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1. Histone serotonylation regulates ependymoma tumorigenesis

Author

Chen, Hsiao-Chi, He, Peihao, McDonald, Malcolm, Williamson, Michael R., Varadharajan, Srinidhi, Lozzi, Brittney, Woo, Junsung, Choi, Dong-Joo, Sardar, Debosmita, Huang-Hobbs, Emmet, Sun, Hua, Ippagunta, Siri M., Jain, Antrix, Rao, Ganesh, Merchant, Thomas E., Ellison, David W., Noebels, Jeffrey L., Bertrand, Kelsey C., Mack, Stephen C., and Deneen, Benjamin

Published
2024
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3. Remote neuronal activity drives glioma progression through SEMA4F

Author

Huang-Hobbs, Emmet, Cheng, Yi-Ting, Ko, Yeunjung, Luna-Figueroa, Estefania, Lozzi, Brittney, Taylor, Kathryn R., McDonald, Malcolm, He, Peihao, Chen, Hsiao-Chi, Yang, Yuhui, Maleki, Ehson, Lee, Zhung-Fu, Murali, Sanjana, Williamson, Michael R., Choi, Dongjoo, Curry, Rachel, Bayley, James, Woo, Junsung, Jalali, Ali, Monje, Michelle, Noebels, Jeffrey L., Harmanci, Akdes Serin, Rao, Ganesh, and Deneen, Benjamin

Published
2023
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6. WONOEP appraisal: Genetic insights into early onset epilepsies.

Author

Quatraccioni, Anne, Cases‐Cunillera, Silvia, Balagura, Ganna, Coleman, Matthew, Rossini, Laura, Mills, James D., Casillas‐Espinosa, Pablo M., Moshé, Solomon L., Sankar, Raman, Baulac, Stéphanie, Noebels, Jeffrey L., Auvin, Stéphane, O'Brien, Terence J., Henshall, David C., Akman, Özlem, and Galanopoulou, Aristea S.

Subjects
SEIZURES (Medicine), NEWBORN infants, MOSAICISM, PARTIAL epilepsy, CHROMOSOMAL rearrangement, EPILEPSY
Abstract

Early onset epilepsies occur in newborns and infants, and to date, genetic aberrations and variants have been identified in approximately one quarter of all patients. With technological sequencing advances and ongoing research, the genetic diagnostic yield for specific seizure disorders and epilepsies is expected to increase. Genetic variants associated with epilepsy include chromosomal abnormalities and rearrangements of various sizes as well as single gene variants. Among these variants, a distinction can be made between germline and somatic, with the latter being increasingly identified in epilepsies with focal cortical malformations in recent years. The identification of the underlying genetic mechanisms of epilepsy syndromes not only revolutionizes the diagnostic schemes but also leads to a better understanding of the diseases and their interrelationships, ultimately providing new opportunities for therapeutic targeting. At the XVI Workshop on Neurobiology of Epilepsy (WONOEP 2022, Talloires, France, July 2022), various etiologies, research models, and mechanisms of genetic early onset epilepsies were presented and discussed. [ABSTRACT FROM AUTHOR]

Published
2024
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7. αII Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function

Author

Huang, Claire Yu-Mei, Zhang, Chuansheng, Ho, Tammy Szu-Yu, Oses-Prieto, Juan, Burlingame, Alma L, Lalonde, Joshua, Noebels, Jeffrey L, Leterrier, Christophe, and Rasband, Matthew N

Subjects
Neurodegenerative, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Action Potentials, Animals, Axons, COS Cells, Cells, Cultured, Chlorocebus aethiops, Cytoskeleton, Gene Deletion, Hippocampus, Mice, Mice, Inbred C57BL, Ranvier's Nodes, Spectrin, ankyrin, axon, axon initial segment, cytoskeleton, node of Ranvier, spectrin, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Spectrins form a submembranous cytoskeleton proposed to confer strength and flexibility to neurons and to participate in ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Neuronal spectrin cytoskeletons consist of diverse β subunits and αII spectrin. Although αII spectrin is found in neurons in both axonal and somatodendritic domains, using proteomics, biochemistry, and superresolution microscopy, we show that αII and βIV spectrin interact and form a periodic AIS cytoskeleton. To determine the role of spectrins in the nervous system, we generated Sptan1f/f mice for deletion of CNS αII spectrin. We analyzed αII spectrin-deficient mice of both sexes and found that loss of αII spectrin causes profound reductions in all β spectrins. αII spectrin-deficient mice die before 1 month of age and have disrupted AIS and many other neurological impairments including seizures, disrupted cortical lamination, and widespread neurodegeneration. These results demonstrate the importance of the spectrin cytoskeleton both at the AIS and throughout the nervous system.SIGNIFICANCE STATEMENT Spectrin cytoskeletons play diverse roles in neurons, including assembly of excitable domains such as the axon initial segment (AIS) and nodes of Ranvier. However, the molecular composition and structure of these cytoskeletons remain poorly understood. Here, we show that αII spectrin partners with βIV spectrin to form a periodic cytoskeleton at the AIS. Using a new αII spectrin conditional knock-out mouse, we show that αII spectrin is required for AIS assembly, neuronal excitability, cortical lamination, and to protect against neurodegeneration. These results demonstrate the broad importance of spectrin cytoskeletons for nervous system function and development and have important implications for nervous system injuries and diseases because disruption of the spectrin cytoskeleton is a common molecular pathology.

