartoma: Unraveling Somatic Variants.

Author

Sami L, Chipaux M, Ferrand-Sorbets S, Doladilhe M, Bulteau C, Raffo E, Rosenberg S, Dorfmuller G, Checri R, De Sainte Agathe JM, Leguern E, Adle-Biassette H, Baldassari S, and Baulac S

Abstract

Objectives: Hypothalamic hamartomas (HHs) are rare developmental brain lesions associated with drug-resistant epilepsy and often subjected to epilepsy surgery. Brain somatic variants in genes affecting the Sonic hedgehog (Shh) and primary cilia signaling pathways have been implicated in approximately 50% of nonsyndromic HH cases. This study aims to characterize a new cohort of 9 HH cases and elucidate their genetic etiology., Methods: We recruited 9 HH cases including 8 nonsyndromic cases of which 4 were type IV HH. Genomic DNA was extracted from peripheral blood and surgical brain tissues, and somatic variants were investigated using high-depth whole-exome sequencing., Results: Pathogenic somatic variants in known HH genes ( GLI3 , OFD1 , and PRKACA) were identified in 7 of the 9 cases. In addition, a 2-hit mutational event comprising a germline variant (predicted to impair kinase activity) and a somatic loss-of-heterozygosity was identified in TNK2 , a gene encoding a brain-expressed tyrosine kinase., Discussion: Our findings reinforce the role of somatic variants in Shh and cilia genes in HH cases while also shedding light on TNK2 as a potential novel disease-causing gene. This study emphasizes the increasing importance of brain mosaicism in epilepsy disorders and underscores the critical role of genetic diagnosis derived from resected brain tissue., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2024
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