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2. Current practice in diagnostic genetic testing of the epilepsies.

Author

Krey, Ilona, Platzer, Konrad, Esterhuizen, Alina, Berkovic, Samuel, Helbig, Ingo, Hildebrand, Michael, Lerche, Holger, Møller, Rikke, Poduri, Annapurna, Sadleir, Lynette, Sisodiya, Sanjay, Weckhuysen, Sarah, Wilmshurst, Jo, Weber, Yvonne, Lemke, Johannes, Cross, J, Lowenstein, Daniel, Mefford, Heathea, Perucca, Piero, Tan, Nigel, Caglayan, Hande, Helbig, Katherine, and Singh, Gagandeep

Subjects
genetic epilepsy, next-generation sequencing, genetic counseling genetic testing, variant of uncertain significance, precision medicine, Diagnostic Techniques and Procedures, Epilepsy, Genetic Testing, Humans
Abstract

Epilepsy genetics is a rapidly developing field, in which novel disease-associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances in genomic knowledge and analysis platforms have begun to make clinical genetic testing accessible for, in principle, people of all ages with epilepsy. For this reason, the Genetics Commission of the International League Against Epilepsy (ILAE) presents this update on clinical genetic testing practice, including current techniques, indications, yield of genetic testing, recommendations for pre- and post-test counseling, and follow-up after genetic testing is completed. We acknowledge that the resources vary across different settings but highlight that genetic diagnostic testing for epilepsy should be prioritized when the likelihood of an informative finding is high. Results of genetic testing, in particular the identification of causative genetic variants, are likely to improve individual care. We emphasize the importance of genetic testing for individuals with epilepsy as we enter the era of precision therapy.

Published
2022

3. Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress

Author

Knowles, Juliet K, Helbig, Ingo, Metcalf, Cameron S, Lubbers, Laura S, Isom, Lori L, Demarest, Scott, Goldberg, Ethan M, George, Alfred L, Lerche, Holger, Weckhuysen, Sarah, Whittemore, Vicky, Berkovic, Samuel F, and Lowenstein, Daniel H

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Clinical Research, Brain Disorders, Neurodegenerative, Epilepsy, Neurological, Good Health and Well Being, Genetic Testing, Humans, Precision Medicine, Seizures, Suggestion, epilepsy, exome sequencing, genomic medicine, personalized medicine, precision medicine, Neurology & Neurosurgery, Clinical sciences
Abstract

The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.

Published
2022

4. Ictal Electroencephalographic Characteristics of Nodding Syndrome: A Comparative Case‐Series from South Sudan, Tanzania, and Uganda

Author

Mazumder, Rajarshi, Lagoro, David Kitara, Nariai, Hiroki, Danieli, Alberto, Eliashiv, Dawn, Engel, Jerome, Bernardina, Bernardo Dalla, Kegele, Josua, Lerche, Holger, Sejvar, James, Matuja, William, Schmutzhard, Erich, Bonanni, Paolo, De Polo, Gianni, Wagner, Thomas, and Winkler, Andrea Sylvia

Subjects
Neurosciences, Mental Health, Brain Disorders, Pediatric, Clinical Research, Good Health and Well Being, Electroencephalography, Humans, Nodding Syndrome, South Sudan, Tanzania, Uganda, Clinical Sciences, Neurology & Neurosurgery
Abstract

Nodding syndrome (NS) is a poorly understood form of childhood-onset epilepsy that is characterized by the pathognomonic ictal phenomenon of repetitive vertical head drops. To evaluate the underlying ictal neurophysiology, ictal EEG features were evaluated in nine participants with confirmed NS from South Sudan, Tanzania, and Uganda and ictal presence of high frequency gamma oscillations on scalp EEG were assessed. Ictal EEG during the head nodding episode predominantly showed generalized slow waves or sharp-and-slow wave complexes followed by electrodecrement. Augmentation of gamma activity (30-70 Hz) was seen during the head nodding episode in all the participants. We confirm that head nodding episodes in persons with NS from the three geographically distinct regions in sub-Saharan Africa share the common features of slow waves with electrodecrement and superimposed gamma activity. ANN NEUROL 2022;92:75-80.