Published
2017

8. Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy

Author

Abreo, Timothy J., primary, Thompson, Emma C., additional, Madabushi, Anuraag, additional, Soh, Heun, additional, Varghese, Nissi, additional, Vanoye, Carlos G., additional, Springer, Kristen, additional, Park, Kristen L., additional, Johnson, Jim, additional, Sims, Scotty, additional, Ji, Zhigang, additional, Chavez, Ana G., additional, Jankovic, Miranda J., additional, Habte, Bereket, additional, Zuberi, Aamir, additional, Lutz, Cathleen, additional, Wang, Zhao, additional, Krishnan, Vaishnav, additional, Dudler, Lisa, additional, Einsele-Scholz, Stephanie, additional, Noebels, Jeffrey L., additional, George, Alfred L., additional, Maheshwari, Atul, additional, Tzingounis, Anastasios V., additional, and Cooper, Edward C., additional

Published
2024
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9. Plural molecular and cellular mechanisms of pore domainKCNQ2encephalopathy

Author

Abreo, Timothy J., primary, Thompson, Emma C., additional, Madabushi, Anuraag, additional, Soh, Heun, additional, Varghese, Nissi, additional, Vanoye, Carlos G., additional, Springer, Kristen, additional, Park, Kristen L., additional, Johnson, Jim, additional, Sims, Scotty, additional, Ji, Zhigang, additional, Chavez, Ana G., additional, Jankovic, Miranda J., additional, Habte, Bereket, additional, Zuberi, Aamir, additional, Lutz, Cathleen, additional, Wang, Zhao, additional, Krishnan, Vaishnav, additional, Dudler, Lisa, additional, Einsele-Scholz, Stephanie, additional, Noebels, Jeffrey L., additional, George, Alfred L., additional, Maheshwari, Atul, additional, Tzingounis, Anastasios V., additional, and Cooper, Edward C., additional

Published
2024
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11. Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model

Author

Hatcher, Asante, Yu, Kwanha, Meyer, Jochen, Aiba, Isamu, Deneen, Benjamin, and Noebels, Jeffrey L.

Subjects
Neurophysiology -- Models, Epilepsy -- Models, Seizures (Medicine) -- Models, Glutamate -- Models, Brain tumors -- Models, Genes, Surgery, Brain, Cancer, Tumors, Glioblastomas, Health care industry
Abstract

Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmacoresistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local [Iba1.sup.+] microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting MapT suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor-driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms., Introduction The invasion of the neocortex by malignant brain tumor cells is accompanied by seizures and cognitive impairments that are highly refractory to treatment even after surgical resection, indicating persistent [...]

Published
2020
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14. Reduced Cognition in Syngap1 Mutants Is Caused by Isolated Damage within Developing Forebrain Excitatory Neurons

Author

Ozkan, Emin D, Creson, Thomas K, Kramár, Enikö A, Rojas, Camilo, Seese, Ron R, Babyan, Alex H, Shi, Yulin, Lucero, Rocco, Xu, Xiangmin, Noebels, Jeffrey L, Miller, Courtney A, Lynch, Gary, and Rumbaugh, Gavin

