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2. Somatic variant analysis of resected brain tissue in epilepsy surgery patients.

Author

Sanders, Maurits W. C. B., Koeleman, Bobby P. C., Brilstra, Eva H., Jansen, Floor E., Baldassari, Sara, Chipaux, Mathilde, Sim, Nam Suk, Ko, Ara, Kang, Hoon‐Chul, Blümcke, Ingmar, Lal, Dennis, Baulac, Stéphanie, Lee, Jeong Ho, Aronica, Eleonora, and Braun, Kees P. J.

Subjects
*FOCAL cortical dysplasia, *EPILEPSY surgery, *GENETIC variation, *PARTIAL epilepsy, *PEOPLE with epilepsy
Abstract

We studied the distribution of germline and somatic variants in epilepsy surgery patients with (suspected) malformations of cortical development (MCD) who underwent surgery between 2015 and 2020 at University Medical Center Utrecht (the Netherlands) and pooled our data with four previously published cohort studies. Tissue analysis yielded a pathogenic variant in 203 of 663 (31%) combined cases. In 126 of 379 (33%) focal cortical dysplasia (FCD) type II cases and 23 of 37 (62%) hemimegalencephaly cases, a pathogenic variant was identified, mostly involving the mTOR signaling pathway. Pathogenic variants in 10 focal epilepsy genes were found in 48 of 178 (27%) FCDI/mild MCD/mMCD with oligodendroglial hyperplasia and epilepsy cases; 36 of these (75%) were SLC35A2 variants. Six of 69 (9%) patients without a histopathological lesion had a pathogenic variant in SLC35A2 (n = 5) or DEPDC5 (n = 1). A germline variant in blood DNA was confirmed in all cases with a pathogenic variant in tissue, with a variant allele frequency (VAF) of ~50%. In seven of 114 patients (6%) with a somatic variant in tissue, mosaicism in blood was detected. More than half of pathogenic somatic variants had a VAF < 5%. Further analysis of the correlation between genetic variants and surgical outcomes will improve patient counseling and may guide postoperative treatment decisions. [ABSTRACT FROM AUTHOR]

Published
2024
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3. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Author

Stamberger, Hannah, Hammer, Trine B., Gardella, Elena, Vlaskamp, Danique R. M., Bertelsen, Birgitte, Mandelstam, Simone, de Lange, Iris, Zhang, Jing, Myers, Candace T., Fenger, Christina, Afawi, Zaid, Almanza Fuerte, Edith P., Andrade, Danielle M., Balcik, Yunus, Ben Zeev, Bruria, Bennett, Mark F., Berkovic, Samuel F., Isidor, Bertrand, Bouman, Arjan, Brilstra, Eva, Busk, Øyvind L., Cairns, Anita, Caumes, Roseline, Chatron, Nicolas, Dale, Russell C., de Geus, Christa, Edery, Patrick, Gill, Deepak, Granild-Jensen, Jacob Bie, Gunderson, Lauren, Gunning, Boudewijn, Heimer, Gali, Helle, Johan R., Hildebrand, Michael S., Hollingsworth, Georgie, Kharytonov, Volodymyr, Klee, Eric W., Koeleman, Bobby P. C., Koolen, David A., Korff, Christian, Küry, Sébastien, Lesca, Gaetan, Lev, Dorit, Leventer, Richard J., Mackay, Mark T., Macke, Erica L., McEntagart, Meriel, Mohammad, Shekeeb S., Monin, Pauline, Montomoli, Martino, Morava, Eva, Moutton, Sebastien, Muir, Alison M., Parrini, Elena, Procopis, Peter, Ranza, Emmanuelle, Reed, Laura, Reif, Philipp S., Rosenow, Felix, Rossi, Massimiliano, Sadleir, Lynette G., Sadoway, Tara, Schelhaas, Helenius J., Schneider, Amy L., Shah, Krati, Shalev, Ruth, Sisodiya, Sanjay M., Smol, Thomas, Stumpel, Connie T. R. M., Stuurman, Kyra, Symonds, Joseph D., Mau-Them, Frederic Tran, Verbeek, Nienke, Verhoeven, Judith S., Wallace, Geoffrey, Yosovich, Keren, Zarate, Yuri A., Zerem, Ayelet, Zuberi, Sameer M., Guerrini, Renzo, Mefford, Heather C., Patel, Chirag, Zhang, Yue-Hua, Møller, Rikke S., and Scheffer, Ingrid E.

Published
2021
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4. De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy

Author

Singh, Sakshi, Gupta, Aditi, Zech, Michael, Sigafoos, Ashley N., Clark, Karl J., Dincer, Yasemin, Wagner, Matias, Humberson, Jennifer B., Green, Sarah, van Gassen, Koen, Brandt, Tracy, Schnur, Rhonda E., Millan, Francisca, Si, Yue, Mall, Volker, Winkelmann, Juliane, Gavrilova, Ralitza H., Klee, Eric W., Engleman, Kendra, Safina, Nicole P., Slaugh, Rachel, Bryant, Emily M., Tan, Wen-Hann, Granadillo, Jorge, Misra, Sunita N., Schaefer, G. Bradley, Towner, Shelley, Brilstra, Eva H., and Koeleman, Bobby P. C.