Published
2022

5. Missense variants in ANO4 cause sporadic encephalopathic or familial epilepsy with evidence for a dominant-negative effect

Author

Yang, Fang, Begemann, Anais, Reichhart, Nadine, Haeckel, Akvile, Steindl, Katharina, Schellenberger, Eyk, Sturm, Ronja Fini, Barth, Magalie, Bassani, Sissy, Boonsawat, Paranchai, Courtin, Thomas, Delobel, Bruno, Gunning, Boudewijn, Hardies, Katia, Jennesson, Mélanie, Legoff, Louis, Linnankivi, Tarja, Prouteau, Clément, Smal, Noor, Spodenkiewicz, Marta, Toelle, Sandra P., Van Gassen, Koen, Van Paesschen, Wim, Verbeek, Nienke, Ziegler, Alban, Zweier, Markus, Horn, Anselm H.C., Sticht, Heinrich, Lerche, Holger, Weckhuysen, Sarah, Strauß, Olaf, and Rauch, Anita

Published
2024
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9. Distinct gene-set burden patterns underlie common generalized and focal epilepsies.

Author

Koko, Mahmoud, Krause, Roland, Sander, Thomas, Bobbili, Dheeraj, Nothnagel, Michael, May, Patrick, and Lerche, Holger

Subjects
Burden analysis, Epilepsy, Exome sequencing, Gene-sets, Ultra-rare variants, Case-Control Studies, Epilepsies, Partial, Epilepsy, Generalized, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Exome Sequencing
Abstract

BACKGROUND: Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis. METHODS: The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. FINDINGS: Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE. INTERPRETATION: Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies. FUNDING: DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).

Published
2021

10. Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia

Author

Lyu, Hang, Boßelmann, Christian M., Johannesen, Katrine M., Koko, Mahmoud, Ortigoza-Escobar, Juan Dario, Aguilera-Albesa, Sergio, Garcia-Navas Núñez, Deyanira, Linnankivi, Tarja, Gaily, Eija, van Ruiten, Henriette J.A., Richardson, Ruth, Betzler, Cornelia, Horvath, Gabriella, Brilstra, Eva, Geerdink, Niels, Orsucci, Daniele, Tessa, Alessandra, Gardella, Elena, Fleszar, Zofia, Schöls, Ludger, Lerche, Holger, Møller, Rikke S., and Liu, Yuanyuan

Published
2023
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11. Shared genetic basis between genetic generalized epilepsy and background electroencephalographic oscillations

Author

Stevelink, Remi, Luykx, Jurjen J, Lin, Bochao D, Leu, Costin, Lal, Dennis, Smith, Alexander W, Schijven, Dick, Carpay, Johannes A, Rademaker, Koen, Baldez, Roiza A Rodrigues, Devinsky, Orrin, Braun, Kees PJ, Jansen, Floor E, Smit, Dirk JA, Koeleman, Bobby PC, Abou‐Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J, Bast, Thomas, Baum, Larry, Becker, Albert J, Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F, Boysen, Katja E, Bradfield, Jonathan P, Brody, Lawrence C, Buono, Russell J, Campbell, Ellen, Cascino, Gregory D, Catarino, Claudia B, Cavalleri, Gianpiero L, Cherny, Stacey S, Chinthapalli, Krishna, Coffey, Alison J, Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J, de Haan, Gerrit‐Jan, De Jonghe, Peter, de Kovel, Carolien GF, Delanty, Norman, Depondt, Chantal, Dlugos, Dennis J, Doherty, Colin P, Elger, Christian E, Eriksson, Johan G, Ferraro, Thomas N, Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A, Freytag, Saskia, Gaus, Verena, Geller, Eric B, Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B, Gui, Hongsheng, Guo, Youling, Haas, Kevin F, Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L, Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andrés, Jamnadas‐Khoda, Jennifer, Johnson, Michael R, Kälviäinen, Reetta, Kantanen, Anne‐Mari, Kasperavičiūte, Dalia, Trenite, Dorothee Kasteleijn‐Nolst, Kirsch, Heidi E, Knowlton, Robert C, Krause, Roland, Krenn, Martin, Kunz, Wolfram S, Kuzniecky, Ruben, Kwan, Patrick, Lau, Yu‐Lung, Lehesjoki, Anna‐Elina, Lerche, Holger, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D, Lopes‐Cendes, Iscia, Lowenstein, Daniel H, Malovini, Alberto, Marson, Anthony G, Mayer, Thomas, McCormack, Mark, and Mills, James L

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Genetics, Brain Disorders, Clinical Research, Human Genome, Neurodegenerative, Epilepsy, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Algorithms, Beta Rhythm, Cohort Studies, Databases, Factual, Electroencephalography, Epilepsy, Generalized, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Mendelian Randomization Analysis, Risk Assessment, Theta Rhythm, beta power, EEG, generalized epilepsy, GGE, oscillations, PRS, International League Against Epilepsy Consortium on Complex Epilepsies, Epi25 Collaborative, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.