Subjects
Biomedical and Clinical Sciences, Neurosciences, Psychology, Behavioral and Social Science, Basic Behavioral and Social Science, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Cognition Disorders, Excitatory Postsynaptic Potentials, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation, Neurons, Prosencephalon, Random Allocation, ras GTPase-Activating Proteins, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Syngap1 haploinsufficiency is a common cause of sporadic intellectual disability. Syngap1 mutations disrupt developing pyramidal neurons, although it remains unclear if this process contributes to cognitive abnormalities. Here, we found that haploinsufficiency restricted to forebrain glutamatergic neurons was sufficient to disrupt cognition and removing mutations from this population prevented cognitive abnormalities. In contrast, manipulating Syngap1 function in GABAergic neurons had no effect on cognition, excitability, or neurotransmission, highlighting the specificity of Syngap1 mutations within forebrain excitatory neurons. Interestingly, cognitive abnormalities were reliably predicted by the emergence of enhanced excitatory synaptic function in mature superficial cortical pyramidal cells, which was a neurophysiological disruption caused by Syngap1 dysfunction in developing, but not adult, forebrain neurons. We conclude that reduced cognition in Syngap1 mutants is caused by isolated damage to developing forebrain glutamatergic neurons. This damage triggers secondary disruptions to synaptic homeostasis in mature cortical pyramidal cells, which perpetuates brain dysfunction into adulthood.

Published
2014

15. List of contributors

Author

Artukoglu, Bekir B., primary, Bachoo, Robert M., additional, Baranzini, Sergio E., additional, Benson, Merrill D., additional, Biglan, Kevin, additional, Blakeney, Iona, additional, Bloch, Michael H., additional, Brady, Melanie, additional, Brandsema, John F., additional, Broccolini, Aldobrando, additional, Brown, Robert H., additional, Cohen, Bernard, additional, Cole, Jordan J., additional, Comi, Anne M., additional, Crabbe, John C., additional, Darras, Basil T., additional, Dowling, Michael M., additional, Dunn, Walter, additional, Elroy-Stein, Orna, additional, Elsheikh, Bakri H., additional, Engel, Andrew G., additional, Fahn, Stanley, additional, Fasching, Liana, additional, Fears, Scott C., additional, Felling, Ryan J., additional, Ferner, Rosalie E., additional, Fink, John K., additional, Gillespie, Charles F., additional, Goldman, Alica M., additional, Goldman, Jill, additional, Gutmann, David H., additional, Haltia, Matti, additional, Hauser, Stephen L., additional, Hilbert, James E., additional, Iliopoulos, Othon, additional, Islam, Monica P., additional, Jenkins, Aaron K., additional, Jia, Xiaoming, additional, Jungbluth, Heinz, additional, Kayani, Saima N., additional, Khemani, Pravin, additional, Kirkham, Fenella J., additional, Kirkorian, A. Yasmine, additional, Kissel, John T., additional, Klein, Christine, additional, Kleopa, Kleopas A., additional, Kolb, Stephen J., additional, Konstantakou, Eumorphia, additional, Lambracht-Washington, Doris, additional, Lennington, Jessica B., additional, Lewis, David A., additional, Liang, Wen-Chen, additional, Lidstone, Paven A., additional, Lohmann, Katja, additional, Lombroso, Paul J., additional, Maher, Elizabeth A., additional, Marshall, Frederick, additional, McCann, Meghan, additional, McGarry, Andrew, additional, Meola, Giovanni, additional, Metelo, Ana, additional, Miller, Bruce L., additional, Mirabella, Massimiliano, additional, Mizutani, Shuki, additional, Mole, Sara E., additional, Moxley, Richard T., additional, Muntoni, Francesco, additional, Nemeroff, Charles B., additional, Nishino, Ichizo, additional, Noebels, Jeffrey L., additional, Pandolfo, Massimo, additional, Pevsner, Jonathan, additional, Ptáček, Louis, additional, Ralph, Jeffrey, additional, Renthal, William, additional, Reus, Victor I., additional, Roach, E. Steve, additional, Rosenberg, Roger N., additional, Savarese, Antonia M., additional, Sawyer, Russell P., additional, Scherer, Steven S., additional, Schiffmann, Raphael, additional, Schulz, Angela, additional, Sewry, Caroline, additional, Shakkottai, Vikram G., additional, Shinagawa, Shunichiro, additional, Singh, Pratibha, additional, Sreedharan, Jemeen, additional, Statland, Jeffrey M., additional, Szabo, Steven T., additional, Szuhay, Gabor, additional, Udd, Bjarne, additional, Vaccarino, Flora M., additional, Volk, David W., additional, Wilson, Kathleen S., additional, Xia, Weiming, additional, and Yu, Gang, additional

Published
2020
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17. Issues related to development of new antiseizure treatments