Published
2020
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6. Identification of candidate genes for developmental colour agnosia in a single unique family

Author

Nijboer, Tanja C. W., primary, Hessel, Ellen V. S., additional, van Haaften, Gijs W., additional, van Zandvoort, Martine J., additional, van der Spek, Peter J., additional, Troelstra, Christine, additional, de Kovel, Carolien G. F., additional, Koeleman, Bobby P. C., additional, van der Zwaag, Bert, additional, Brilstra, Eva H., additional, and Burbach, J. Peter H., additional

Published
2023
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7. 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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8. De novo variants in neurodevelopmental disorders with epilepsy

Author

Heyne, Henrike O., Singh, Tarjinder, Stamberger, Hannah, Abou Jamra, Rami, Caglayan, Hande, Craiu, Dana, De Jonghe, Peter, Guerrini, Renzo, Helbig, Katherine L., Koeleman, Bobby P. C., Kosmicki, Jack A., Linnankivi, Tarja, May, Patrick, Muhle, Hiltrud, Møller, Rikke S., Neubauer, Bernd A., Palotie, Aarno, Pendziwiat, Manuela, Striano, Pasquale, Tang, Sha, Wu, Sitao, EuroEPINOMICS RES Consortium, Poduri, Annapurna, Weber, Yvonne G., Weckhuysen, Sarah, Sisodiya, Sanjay M., Daly, Mark J., Helbig, Ingo, Lal, Dennis, and Lemke, Johannes R.

Published
2018
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9. Abnormal islet sphingolipid metabolism in type 1 diabetes

Author

Holm, Laurits J., Krogvold, Lars, Hasselby, Jane P., Kaur, Simranjeet, Claessens, Laura A., Russell, Mark A., Mathews, Clayton E., Hanssen, Kristian F., Morgan, Noel G., Koeleman, Bobby P. C., Roep, Bart O., Gerling, Ivan C., Pociot, Flemming, Dahl-Jørgensen, Knut, and Buschard, Karsten

Published
2018
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10. Identification of candidate genes for developmental colour agnosia in a single unique family

Author

Revalidatiegeneeskunde Onderzoek, Brain, Genetica Sectie Research, Cancer, Child Health, Neuropsychologie, Genetica Groep Koeleman, Circulatory Health, Genetica Sectie Genoomdiagnostiek, Genetica Klinische Genetica, TN groep Hol, Nijboer, Tanja C W, Hessel, Ellen V S, van Haaften, Gijs W, van Zandvoort, Martine J, van der Spek, Peter J, Troelstra, Christine, de Kovel, Carolien G F, Koeleman, Bobby P C, van der Zwaag, Bert, Brilstra, Eva H, Burbach, J Peter H, Revalidatiegeneeskunde Onderzoek, Brain, Genetica Sectie Research, Cancer, Child Health, Neuropsychologie, Genetica Groep Koeleman, Circulatory Health, Genetica Sectie Genoomdiagnostiek, Genetica Klinische Genetica, TN groep Hol, Nijboer, Tanja C W, Hessel, Ellen V S, van Haaften, Gijs W, van Zandvoort, Martine J, van der Spek, Peter J, Troelstra, Christine, de Kovel, Carolien G F, Koeleman, Bobby P C, van der Zwaag, Bert, Brilstra, Eva H, and Burbach, J Peter H

Published
2023

11. Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.

Author

Custodio, Helena Martins, Clayton, Lisa M, Bellampalli, Ravishankara, Pagni, Susanna, Silvennoinen, Katri, Caswell, Richard, Consortium, Genomics England Research, Brunklaus, Andreas, Guerrini, Renzo, Koeleman, Bobby P C, Lemke, Johannes R, Møller, Rikke S, Scheffer, Ingrid E, Weckhuysen, Sarah, Zara, Federico, Zuberi, Sameer, Kuchenbaecker, Karoline, Balestrini, Simona, Mills, James D, and Sisodiya, Sanjay M

Subjects
EPILEPSY, FOCAL cortical dysplasia, DISEASE risk factors, MONOGENIC & polygenic inheritance (Genetics), PHENOTYPES, EARLY death
Abstract

Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A -related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. The polygenic risk score for intelligence was lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors. [ABSTRACT FROM AUTHOR]

Published
2023
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12. Genome-wide copy number variant screening of Saudi schizophrenia patients reveals larger deletions in cases versus controls

Author

Abumadini, Mahdi S., primary, Al Ghamdi, Kholoud S., additional, Alqahtani, Abdullah H., additional, Almedallah, Dana K., additional, Callans, Lauren, additional, Jarad, Jumanah A., additional, Cyrus, Cyril, additional, Koeleman, Bobby P. C., additional, Keating, Brendan J., additional, Pankratz, Nathan, additional, and Al-Ali, Amein K., additional

Published
2023
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13. Mosaicism of de novo pathogenic SCN1A variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes

Author

de Lange, Iris M., Koudijs, Marco J., van ʼt Slot, Ruben, Gunning, Boudewijn, Sonsma, Anja C. M., van Gemert, Lisette J. J. M., Mulder, Flip, Carbo, Ellen C., van Kempen, Marjan J. A., Verbeek, Nienke E., Nijman, Isaac J., Ernst, Robert F., Savelberg, Sanne M. C., Knoers, Nine V. A. M., Brilstra, Eva H., and Koeleman, Bobby P. C.

Published
2018
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16. Individualised prediction of drug resistance and seizure recurrence after medication withdrawal in people with juvenile myoclonic epilepsy: A systematic review and individual participant data meta-analysis