Published
2021

12. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Abbott, Kristin M., Banka, Siddharth, de Boer, Elke, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Denommé-Pichon, Anne-Sophie, Faivre, Laurence, Gilissen, Christian, Haack, Tobias B., Havlovicova, Marketa, Hoischen, Alexander, Jackson, Adam, Kerstjens, Mieke, Kleefstra, Tjitske, Martín, Estrella López, Macek, Milan, Jr., Matalonga, Leslie, Maystadt, Isabelle, Morleo, Manuela, Nigro, Vicenzo, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca C., Renieri, Alessandra, Riess, Olaf, Rooryck, Caroline, Ryba, Lukas, Agathe, Jean-Madeleine de Sainte, Santen, Gijs W.E., Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Trimouille, Aurélien, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Zguro, Kristina, Boer, Elke de, Cohen, Enzo, Danis, Daniel, Gao, Fei, Horvath, Rita, Johari, Mridul, Johanson, Lennart, Li, Shuang, Morsy, Heba, Nelson, Isabelle, Paramonov, Ida, te Paske, Iris B.A.W., Robinson, Peter, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vandrovcova, Jana, Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, ‘t Hoen, Peter A.C., Vissers, Lisenka E.L.M., Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, Paske, Iris te, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Alexander, Elizabeth, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Ben Yaou, Rabah, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Efthymiou, Stephanie, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Varavallo, Alessandra, Banfi, Sandro, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Kerstjens Frederikse, Wilhemina S., Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, Lacombe, Didier, Trimouille, Aurelien, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Hackman, Peter, Udd, Bjarne, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Osorio, Andrés Nascimento, Depienne, Christel, Roos, Andreas, Cordts, Isabell, Deschauer, Marcus, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Başak, Ayşe Nazlı, Claeys, Kristl, Boztug, Kaan, Haimel, Matthias, W.E, Gijs, Ruivenkamp, Claudia A.L., Natera de Benito, Daniel, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Radio, Francesca Clementina, Balicza, Peter, Molnar, Maria Judit, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Delgado, Beatriz Martínez, Alonso García de la Rosa, F. Javier, Schröck, Evelin, Rump, Andreas, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Chinnery, Patrick F., Ratnaike, Thiloka, Schon, Katherine, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, May, Patrick, Beeson, David, Cossins, Judith, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Afenjar, Alexandra, Goldenberg, Alice, Masurel, Alice, Phan, Alice, Dieux-Coeslier, Anne, Fargeot, Anne, Guerrot, Anne-Marie, Toutain, Annick, Molin, Arnaud, Sorlin, Arthur, Putoux, Audrey, Jouret, Béatrice, Laudier, Béatrice, Demeer, Bénédicte, Doray, Bérénice, Bonniaud, Bertille, Isidor, Bertrand, Gilbert-Dussardier, Brigitte, Leheup, Bruno, Reversade, Bruno, Paul, Carle, Vincent-Delorme, Catherine, Neiva, Cecilia, Poirsier, Céline, Quélin, Chloé, Chiaverini, Christine, Coubes, Christine, Francannet, Christine, Colson, Cindy, Desplantes, Claire, Wells, Constance, Goizet, Cyril, Sanlaville, Damien, Amram, Daniel, Lehalle, Daphné, Geneviève, David, Gaillard, Dominique, Zivi, Einat, Sarrazin, Elisabeth, Steichen, Elisabeth, Schaefer, Élise, Lacaze, Elodie, Jacquemin, Emmanuel, Bongers, Ernie, Kilic, Esra, Colin, Estelle, Giuliano, Fabienne, Prieur, Fabienne, Laffargue, Fanny, Morice-Picard, Fanny, Petit, Florence, Cartault, François, Feillet, François, Baujat, Geneviève, Morin, Gilles, Diene, Gwenaëlle, Journel, Hubert, Perthus, Isabelle, Lespinasse, James, Alessandri, Jean-Luc, Amiel, Jeanne, Martinovic, Jelena, Delanne, Julian, Albuisson, Juliette, Lambert, Laëtitia, Perrin, Laurence, Ousager, Lilian Bomme, Van Maldergem, Lionel, Pinson, Lucile, Ruaud, Lyse, Samimi, Mahtab, Bournez, Marie, Bonnet-Dupeyron, Marie Noëlle, Vincent, Marie, Jacquemont, Marie-Line, Cordier-Alex, Marie-Pierre, Gérard-Blanluet, Marion, Willems, Marjolaine, Spodenkiewicz, Marta, Doco-Fenzy, Martine, Rossi, Massimiliano, Renaud, Mathilde, Fradin, Mélanie, Mathieu, Michèle, Holder-Espinasse, Muriel H., Houcinat, Nada, Hanna, Nadine, Leperrier, Nathalie, Chassaing, Nicolas, Philip, Nicole, Boute, Odile, Van Kien, Philippe Khau, Parent, Philippe, Bitoun, Pierre, Sarda, Pierre, Vabres, Pierre, Jouk, Pierre-Simon, Touraine, Renaud, El Chehadeh, Salima, Whalen, Sandra, Marlin, Sandrine, Passemard, Sandrine, Grotto, Sarah, Bellanger, Séverine Audebert, Blesson, Sophie, Nambot, Sophie, Naudion, Sophie, Lyonnet, Stanislas, Odent, Sylvie, Attie-Bitach, Tania, Busa, Tiffany, Drouin-Garraud, Valérie, Layet, Valérie, Bizaoui, Varoona, Cusin, Véronica, Capri, Yline, Alembik, Yves, Jean-Marçais, Nolwenn, López-Martín, Estrella, Macek, Milan, Mencarelli, Maria Antonietta, Moutton, Sébastien, Pfundt, Rolph, Safraou, Hana, Thauvin-Robinet, Christel, Thevenon, Julien, Tran Mau-Them, Frédéric, de Vries, Bert B.A., Willemsen, Marjolein H., and Philippe, Christophe