Author

Wilcox, Karen S, Dixon‐Salazar, Tracy, Sills, Graeme J, Ben‐Menachem, Elinor, White, H Steve, Porter, Roger J, Dichter, Marc A, Moshé, Solomon L, Noebels, Jeffrey L, Privitera, Michael D, and Rogawski, Michael A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Neurodegenerative, Epilepsy, Brain Disorders, Neurological, Adult, Animals, Anticonvulsants, Child, Disease Models, Animal, Drug Discovery, Drug Evaluation, Drug Industry, Drugs, Investigational, Humans, Research Support as Topic, Translational Research, Biomedical, Antiseizure drug, Pharmacoresistant epilepsy, Animal models of epilepsy, Translational Medical Research, Neurology & Neurosurgery, Clinical sciences
Abstract

This report represents a summary of the discussions led by the antiseizure treatment working group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Working Groups joint meeting in London (London Meeting). We review here what is currently known about the pharmacologic characteristics of current models of refractory seizures, both for adult and pediatric epilepsy. In addition, we address how the National Institute of Neurological Disorders and Stroke (NINDS)-funded Anticonvulsant Screening Program (ASP) is evolving to incorporate appropriate animal models in the search for molecules that might be sufficiently novel to warrant further pharmacologic development. We also briefly address what we believe is necessary, going forward, to achieve the goal of stopping seizures in all patients, with a call to arms for funding agencies, the pharmaceutical industry, and basic researchers.

Published
2013

19. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes

Author

Chao, Hsiao-Tuan, Chen, Hongmei, Samaco, Rodney C, Xue, Mingshan, Chahrour, Maria, Yoo, Jong, Neul, Jeffrey L, Gong, Shiaoching, Lu, Hui-Chen, Heintz, Nathaniel, Ekker, Marc, Rubenstein, John LR, Noebels, Jeffrey L, Rosenmund, Christian, and Zoghbi, Huda Y

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Rare Diseases, Pediatric, Neurosciences, Rett Syndrome, Mental Health, Genetics, Intellectual and Developmental Disabilities (IDD), Neurodegenerative, Brain Disorders, Autism, Aetiology, 2.1 Biological and endogenous factors, Congenital, Mental health, Animals, Autistic Disorder, Brain, Compulsive Behavior, Disease Models, Animal, Electroencephalography, Genotype, Glutamate Decarboxylase, Hippocampus, Homeodomain Proteins, Inhibitory Postsynaptic Potentials, Long-Term Potentiation, Male, Methyl-CpG-Binding Protein 2, Mice, Mice, Transgenic, Neural Inhibition, Neuronal Plasticity, Neurons, Phenotype, Presynaptic Terminals, Psychomotor Disorders, Reflex, Startle, Respiration, Self-Injurious Behavior, Signal Transduction, Stereotypic Movement Disorder, Survival Rate, Synaptic Transmission, Vesicular Inhibitory Amino Acid Transport Proteins, gamma-Aminobutyric Acid, General Science & Technology
Abstract

Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (γ-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

Published
2010

24. Remote neuronal activity drives glioma infiltration via Sema4f

Author

Huang-Hobbs, Emmet, primary, Cheng, Yi-Ting, additional, Ko, Yeunjung, additional, Luna-Figueroa, Estefania, additional, Lozzi, Brittney, additional, Taylor, Kathryn, additional, McDonald, Malcolm, additional, He, Peihao, additional, Chen, Hsiao-Chi, additional, Yang, Yuhui, additional, Maleki, Ehson, additional, Lee, Zhung-Fu, additional, Murali, Sanjana, additional, Williamson, Michael, additional, Choi, Dongjoo, additional, Curry, Rachel, additional, Bayley, James, additional, Woo, Junsung, additional, Jalali, Ali, additional, Monje, Michelle, additional, Noebels, Jeffrey L, additional, Serin-Harmanci, Akdes, additional, Rao, Ganesh, additional, and Deneen, Benjamin, additional

Published
2023
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25. Remote neuronal activity drives glioma infiltration via Sema4f

Author

Huang-Hobbs, Emmet, Cheng, Yi-Ting, Ko, Yeunjung, Luna-Figueroa, Estefania, Lozzi, Brittney, Taylor, Kathryn R, McDonald, Malcolm, He, Peihao, Chen, Hsiao-Chi, Yang, Yuhui, Maleki, Ehson, Lee, Zhung-Fu, Murali, Sanjana, Williamson, Michael, Choi, Dongjoo, Curry, Rachel, Bayley, James, Woo, Junsung, Jalali, Ali, Monje, Michelle, Noebels, Jeffrey L, Harmanci, Akdes Serin, Rao, Ganesh, and Deneen, Benjamin

Subjects
Article
Abstract

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput,in vivoscreening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.