Author

Stevelink, Remi, Al-Toma, Dania, Jansen, Floor E., Lamberink, Herm J., Asadi-Pooya, Ali A., Farazdaghi, Mohsen, Cação, Gonçalo, Jayalakshmi, Sita, Patil, Anuja, Özkara, Çiğdem, Aydın, Şenay, Gesche, Joanna, Beier, Christoph P., Stephen, Linda J., Brodie, Martin J., Unnithan, Gopeekrishnan, Radhakrishnan, Ashalatha, Höfler, Julia, Trinka, Eugen, Krause, Roland, Irelli, Emanuele Cerulli, Bonaventura, Carlo Di, Szaflarski, Jerzy P., Hernández-Vanegas, Laura E., Moya-Alfaro, Monica L., Zhang, Yingying, Zhou, Dong, Pietrafusa, Nicola, Specchio, Nicola, Japaridze, Giorgi, Beniczky, Sándor, Janmohamed, Mubeen, Kwan, Patrick, Syvertsen, Marte, Selmer, Kaja K., Vorderwülbecke, Bernd J., Holtkamp, Martin, Viswanathan, Lakshminarayanapuram G., Sinha, Sanjib, Baykan, Betül, Altindag, Ebru, Podewils, Felix Von, Schulz, Juliane, Seneviratne, Udaya, Viloria-Alebesque, Alejandro, Karakis, Ioannis, D'Souza, Wendyl J., Sander, Josemir W., Koeleman, Bobby P. C., Otte, Willem M., Braun, Kees P. J., Stevelink, Remi, Al-Toma, Dania, Jansen, Floor E., Lamberink, Herm J., Asadi-Pooya, Ali A., Farazdaghi, Mohsen, Cação, Gonçalo, Jayalakshmi, Sita, Patil, Anuja, Özkara, Çiğdem, Aydın, Şenay, Gesche, Joanna, Beier, Christoph P., Stephen, Linda J., Brodie, Martin J., Unnithan, Gopeekrishnan, Radhakrishnan, Ashalatha, Höfler, Julia, Trinka, Eugen, Krause, Roland, Irelli, Emanuele Cerulli, Bonaventura, Carlo Di, Szaflarski, Jerzy P., Hernández-Vanegas, Laura E., Moya-Alfaro, Monica L., Zhang, Yingying, Zhou, Dong, Pietrafusa, Nicola, Specchio, Nicola, Japaridze, Giorgi, Beniczky, Sándor, Janmohamed, Mubeen, Kwan, Patrick, Syvertsen, Marte, Selmer, Kaja K., Vorderwülbecke, Bernd J., Holtkamp, Martin, Viswanathan, Lakshminarayanapuram G., Sinha, Sanjib, Baykan, Betül, Altindag, Ebru, Podewils, Felix Von, Schulz, Juliane, Seneviratne, Udaya, Viloria-Alebesque, Alejandro, Karakis, Ioannis, D'Souza, Wendyl J., Sander, Josemir W., Koeleman, Bobby P. C., Otte, Willem M., and Braun, Kees P. J.

Abstract

Summary Background A third of people with juvenile myoclonic epilepsy (JME) are drug-resistant. Three-quarters have a seizure relapse when attempting to withdraw anti-seizure medication (ASM) after achieving seizure-freedom. It is currently impossible to predict who is likely to become drug-resistant and safely withdraw treatment. We aimed to identify predictors of drug resistance and seizure recurrence to allow for individualised prediction of treatment outcomes in people with JME. Methods We performed an individual participant data (IPD) meta-analysis based on a systematic search in EMBASE and PubMed – last updated on March 11, 2021 – including prospective and retrospective observational studies reporting on treatment outcomes of people diagnosed with JME and available seizure outcome data after a minimum one-year follow-up. We invited authors to share standardised IPD to identify predictors of drug resistance using multivariable logistic regression. We excluded pseudo-resistant individuals. A subset who attempted to withdraw ASM was included in a multivariable proportional hazards analysis on seizure recurrence after ASM withdrawal. The study was registered at the Open Science Framework (OSF; https://osf.io/b9zjc/). Findings 368) was predicted by an earlier age at the start of withdrawal, shorter seizure-free interval and more currently used ASMs, resulting in an average internal-external cross-validation concordance-statistic of 0·70 (95%CI 0·68–0·73). Interpretation We were able to predict and validate clinically relevant personalised treatment outcomes for people with JME. Individualised predictions are accessible as nomograms and web-based tools. Funding MING fonds.

Published
2022

17. Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes

Author

de Kovel, Carolien G. F., Syrbe, Steffen, Brilstra, Eva H., Verbeek, Nienke, Kerr, Bronwyn, Dubbs, Holly, Bayat, Allan, Desai, Sonal, Naidu, Sakkubai, Srivastava, Siddharth, Cagaylan, Hande, Yis, Uluc, Saunders, Carol, Rook, Martin, Plugge, Susanna, Muhle, Hiltrud, Afawi, Zaid, Klein, Karl-Martin, Jayaraman, Vijayakumar, Rajagopalan, Ramakrishnan, Goldberg, Ethan, Marsh, Eric, Kessler, Sudha, Bergqvist, Christina, Conlin, Laura K., Krok, Bryan L., Thiffault, Isabelle, Pendziwiat, Manuela, Helbig, Ingo, Polster, Tilman, Borggraefe, Ingo, Lemke, Johannes R., van den Boogaardt, Marie-José, Møller, Rikke S., and Koeleman, Bobby P. C.

Published
2017
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18. Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

Author

Androsova, Ganna, Krause, Roland, Borghei, Mojgansadat, Wassenaar, Merel, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Berghuis, Bianca, Campbell, Ellen, Coppola, Antonietta, Francis, Ben, Wolking, Stefan, Cavalleri, Gianpiero L., Craig, John, Delanty, Norman, Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Sisodiya, Sanjay M., Depondt, Chantal, Brodie, Martin J., Chinthapalli, Krishna, de Haan, Gerrit‐Jan, Doherty, Colin, Gudmundsson, Lárus J., Heavin, Sinead, Ingason, Andres, Johnson, Michael, Kennedy, Clare, Krenn, Martin, McCormack, Mark, OʼBrien, Terence J., Pandolfo, Massimo, Pataraia, Ekaterina, Petrovski, Slave, Rau, Sarah, Sargsyan, Narek, Slattery, Lisa, Stefánsson, Kári, Stern, William, Tostevin, Anna, Willis, Joseph, and Zimprich, Fritz

Published
2017
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19. Distinct genetic basis of common epilepsies and structural magnetic resonance imaging measures.