Published
2023
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13. Polygenic burden in focal and generalized epilepsies

Author

Leu, Costin, Stevelink, Remi, Smith, Alexander W, Goleva, Slavina B, Kanai, Masahiro, Ferguson, Lisa, Campbell, Ciaran, Kamatani, Yoichiro, Okada, Yukinori, Sisodiya, Sanjay M, Cavalleri, Gianpiero L, Koeleman, Bobby PC, Lerche, Holger, Jehi, Lara, Davis, Lea K, Najm, Imad M, Palotie, Aarno, Daly, Mark J, Busch, Robyn M, Consortium, Epi25, and Lal, Dennis

Subjects
Biomedical and Clinical Sciences, Clinical Research, Neurosciences, Brain Disorders, Neurodegenerative, Epilepsy, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Cohort Studies, Cost of Illness, Databases, Factual, Epilepsies, Partial, Epilepsy, Generalized, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, White People, Epi25 Consortium, common variant risk, epilepsy, genetic generalized epilepsy, genetics, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Published
2019

16. Optimizing clinical interpretability of functional evidence in epilepsy-related ion channel variants

Author

Parthasarathy, Shridhar, primary, Cohen, Stacey R, additional, Fitch, Eryn, additional, Vaidiswaran, Priya, additional, Ruggiero, Sarah M, additional, Lusk, Laina, additional, Chisari, Victoria, additional, Lewis-Smith, David, additional, Lauxmann, Stephan, additional, Bosselmann, Christian M, additional, Thompson, Christopher H, additional, Wengert, Eric R, additional, Hedrich, Ulrike, additional, Ganesan, Shiva, additional, Balagura, Ganna, additional, Krause, Roland, additional, Xian, Julie, additional, Galer, Peter D, additional, Pendziwiat, Manuela, additional, Perez-Palma, Eduardo, additional, Vihinen, Mauno, additional, Hart, Jennifer, additional, Landrum, Melissa J, additional, Lal, Dennis, additional, Cooper, Edward C, additional, Lerche, Holger, additional, Goldberg, Ethan M, additional, Brunklaus, Andreas, additional, Vanoye, Carlos G, additional, Schorge, Stephanie, additional, George, Alfred L, additional, and Helbig, Ingo, additional

Published
2024
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17. Electrophysiological signatures of a developmental delay in a stem cell model ofKCNQ2developmental and epileptic encephalopathy

Author

Rosa, Filip, primary, Theiss, Stephan, additional, Krepp, Susanne, additional, Loeffler, Heidi, additional, Mendes, Dulini, additional, Klingenstein, Stefanie, additional, Liebau, Stefan, additional, Weckhuysen, Sarah, additional, Alber, Michael, additional, Petrou, Steven, additional, Lerche, Holger, additional, Maljevic, Snezana, additional, and Wuttke, Thomas V, additional

Published
2024
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18. Clinical spectrum of STX1B-related epileptic disorders.

Author

Cilio, Maria, Van Paesschen, Wim, Svendsen, Lene, Oates, Stephanie, Hughes, Elaine, Goyal, Sushma, Brown, Kathleen, Sifuentes Saenz, Margarita, Dorn, Thomas, Muhle, Hiltrud, Pagnamenta, Alistair, Vavoulis, Dimitris, Knight, Samantha, Taylor, Jenny, Canevini, Maria, Darra, Francesca, Gavrilova, Ralitza, Powis, Zöe, Tang, Shan, Marquetand, Justus, Armstrong, Martin, McHale, Duncan, Klee, Eric, Kluger, Gerhard, Lowenstein, Daniel, Weckhuysen, Sarah, Pal, Deb, Helbig, Ingo, Guerrini, Renzo, Thomas, Rhys, Rees, Mark, Lesca, Gaetan, Sisodiya, Sanjay, Weber, Yvonne, Lal, Dennis, Marini, Carla, Lerche, Holger, Schubert, Julian, Wolking, Stefan, May, Patrick, Mei, Davide, Møller, Rikke, Balestrini, Simona, Helbig, Katherine, Altuzarra, Cecilia, Chatron, Nicolas, Kaiwar, Charu, Stöhr, Katharina, Widdess-Walsh, Peter, Mendelsohn, Bryce, and Numis, Adam

Subjects
Adolescent, Anticonvulsants, Child, Child, Preschool, Developmental Disabilities, Drug Resistant Epilepsy, Electroencephalography, Epilepsies, Partial, Epileptic Syndromes, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Learning Disabilities, Loss of Function Mutation, Male, Mutation, Missense, Phenotype, Seizures, Febrile, Sequence Analysis, DNA, Syntaxin 1, Young Adult
Abstract

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

Published
2019

20. Bi-allelic PRRT2 variants may predispose to Self-limited Familial Infantile Epilepsy

Author

Koko, Mahmoud, primary, Elseed, Maha A., additional, Mohammed, Inaam N., additional, Hamed, Ahlam A., additional, Abd Allah, Amal S. I., additional, Yahia, Ashraf, additional, Siddig, Rayan A., additional, Altmüller, Janine, additional, Toliat, Mohammad Reza, additional, Elmahdi, Esra O., additional, Amin, Mutaz, additional, Ahmed, Elhami A., additional, Eltazi, Isra Z. M., additional, Elmugadam, Fatima A., additional, Abdelgadir, Wasma A., additional, Eltaraifee, Esraa, additional, Ibrahim, Mohamed O. M., additional, Ali, Nabila M. H., additional, Malik, Hiba M., additional, Babai, Arwa M., additional, Bakhit, Yousuf H., additional, Nürnberg, Peter, additional, Ibrahim, Muntaser E., additional, Salih, Mustafa A., additional, Schubert, Julian, additional, Elsayed, Liena E. O., additional, and Lerche, Holger, additional

Published
2024
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21. Complex biophysical changes and reduced neuronal firing in anSCN8Avariant associated with developmental delay and epilepsy

Author

Quinn, Shir, primary, Zhang, Nan, additional, Fenton, Timothy A., additional, Brusel, Marina, additional, Muruganandam, Preethi, additional, Peleg, Yoav, additional, Giladi, Moshe, additional, Haitin, Yoni, additional, Lerche, Holger, additional, Bassan, Haim, additional, Liu, Yuanyuan, additional, Ben-Shalom, Roy, additional, and Rubinstein, Moran, additional

Published
2023
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24. Differential excitatory vs inhibitory SCN expression at single cell level regulates brain sodium channel function in neurodevelopmental disorders

Author

Du, Juanjiangmeng, Simmons, Sean, Brunklaus, Andreas, Adiconis, Xian, Hession, Cynthia C., Fu, Zhanyan, Li, Yinqing, Shema, Reut, Møller, Rikke S., Barak, Boaz, Feng, Guoping, Meisler, Miriam, Sanders, Stephan, Lerche, Holger, Campbell, Arthur J., McCarroll, Steven, Levin, Joshua Z., and Lal, Dennis

Published
2020
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31. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