Author

Stevelink, Remi, Koeleman, Bobby P. C., and Sisodiya, Sanjay M.

Subjects
*EPILEPSY, *MAGNETIC resonance imaging, *GENOME-wide association studies, *GENETIC correlations, *PARTIAL epilepsy, *GRAY matter (Nerve tissue), *WHITE matter (Nerve tissue)
Abstract

Focal and generalized epilepsies are associated with robust differences in magnetic resonance imaging (MRI) measures of subcortical structures, gray matter, and white matter. However, it is unknown whether such structural brain differences reflect the cause or consequence of epilepsy or its treatment. Analyses of common genetic variants underlying both common epilepsy risk and variability in structural brain measures can give further insights, as such inherited variants are not influenced by disease or treatment. Here, we performed genetic correlation analyses using data from the largest genome‐wide association study (GWAS) on common epilepsy (n = 27 559 cases and 42 436 controls) and GWASs on MRI measures of white (n = 33 292) or gray matter (n = 51 665). We did not detect any significant genetic correlation between any type of common epilepsy and any of 280 measures of gray matter, white matter, or subcortical structures. These results suggest that there are distinct genetic bases underlying risk of common epilepsy and for structural brain measures. This would imply that the genetic basis of normal structural brain variation is unrelated to that of common epilepsy. Structural changes in epilepsy could rather be the consequence of epilepsy, its comorbidities, or its treatment, offering a cumulative record of disease. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications

Author

Wolking, Stefan, Campbell, Ciarán, Stapleton, Caragh, McCormack, Mark, Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Sisodiya, Sanjay M., Cavalleri, Gianpiero L., Lerche, Holger, and Epipgx Consortium

Subjects
Neurologie [D14] [Sciences de la santé humaine], Neurology [D14] [Human health sciences], respiratory system, musculoskeletal system, respiratory tract diseases
Abstract

Objective: Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation.Methods: A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance.Results: We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs.Significance: This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.

Published
2021

23. CHD2 variants are a risk factor for photosensitivity in epilepsy

Author

Galizia, Elizabeth C., Myers, Candace T., Leu, Costin, de Kovel, Carolien G. F., Afrikanova, Tatiana, Cordero-Maldonado, Maria Lorena, Martins, Teresa G., Jacmin, Maxime, Drury, Suzanne, Krishna Chinthapalli, V., Muhle, Hiltrud, Pendziwiat, Manuela, Sander, Thomas, Ruppert, Ann-Kathrin, Møller, Rikke S., Thiele, Holger, Krause, Roland, Schubert, Julian, Lehesjoki, Anna-Elina, Nürnberg, Peter, Lerche, Holger, Palotie, Aarno, Coppola, Antonietta, Striano, Salvatore, Gaudio, Luigi Del, Boustred, Christopher, Schneider, Amy L., Lench, Nicholas, Jocic-Jakubi, Bosanka, Covanis, Athanasios, Capovilla, Giuseppe, Veggiotti, Pierangelo, Piccioli, Marta, Parisi, Pasquale, Cantonetti, Laura, Sadleir, Lynette G., Mullen, Saul A., Berkovic, Samuel F., Stephani, Ulrich, Helbig, Ingo, Crawford, Alexander D., Esguerra, Camila V., Kasteleijn-Nolst Trenité, Dorothee G. A., Koeleman, Bobby P. C., Mefford, Heather C., Scheffer, Ingrid E., and Sisodiya, Sanjay M.

Published
2015
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25. 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, Rodrigues Baldez, Roiza A., Devinsky, Orrin, Braun, Kees P. J., Jansen, Floor E., Smit, Dirk J. A., Koeleman, Bobby P. C., International League Against Epilepsy Consortium On ComplexEpilepsies, Epi25 Collaborative, May, Patrick, Krause, Roland, Stevelink, Remi, Luykx, Jurjen J., Lin, Bochao D., Leu, Costin, Lal, Dennis, Smith, Alexander W., Schijven, Dick, Carpay, Johannes A., Rademaker, Koen, Rodrigues Baldez, Roiza A., Devinsky, Orrin, Braun, Kees P. J., Jansen, Floor E., Smit, Dirk J. A., Koeleman, Bobby P. C., International League Against Epilepsy Consortium On ComplexEpilepsies, Epi25 Collaborative, May, Patrick, and Krause, Roland

Abstract

Objective Paroxysmal 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. Methods Confounding 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. Results Our 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. Significance Our 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

26. Climate change and epilepsy: Insights from clinical and basic science studies

Author

Gulcebi, Medine I., Bartolini, Emanuele, Lee, Omay, Lisgaras, Christos Panagiotis, Onat, Filiz, Mifsud, Janet, Striano, Pasquale, Vezzani, Annamaria, Hildebrand, Michael S., Jimenez-Jimenez, Diego, Junck, Larry, Lewis-Smith, David, Scheffer, Ingrid E., Thijs, Roland D., Zuberi, Sameer M., Blenkinsop, Stephen, Fowler, Hayley J., Foley, Aideen, Balestrini, Simona, Berkovic, Samuel, Cavalleri, Gianpiero, Correa, Daniel José, Custodio, Helena Martins, Galovic, Marian, Guerrini, Renzo, Henshall, David, Howard, Olga, Hughes, Kelvin, Katsarou, Anna, Koeleman, Bobby P. C., Krause, Roland, Lowenstein, Daniel, Mandelenaki, Despoina, Marini, Carla, O'Brien, Terence J., Pace, Adrian, Palma, Luca De, Perucca, Piero, Pitkänen, Asla, Quinn, Finola, Selmer, Kaja Kristine, Steward, Charles A., Swanborough, Nicola, Thijs, Roland, Tittensor, Phil, Trivisano, Marina, Weckhuysen, Sarah, Zara, Federico, Sisodiya, Sanjay M., Gulcebi, Medine I., Bartolini, Emanuele, Lee, Omay, Lisgaras, Christos Panagiotis, Onat, Filiz, Mifsud, Janet, Striano, Pasquale, Vezzani, Annamaria, Hildebrand, Michael S., Jimenez-Jimenez, Diego, Junck, Larry, Lewis-Smith, David, Scheffer, Ingrid E., Thijs, Roland D., Zuberi, Sameer M., Blenkinsop, Stephen, Fowler, Hayley J., Foley, Aideen, Balestrini, Simona, Berkovic, Samuel, Cavalleri, Gianpiero, Correa, Daniel José, Custodio, Helena Martins, Galovic, Marian, Guerrini, Renzo, Henshall, David, Howard, Olga, Hughes, Kelvin, Katsarou, Anna, Koeleman, Bobby P. C., Krause, Roland, Lowenstein, Daniel, Mandelenaki, Despoina, Marini, Carla, O'Brien, Terence J., Pace, Adrian, Palma, Luca De, Perucca, Piero, Pitkänen, Asla, Quinn, Finola, Selmer, Kaja Kristine, Steward, Charles A., Swanborough, Nicola, Thijs, Roland, Tittensor, Phil, Trivisano, Marina, Weckhuysen, Sarah, Zara, Federico, and Sisodiya, Sanjay M.