Author

Appenzeller, Silke, Balling, Rudi, Barisic, Nina, Baulac, Stéphanie, Caglayan, Hande, Craiu, Dana, De Jonghe, Peter, Depienne, Christel, Dimova, Petia, Djémié, Tania, Gormley, Padhraig, Guerrini, Renzo, Helbig, Ingo, Hjalgrim, Helle, Hoffman-Zacharska, Dorota, Jähn, Johanna, 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, Pendziwiat, 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 Spiczak, Sarah, Weber, Yvonne, Weckhuysen, Sarah, Zara, Federico, Abou-Khalil, Bassel, Alldredge, Brian K, Andermann, Eva, Andermann, Frederick, Amron, Dina, Bautista, Jocelyn F, Berkovic, Samuel F, Bluvstein, Judith, Boro, Alex, Cascino, Gregory, Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P, Fiol, Miguel, Fountain, Nathan B, French, Jacqueline, Friedman, Daniel, Geller, Eric B, Glauser, Tracy, Glynn, Simon, Haas, Kevin, Haut, Sheryl R, Hayward, Jean, Helmers, Sandra L, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E, Knowlton, Robert C, Kossoff, Eric H, Kuperman, Rachel, Kuzniecky, Ruben, Lowenstein, Daniel H, McGuire, Shannon M, Motika, Paul V, Novotny, Edward J, Ottman, Ruth, Paolicchi, Juliann M, Parent, Jack, Park, Kristen, Poduri, Annapurna, Sadleir, Lynette, Scheffer, Ingrid E, Shellhaas, Renée A, Sherr, Elliott, Shih, Jerry J, Singh, Rani, Sirven, Joseph, Smith, Michael C, Sullivan, Joe, and Thio, Liu Lin

Subjects
Genetics, Pediatric, Neurosciences, Epilepsy, Brain Disorders, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Cohort Studies, Dynamin I, Exome, Fatty Acid Synthase, Type I, Female, Gene Regulatory Networks, Humans, Infant, Newborn, Lennox Gastaut Syndrome, Male, Mutation, Protein Interaction Maps, Receptors, GABA-B, Ryanodine Receptor Calcium Release Channel, Spasms, Infantile, Synaptic Transmission, EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, Epi4K Consortium, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
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

32. Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

Author

Park, Joohyun, primary, Tucci, Arianna, additional, Cipriani, Valentina, additional, Demidov, German, additional, Rocca, Clarissa, additional, Senderek, Jan, additional, Butryn, Michaela, additional, Velic, Ana, additional, Lam, Tanya, additional, Galanaki, Evangelia, additional, Cali, Elisa, additional, Vestito, Letizia, additional, Maroofian, Reza, additional, Deininger, Natalie, additional, Rautenberg, Maren, additional, Admard, Jakob, additional, Hahn, Gesa-Astrid, additional, Bartels, Claudius, additional, van Os, Nienke J.H., additional, Horvath, Rita, additional, Chinnery, Patrick F., additional, Tiet, May Yung, additional, Hewamadduma, Channa, additional, Hadjivassiliou, Marios, additional, Downes, Susan M., additional, Németh, Andrea H., additional, Tofaris, George K., additional, Wood, Nicholas W., additional, Hayer, Stefanie N., additional, Bender, Friedemann, additional, Menden, Benita, additional, Cordts, Isabell, additional, Klein, Katrin, additional, Nguyen, Huu Phuc, additional, Krauss, Joachim K., additional, Blahak, Christian, additional, Strom, Tim M., additional, Sturm, Marc, additional, van de Warrenburg, Bart, additional, Lerche, Holger, additional, Maček, Boris, additional, Synofzik, Matthis, additional, Ossowski, Stephan, additional, Timmann, Dagmar, additional, Wolf, Marc E., additional, Smedley, Damian, additional, Riess, Olaf, additional, Schöls, Ludger, additional, Houlden, Henry, additional, Haack, Tobias B., additional, and Hengel, Holger, additional

Published
2023
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34. Rare coding variants in genes encoding GABAA 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-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Dennis, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, 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, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerses, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, François, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-François, Cieuta-Walti, Cécile, 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, Arfan Ikram, M, Uitterlinden, André 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, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, Sonsma, Anja C.M., Jonghe, Peter De, and Ikram, M Arfan

Published
2018
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35. Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy

Author

Bobbili, Dheeraj R., Lal, Dennis, May, Patrick, Reinthaler, Eva M., Jabbari, Kamel, Thiele, Holger, Nothnagel, Michael, Jurkowski, Wiktor, Feucht, Martha, Nürnberg, Peter, Lerche, Holger, Zimprich, Fritz, Krause, Roland, Neubauer, Bernd A., Reinthaler, Eva M., Zimprich, Fritz, Feucht, Martha, Steinböck, Hannelore, Neophytou, Birgit, Geldner, Julia, Gruber-Sedlmayr, Ursula, Haberlandt, Edda, Ronen, Gabriel M., Altmüller, Janine, Lal, Dennis, Nürnberg, Peter, Sander, Thomas, Thiele, Holger, Krause, Roland, May, Patrick, Balling, Rudi, Lerche, Holger, Neubauer, Bernd A., and EUROEPINOMICS COGIE Consortium

Published
2018
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39. Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model