Abstract

Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, compl

Published
2021

27. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Author

Wolking, Stefan, Moreau, Claudia, McCormack, Mark, Krause, Roland, Krenn, Martin, Consortium, Epipgx, Berkovic, Samuel, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Petrovski, Slave, Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Sisodiya, Sanjay M., Girard, Simon L., Cossette, Patrick, Wolking, Stefan, Moreau, Claudia, McCormack, Mark, Krause, Roland, Krenn, Martin, Consortium, Epipgx, Berkovic, Samuel, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Petrovski, Slave, Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Sisodiya, Sanjay M., Girard, Simon L., and Cossette, Patrick

Abstract

Objective Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE. Interpretation Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings.

Published
2021

30. Additional file 1 of Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Author

Lal, Dennis, May, Patrick, Perez-Palma, Eduardo, Samocha, Kaitlin E., Kosmicki, Jack A., Robinson, Elise B., Møller, Rikke S., Krause, Roland, Nürnberg, Peter, Weckhuysen, Sarah, Jonghe, Peter De, Guerrini, Renzo, Niestroj, Lisa M., Du, Juliana, Marini, Carla, Ware, James S., Kurki, Mitja, Padhraig Gormley, Tang, Sha, Sitao Wu, Biskup, Saskia, Annapurna Poduri, Neubauer, Bernd A., Koeleman, Bobby P. C., Helbig, Katherine L., Weber, Yvonne G., Helbig, Ingo, Majithia, Amit R., Palotie, Aarno, and Daly, Mark J.

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ComputingMilieux_COMPUTERSANDEDUCATION, Data_FILES, ComputerApplications_COMPUTERSINOTHERSYSTEMS
Abstract

Additional file 1: Supplementary methods, figures, and table.

Published
2020
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31. Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study

Author

Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Moller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, Lerche, Holger, Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Moller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, and Lerche, Holger

Abstract

Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE - responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10(-5)) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.

Published
2020

32. Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Author

Lal, Dennis, May, Patrick, Perez-Palma, Eduardo, Samocha, Kaitlin E., Kosmicki, Jack A., Robinson, Elise B., Moller, Rikke S., Krause, Roland, Nuernberg, Peter, Weckhuysen, Sarah, De Jonghe, Peter, Guerrini, Renzo, Niestroj, Lisa M., Du, Juliana, Marini, Carla, Ware, James S., Kurki, Mitja, Gormley, Padhraig, Tang, Sha, Wu, Sitao, Biskup, Saskia, Poduri, Annapurna, Neubauer, Bernd A., Koeleman, Bobby P. C., Helbig, Katherine L., Weber, Yvonne G., Helbig, Ingo, Majithia, Amit R., Palotie, Aarno, Daly, Mark J., Lal, Dennis, May, Patrick, Perez-Palma, Eduardo, Samocha, Kaitlin E., Kosmicki, Jack A., Robinson, Elise B., Moller, Rikke S., Krause, Roland, Nuernberg, Peter, Weckhuysen, Sarah, De Jonghe, Peter, Guerrini, Renzo, Niestroj, Lisa M., Du, Juliana, Marini, Carla, Ware, James S., Kurki, Mitja, Gormley, Padhraig, Tang, Sha, Wu, Sitao, Biskup, Saskia, Poduri, Annapurna, Neubauer, Bernd A., Koeleman, Bobby P. C., Helbig, Katherine L., Weber, Yvonne G., Helbig, Ingo, Majithia, Amit R., Palotie, Aarno, and Daly, Mark J.

Abstract

Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.

Published
2020

33. Testing association of rare genetic variants with resistance to three common antiseizure medications

Author

European Commission - EC [sponsor], Wolking, Stefan, Moreau, Claudia, Nies, Anne T., Schaeffeler, Elke, McCormack, Mark, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weber, Yvonne G., Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Schwab, Matthias, Krause, Roland, Sisodiya, Sanjay M., Cossette, Patrick, Girard, Simon L., Lerche, Holger, EpiPGX Consortium, European Commission - EC [sponsor], Wolking, Stefan, Moreau, Claudia, Nies, Anne T., Schaeffeler, Elke, McCormack, Mark, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weber, Yvonne G., Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Schwab, Matthias, Krause, Roland, Sisodiya, Sanjay M., Cossette, Patrick, Girard, Simon L., Lerche, Holger, and EpiPGX Consortium

Abstract

Objective Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). Methods A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set–based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. Results We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. Significance In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.