Author

Auffenberg, Eva, Hedrich, Ulrike B.S., Barbieri, Raffaella, Miely, Daniela, Groschup, Bernhard, Wuttke, Thomas V., Vogel, Niklas, Luhrs, Philipp, Zanardi, Ilaria, Bertelli, Sara, Spielmann, Nadine, Gailus-Durner, Valerie, Fuchs, Helmut, de Angelis, Martin Hrabe, Pusch, Michael, Dichgans, Martin, Lerche, Holger, Gavazzo, Paola, Plesnila, Nikolaus, and Freilinger, Tobias

Subjects
Cerebral cortex -- Physiological aspects -- Health aspects, Neural oscillations -- Health aspects -- Genetic aspects, Migraine -- Models -- Genetic aspects -- Physiological aspects, Neural transmission -- Health aspects -- Genetic aspects, Health care industry
Abstract

Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated [Na.sup.+] channel [Na.sub.V]1.1 predominantly expressed in inhibitory interneurons. Homozygous [Scn1a.sup.L1649Q] knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous [Scn1a.sup.L1649Q] knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired [Na.sup.+]*-channel inactivation and increased ramp [Na.sup.+] currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using [K.sup.+]-sensitive electrodes revealed an increase in extracellular [K.sup.+] in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous [Scn1a.sup.L1649Q] knock-in mice was partially rescued by GS967, a blocker of persistent [Na.sup.+] currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD., Introduction With a prevalence of 10% to 15% in the general population, migraine is one of the most common neurological diseases (1, 2) and is rated as one of the [...]

Published
2021
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41. Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia

Author

Lyu, Hang, primary, Bosselmann, Christian M, additional, Johannesen, Katrine M, additional, Koko, Mahmoud E., additional, Ortigoza-Escobar, Juan Dario, additional, Aguilera-Albesa, Sergio, additional, Garcia-Navas Nunez, Deyanira, additional, Linnankivi, Tarja, additional, Gaily, Eija, additional, van Ruiten, Henriette JA, additional, Richardson, Ruth, additional, Betzler, Cornelia, additional, Horvath, Gabriella, additional, Brilstra, Eva, additional, Geerdink, Niels, additional, Orsucci, Daniele, additional, Tessa, Alessandra, additional, Gardella, Elena, additional, Fleszar, Zofia, additional, Schoels, Ludger, additional, Lerche, Holger, additional, Moeller, Rikke S, additional, and Liu, Yuanyuan, additional

Published
2023
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44. Bi-allelic PRRT2variants may predispose to Self-limited Familial Infantile Epilepsy

Author

Koko, Mahmoud, Elseed, Maha A., Mohammed, Inaam N., Hamed, Ahlam A., Abd Allah, Amal S. I., Yahia, Ashraf, Siddig, Rayan A., Altmüller, Janine, Toliat, Mohammad Reza, Elmahdi, Esra O., Amin, Mutaz, Ahmed, Elhami A., Eltazi, Isra Z. M., Elmugadam, Fatima A., Abdelgadir, Wasma A., Eltaraifee, Esraa, Ibrahim, Mohamed O. M., Ali, Nabila M. H., Malik, Hiba M., Babai, Arwa M., Bakhit, Yousuf H., Nürnberg, Peter, Ibrahim, Muntaser E., Salih, Mustafa A., Schubert, Julian, Elsayed, Liena E. O., and Lerche, Holger

Abstract

Heterozygous PRRT2variants are frequently implicated in Self-limited Infantile Epilepsy, whereas homozygous variants are so far linked to severe presentations including developmental and epileptic encephalopathy, movement disorders, and intellectual disability. In a study aiming to explore the genetics of epilepsy in the Sudanese population, we investigated several families including a consanguineous family with three siblings diagnosed with self-limited infantile epilepsy. We evaluated both dominant and recessive inheritance using whole exome sequencing and genomic arrays. We identified a pathogenic homozygous splice-site variant in the first intron of PRRT2[NC_000016.10(NM_145239.3):c.-65-1G > A] that segregated with the phenotype in this family. This work taps into the genetics of epilepsy in an underrepresented African population and suggests that the phenotypes of homozygous PRRT2variants may include milder epilepsy presentations without movement disorders.

Published
2024
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45. Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy

Author

Kudin, Alexei P., Baron, Gregor, Zsurka, Gábor, Hampel, Kevin G., Elger, Christian E., Grote, Alexander, Weber, Yvonne, Lerche, Holger, Thiele, Holger, Nürnberg, Peter, Schulz, Herbert, Ruppert, Ann-Kathrin, Sander, Thomas, Cheng, Qing, Arnér, Elias SJ, Schomburg, Lutz, Seeher, Sandra, Fradejas-Villar, Noelia, Schweizer, Ulrich, and Kunz, Wolfram S.