Published
2020

34. Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study

Author

EpiPGx Consortium, Wolking, Stefan, Schulz, Herbert, Nies, Anne T, McCormack, Mark, Schäffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl Martin, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico J., Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay M., Schwab, Matthias, Sander, Thomas, Lerche, Holger, EpiPGx Consortium, Wolking, Stefan, Schulz, Herbert, Nies, Anne T, McCormack, Mark, Schäffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl Martin, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico J., Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay M., Schwab, Matthias, Sander, Thomas, and Lerche, Holger

Abstract

Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.

Published
2020

35. Modifier genes in SCN1A-related epilepsy syndromes

Author

Genetica Klinische Genetica, Child Health, CMM USEQ Facility, Genetica, Genetica Oper. Mangt Genoom Diagnostiek, Brain, Cancer, CMM Groep Cuppen, Genetica Groep Koeleman, Circulatory Health, de Lange, Iris M, Mulder, Flip, van 't Slot, Ruben, Sonsma, Anja C M, van Kempen, Marjan J A, Nijman, Isaac J, Ernst, Robert F, Knoers, Nine V A M, Brilstra, Eva H, Koeleman, Bobby P C, Genetica Klinische Genetica, Child Health, CMM USEQ Facility, Genetica, Genetica Oper. Mangt Genoom Diagnostiek, Brain, Cancer, CMM Groep Cuppen, Genetica Groep Koeleman, Circulatory Health, de Lange, Iris M, Mulder, Flip, van 't Slot, Ruben, Sonsma, Anja C M, van Kempen, Marjan J A, Nijman, Isaac J, Ernst, Robert F, Knoers, Nine V A M, Brilstra, Eva H, and Koeleman, Bobby P C

Published
2020

36. De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy

Author

Genetica Groep Koeleman, Circulatory Health, Cancer, Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Klinische Genetica, Brain, Singh, Sakshi, Gupta, Aditi, Zech, Michael, Sigafoos, Ashley N, Clark, Karl J, Dincer, Yasemin, Wagner, Matias, Humberson, Jennifer B, Green, Sarah, van Gassen, Koen, Brandt, Tracy, Schnur, Rhonda E, Millan, Francisca, Si, Yue, Mall, Volker, Winkelmann, Juliane, Gavrilova, Ralitza H, Klee, Eric W, Engleman, Kendra, Safina, Nicole P, Slaugh, Rachel, Bryant, Emily M, Tan, Wen-Hann, Granadillo, Jorge, Misra, Sunita N, Schaefer, G Bradley, Towner, Shelley, Brilstra, Eva H, Koeleman, Bobby P C, Genetica Groep Koeleman, Circulatory Health, Cancer, Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Klinische Genetica, Brain, Singh, Sakshi, Gupta, Aditi, Zech, Michael, Sigafoos, Ashley N, Clark, Karl J, Dincer, Yasemin, Wagner, Matias, Humberson, Jennifer B, Green, Sarah, van Gassen, Koen, Brandt, Tracy, Schnur, Rhonda E, Millan, Francisca, Si, Yue, Mall, Volker, Winkelmann, Juliane, Gavrilova, Ralitza H, Klee, Eric W, Engleman, Kendra, Safina, Nicole P, Slaugh, Rachel, Bryant, Emily M, Tan, Wen-Hann, Granadillo, Jorge, Misra, Sunita N, Schaefer, G Bradley, Towner, Shelley, Brilstra, Eva H, and Koeleman, Bobby P C

Published
2020

37. Genomic and clinical predictors of lacosamide response in refractory epilepsies

Author

Heavin, Sinéad B., McCormack, Mark, Wolking, Stefan, Slattery, Lisa, Walley, Nicole, Avbersek, Andreja, Novy, Jan, Sinha, Saurabh R., Radtke, Rod, Doherty, Colin, Auce, Pauls, Craig, John, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., O'Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Stefansson, Hreinn, Striano, Pasquale, Zara, Federico, EPIGEN Consortium, EpiPGX Consortium, Depondt, Chantal, Sisodiya, Sanjay, Goldstein, David, Lerche, Holger, Cavalleri, Gianpiero L., Delanty, Norman, EPIGEN Consortium, EpiPGX Consortium, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, and Medical Research Council (MRC)

Subjects
Oncology, medicine.medical_specialty, Candidate gene, lacosamide, Lacosamide, Neurology [D14] [Human health sciences], Clinical Neurology, Genome-wide association study, lcsh:RC346-429, 03 medical and health sciences, 0302 clinical medicine, Refractory, Internal medicine, Medicine, GWAS, EpiPGX Consortium, Exome, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, Genetic association, pharmacogenomics, 0303 health sciences, Neurologie [D14] [Sciences de la santé humaine], business.industry, EPIGEN Consortium, Généralités, pharmacoresistance, refractory, 3. Good health, Neurology, Pharmacogenomics, Cohort, Full‐length Original Research, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Objective: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting. Methods: We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes. Results: Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

41. Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Author

Kasperavičiūtė, Dalia, Catarino, Claudia B., Matarin, Mar, Leu, Costin, Novy, Jan, Tostevin, Anna, Leal, Bárbara, Hessel, Ellen V. S., Hallmann, Kerstin, Hildebrand, Michael S., Dahl, Hans-Henrik M., Ryten, Mina, Trabzuni, Daniah, Ramasamy, Adaikalavan, Alhusaini, Saud, Doherty, Colin P., Dorn, Thomas, Hansen, Jörg, Krämer, Günter, Steinhoff, Bernhard J., Zumsteg, Dominik, Duncan, Susan, Kälviäinen, Reetta K., Eriksson, Kai J., Kantanen, Anne-Mari, Pandolfo, Massimo, Gruber-Sedlmayr, Ursula, Schlachter, Kurt, Reinthaler, Eva M., Stogmann, Elisabeth, Zimprich, Fritz, Théâtre, Emilie, Smith, Colin, O’Brien, Terence J., Meng Tan, K., Petrovski, Slave, Robbiano, Angela, Paravidino, Roberta, Zara, Federico, Striano, Pasquale, Sperling, Michael R., Buono, Russell J., Hakonarson, Hakon, Chaves, João, Costa, Paulo P., Silva, Berta M., da Silva, António M., de Graan, Pierre N. E., Koeleman, Bobby P. C., Becker, Albert, Schoch, Susanne, von Lehe, Marec, Reif, Philipp S., Rosenow, Felix, Becker, Felicitas, Weber, Yvonne, Lerche, Holger, Rössler, Karl, Buchfelder, Michael, Hamer, Hajo M., Kobow, Katja, Coras, Roland, Blumcke, Ingmar, Scheffer, Ingrid E., Berkovic, Samuel F., Weale, Michael E., Delanty, Norman, Depondt, Chantal, Cavalleri, Gianpiero L., Kunz, Wolfram S., and Sisodiya, Sanjay M.

Published
2013
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42. Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy

Author

Lal, Dennis, Trucks, Holger, Mller, Rikke S., Hjalgrim, Helle, Koeleman, Bobby P. C., de Kovel, Carolien G. F., Visscher, Frank, Weber, Yvonne G., Lerche, Holger, Becker, Felicitas, Schankin, Christoph J., Neubauer, Bernd A., Surges, Rainer, Kunz, Wolfram S., Zimprich, Fritz, Franke, Andre, Illig, Thomas, Ried, Janina S., Leu, Costin, Nürnberg, Peter, and Sander, Thomas

Published
2013
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43. Association of a non-synonymous functional variant of the ITGAM gene with systemic sclerosis

Author

Carmona, F David, Simeon, Carmen P, Beretta, Lorenzo, Carreira, Patricia, Vonk, Madelon C, Ríos-Fernández, Raquel, Espinosa, Gerard, Navarrete, Nuria, Vicente-Rabaneda, Esther, Rodríguez-Rodríguez, Luis, Tolosa, Carlos, García-Hernández, Francisco J, Castellví, Iván, Egurbide, María Victoria, Fonollosa, Vicente, González-Gay, Miguel A, Rodríguez-Carballeira, Mónica, Díaz-Gónzalez, Federico, Sáez-Comet, Luis, Hesselstrand, Roger, Riemekasten, Gabriela, Witte, Torsten, Voskuyl, Alexandre E, Schuerwegh, Annemie J, Madhok, Rajan, Shiels, Paul, Fonseca, Carmen, Denton, Christopher, Nordin, Annika, Palm, Øyvind, Hoffmann-Vold, Anna-Maria, Airó, Paolo, Scorza, Raffaella, Lunardi, Claudio, van Laar, Jacob M, Hunzelmann, Nicolas, Kreuter, Alexander, Herrick, Ariane, Worthington, Jane, Koeleman, Bobby P C, Radstake, Timothy R D J, and Martín, Javier

Published
2011
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45. NaV1.1 and NaV1.6 selective compounds reduce the behavior phenotype and epileptiform activity in a novel zebrafish model for Dravet Syndrome

Author

Weuring, Wout J., primary, Singh, Sakshi, additional, Volkers, Linda, additional, Rook, Martin B., additional, van ‘t Slot, Ruben H., additional, Bosma, Marjolein, additional, Inserra, Marco, additional, Vetter, Irina, additional, Verhoeven-Duif, Nanda M., additional, Braun, Kees P. J., additional, Rivara, Mirko, additional, and Koeleman, Bobby P. C., additional

Published
2020
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46. Modifier genes in SCN1A ‐related epilepsy syndromes

Author

de Lange, Iris M., primary, Mulder, Flip, additional, Slot, Ruben, additional, Sonsma, Anja C. M., additional, Kempen, Marjan J. A., additional, Nijman, Isaac J., additional, Ernst, Robert F., additional, Knoers, Nine V. A. M., additional, Brilstra, Eva H., additional, and Koeleman, Bobby P. C., additional

Published
2020
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49. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

Author

de Kovel, Carolien G. F., Trucks, Holger, Helbig, Ingo, Mefford, Heather C., Baker, Carl, Leu, Costin, Kluck, Christian, Muhle, Hiltrud, von Spiczak, Sarah, Ostertag, Philipp, Obermeier, Tanja, Kleefu-Lie, Ailing A., Hallmann, Kerstin, Steffens, Michael, Gaus, Verena, Klein, Karl M., Hamer, Hajo M., Rosenow, Felix, Brilstra, Eva H., Trenité, Dorothée Kasteleijn-Nolst, Swinkels, Marielle E. M., Weber, Yvonne G., Unterberger, Iris, Zimprich, Fritz, Urak, Lydia, Feucht, Martha, Fuchs, Karoline, Møller, Rikke S., Hjalgrim, Helle, De Jonghe, Peter, Suls, Arvid, Rückert, Ina-Maria, Wichmann, Heinz-Erich, Franke, Andre, Schreiber, Stefan, Nürnberg, Peter, Elger, Christian E., Lerche, Holger, Stephani, Ulrich, Koeleman, Bobby P. C., Lindhout, Dick, Eichler, Evan E., and Sander, Thomas