Published
2017
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47. GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response.

Author

Wilke, Carlo, Pellerin, David, Mengel, David, Traschütz, Andreas, Danzi, Matt C, Dicaire, Marie-Josée, Neumann, Manuela, Lerche, Holger, Bender, Benjamin, Houlden, Henry, group, RFC1 study, Züchner, Stephan, Schöls, Ludger, Brais, Bernard, and Synofzik, Matthis

Subjects
SPINOCEREBELLAR ataxia, PROGRESSIVE supranuclear palsy, NATURAL history, ATAXIA, PHENOTYPES
Abstract

Ataxia due to an autosomal dominant intronic GAA repeat expansion in FGF14 [GAA- FGF14 ataxia, spinocerebellar ataxia 27B (SCA27B)] has recently been identified as one of the most common genetic late-onset ataxias. We here aimed to characterize its phenotypic profile, natural history progression, and 4-aminopyridine (4-AP) treatment response. We conducted a multi-modal cohort study of 50 GAA- FGF14 patients, comprising in-depth phenotyping, cross-sectional and longitudinal progression data (up to 7 years), MRI findings, serum neurofilament light (sNfL) levels, neuropathology, and 4-AP treatment response data, including a series of n -of-1 treatment studies. GAA- FGF14 ataxia consistently presented as late-onset [60.0 years (53.5–68.5), median (interquartile range)] pancerebellar syndrome, partly combined with afferent sensory deficits (55%) and dysautonomia (28%). Dysautonomia increased with duration while cognitive impairment remained infrequent, even in advanced stages. Cross-sectional and longitudinal assessments consistently indicated mild progression of ataxia [0.29 Scale for the Assessment and Rating of Ataxia (SARA) points/year], not exceeding a moderate disease severity even in advanced stages (maximum SARA score: 18 points). Functional impairment increased relatively slowly (unilateral mobility aids after 8 years in 50% of patients). Corresponding to slow progression and low extra-cerebellar involvement, sNfL was not increased relative to controls. Concurrent second diseases (including progressive supranuclear palsy neuropathology) represented major individual aggravators of disease severity, constituting important caveats for planning future GAA- FGF14 trials. A treatment response to 4-AP with relevance for everyday living was reported by 86% of treated patients. A series of three prospective n -of-1 treatment experiences with on/off design showed marked reduction in daily symptomatic time and symptom severity on 4-AP. Our study characterizes the phenotypic profile, natural history progression, and 4-AP treatment response of GAA- FGF14 ataxia. It paves the way towards large-scale natural history studies and 4-AP treatment trials in this newly discovered, possibly most frequent, and treatable late-onset ataxia. [ABSTRACT FROM AUTHOR]

Published
2023
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49. Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Author

Yaldiz, Burcu, Kucuk, Erdi, Hampstead, Juliet, Hofste, Tom, Pfundt, Rolph, Corominas Galbany, Jordi, Rinne, Tuula, Yntema, Helger G., Hoischen, Alexander, Nelen, Marcel, Gilissen, Christian, consortium, Solve-R. D., Riess, Olaf, Haack, Tobias B., Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, Hoen, Peter A. C. T, Vissers, Lisenka E. L. M., Steyaert, Wouter, Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, te Paske, Iris, Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Kleefstra, Tjitske, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Töpf, Ana, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Matalonga, Leslie, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Vandrovcova, Jana, Efthymiou, Stephanie, Morsy, Heba, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Abbott, Kristin M., Frederikse, Wilhemina Skerstjens, Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Verloes, Alain, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, de Sainte Agathe, Jean-Madeleine, Rooryck, Caroline, Lacombe, Didier, Trimouille, Aurelien, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Balicza, Peter, Molnar, Maria Judit, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Osorio, Andrés Nascimento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Beeson, David, Cossins, Judith, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Horvath, Rita, Chinnery, Patrick F., Ratnaike, Thiloka, Gao, Fei, Schon, Katherine, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Başak, Ayşe Nazlı, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Claeys, Kristl, Santen, Gijs W. E., Bijlsma, Emilia K., Hoffer, Mariette J. V., Ruivenkamp, Claudia A. L., Boztug, Kaan, Haimel, Matthias, Maystadt, Isabelle, Cordts, Isabelle, Deschauer, Marcus, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Depienne, Christel, Roos, Andreas, May, Patrick, and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Multidisciplinary, general & others [D99] [Human health sciences]
Abstract

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques.

Published
2023

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