Published
2010

50. Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Author

McCormack, Mark, Gui, Hongsheng, Ingason, Andrés, Speed, Doug, Wright, Galen E B, Zhang, Eunice J., Secolin, Rodrigo, Yasuda, Clarissa, Kwok, Maxwell, Wolking, Stefan, Becker, Felicitas, Rau, Sarah, Avbersek, Andreja, Heggeli, Kristin, Leu, Costin, Depondt, Chantal, Sills, Graeme J., Marson, Anthony G., Auce, Pauls, Brodie, Martin J., Francis, Ben, Johnson, Michael R., Koeleman, Bobby P C, Striano, Pasquale, Coppola, Antonietta, Zara, Federico, Kunz, Wolfram S., Sander, Josemir W., Lerche, Holger, Klein, Karl Martin, Weckhuysen, Sarah, Krenn, Martin, Gudmundsson, Lárus J, Stefánsson, Kári, Krause, Roland, Shear, Neil, Ross, Colin J D, Delanty, Norman, Pirmohamed, Munir, Carleton, Bruce C., Cendes, Fernando, Lopes-Cendes, Iscia, Liao, Wei-Ping, O'Brien, Terence J., Sisodiya, Sanjay M., Cherny, Stacey, Kwan, Patrick, Baum, Larry, Cavalleri, Gianpiero L., International League Against Epilepsy Consortium on Complex Epilepsies, Bisulli, Francesca, Mccormack, Mark, Gui, Hongsheng, Ingason, André, Speed, Doug, Wright, Galen E B, Zhang, Eunice J, Secolin, Rodrigo, Yasuda, Clarissa, Kwok, Maxwell, Wolking, Stefan, Becker, Felicita, Rau, Sarah, Avbersek, Andreja, Heggeli, Kristin, Leu, Costin, Depondt, Chantal, Sills, Graeme J, Marson, Anthony G, Auce, Paul, Brodie, Martin J, Francis, Ben, Johnson, Michael R, Koeleman, Bobby P C, Striano, Pasquale, Coppola, Antonietta, Zara, Federico, Kunz, Wolfram S, Sander, Josemir W, Lerche, Holger, Klein, Karl Martin, Weckhuysen, Sarah, Krenn, Martin, Gudmundsson, Lárus J, Stefánsson, Kári, Krause, Roland, Shear, Neil, Ross, Colin J D, Delanty, Norman, Pirmohamed, Munir, Carleton, Bruce C, Cendes, Fernando, Lopes-Cendes, Iscia, Liao, Wei-Ping, O'Brien, Terence J, Sisodiya, Sanjay M, Cherny, Stacey, Kwan, Patrick, Baum, Larry, Cavalleri, Gianpiero L, EPIGEN Consortium, Canadian Pharmacogenomics Network, for the EpiPGX Consortium, Int League Epilepsy Consortium, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, McCormack, Mark, Zhang, Eunice J., Sills, Graeme J., Marson, Anthony G., Brodie, Martin J., Johnson, Michael R., Kunz, Wolfram S., Sander, Josemir W., Carleton, Bruce C., O'Brien, Terence J., Sisodiya, Sanjay M., Cavalleri, Gianpiero L., International League Against Epilepsy Consortium on Complex Epilepsie, and Bisulli, Francesca

Subjects
0301 basic medicine, Linkage disequilibrium, Pharmacogenomic Variants, Neurology [D14] [Human health sciences], Genome-wide association study, HLA-A-ASTERISK-3101, Linkage Disequilibrium, 0302 clinical medicine, Flogaveiki, INDUCED HYPERSENSITIVITY REACTIONS, Medicine, genetics, POPULATION, education.field_of_study, Public health, Taugavísindi, 3. Good health, Carbamazepine, Neurology, Factor H, Complement Factor H, Association studies in genetics, Lýðheilsa, Anticonvulsants, Drug Eruptions, Erfðarannsóknir, Life Sciences & Biomedicine, STEVENS-JOHNSON-SYNDROME, Population, Antiepileptic drugs, adverse drug reaction, Clinical Neurology, Mutation, Missense, Human leukocyte antigen, Complement factor I, Case control studies, White People, Article, 03 medical and health sciences, Asian People, RISK-FACTOR, Seizures, Genetic variation, Humans, GENOME-WIDE ASSOCIATION, education, METAANALYSIS, Retrospective Studies, Science & Technology, Neurology & Neurosurgery, Neurologie [D14] [Sciences de la santé humaine], Epilepsy, HLA-A Antigens, business.industry, Genetic Variation, Correction, CUTANEOUS ADVERSE-REACTIONS, 1103 Clinical Sciences, Généralités, 1702 Cognitive Science, GENOTYPES, 030104 developmental biology, Apolipoproteins, Case-Control Studies, Phenytoin, LAMOTRIGINE, Immunology, Alternative complement pathway, epilepsy, Neurosciences & Neurology, Neurology (clinical), Human medicine, 1109 Neurosciences, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients., This study was not industry-sponsored. The work was supported by a grant from the European Commission (7th Framework Programme Grant 279062, EpiPGX). M.M.C. and G.L.C. are supported by Science Foundation Ireland, grant 13/CDA/2223, and an RCSI seed funding grant GA 14-1899. This project was supported by the General Research Funds (HKU7623/08M and HKU7747/07M to S.C., CUHK4466/06M to P.K.) and Health and Medical Research Fund (HMRF 01120086 to P.K.) from Hong Kong. Some results presented in this article were prepared using the HPC facilities of the University of Luxembourg. This work was partly undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme (J.W.S., S.M.S.). The work was also supported by the Epilepsy Society, UK (J.W.S., S.M.S.), by the foundation “no epilep,” the German Chapter of the ILAE (DGfE) (both to H.L.). F.C. and I.L.-C. are supported by Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil, through grant 2013/07559-3. J.E.Z. and M.P. thank the NHS Chair of Pharmacogenetics programme and MRC Centre for Drug Safety Science for support in Liverpool. B.C.C. and C.J.D.R. are supported by the Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Network (FRN-117588), the Canada Foundation for Innovation and the Canadian Dermatology Foundation. G.E.B.W. is supported by a CIHR Fellowship. The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. M.M.C., H.G., and G.L.C. had full access to all the data in the study and the corresponding authors had final responsibility for the decision to submit for publication. The Article Processing Charge was funded by the European Commission OpenAIRE2020 project.

Published
2017

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