Published
2023
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29. WWOX P47T loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12

Author

Hussain, Tabish, primary, Sanchez, Kevin, additional, Crayton, Jennifer, additional, Saha, Dhurjhoti, additional, Jeter, Collene, additional, Lu, Yue, additional, Abba, Martin, additional, Seo, Ryan, additional, Noebels, Jeffrey L, additional, Fonken, Laura, additional, and Aldaz, C Marcelo, additional

Published
2022
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30. List of Contributors

Author

Abbink, Truus E.M., Abdallah, Sarah B., Agin-Liebes, Julian, Bachoo, Robert M., Baek, Peter, Baranzini, Sergio E., Bear, Lauren, Biglan, Kevin, Bloch, Michael H., Bonnet, Wilmot, Brady, Melanie, Brandsema, John F., Broccolini, Aldobrando, Brown, Robert H., Cohen, Bernard, Cole, Jordan J., Comi, Anne M., Crabbe, John C., Darras, Basil T., Delia, Domenico, Doran, Sarah, Dowling, Michael M., Dunn, Walter, Elsheikh, Bakri, Engel, Andrew G., Fahn, Stanley, Fasching, Liana, Fears, Scott C., Felling, Ryan J., Fernandez, Thomas V., Ferner, Rosalie E., Fink, John K., Gellera, Cinzia, Gillespie, Charles F., Goldman, Alica M., Gospe, Sidney M., Jr., Gu, Yian, Gutmann, David H., Hadziamehtovic, Una, Hauser, Stephen L., Hilbert, James E., Hosoi, Yasushi, Ibrahim, Ahmed N., Iliopoulos, Othon, Islam, Monica P., Jenkins, Aaron K., Jia, Xiaoming, Jungbluth, Heinz, Kane, John P., Katz, Natalie K., Kayani, Saima N., Kirkham, Fenella J., Kirkorian, A. Yasmine, Kissel, John T., Klein, Christine, Kleopa, Kleopas A., Kolb, Stephen J., Konstantakou, Evmorfia, Kruer, Michael C., Lambracht-Washington, Doris, Larson, Austin, Lee, Joseph H., Lewis, David A., Liang, Wen-Chen, Lin, Ziqiang, Lohmann, Katja, Lombroso, Paul, Lucchini, Matteo, Maher, Elizabeth A., Malloy, Mary J., Manoli, Irini, Marin-Valencia, Isaac, Marshall, Fred, Mayeux, Richard, McGarry, Andrew, Menkes, John H., Meola, Giovanni, Miller, Bruce L., Mirabella, Massimiliano, Miyajima, Hiroaki, Mizutani, Shuki, Mole, Sara E., Moxley, Richard T., III, Nemeroff, Charles B., Nemeth, Christina, Nishino, Ichizo, Noebels, Jeffrey L., Nordlie, Sandra M.H., Oksenberg, Jorge R., Oldfors, Anders, Olfson, Emily, Padilla-Lopez, Sergio, Pandolfo, Massimo, Pascual, Juan M., Patel, Shailendra B., Pena, Izabella A., Ptáček, Louis, Ralph, Jeffrey, Reilly, Mary M., Renthal, William, Reus, Victor I., Roach, E. Steve, Rosenberg, Roger N., Rosenblatt, David S., Rossor, Alexander M., Salen, Gerald, Savarese, Antonia M., Sawyer, Russell P., Scherer, Steven S., Schneider, Susanne A., Schulz, Angela, Selcen, Duygu, Shakkottai, Vikram G., Solomon, Chase, Sreedharan, Jemeen, Statland, Jeffrey M., Taroni, Franco, Tuschl, Karin, Udd, Bjarne, Umaña, Luis Alfredo, Vaccarino, Flora M., van der Knaap, Marjo S., van Karnebeek, Clara, Venditti, Charles P., Voermans, Nicol C., Volk, David W., Waldrop, Megan A., Watkins, David, Wilson, Golder N., Wilson, Kathleen S., Xia, Weiming, and Yu, Gang

Published
2025
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32. SUDEP Animal Models

Author

Goldman, Alica M., primary, Buchanan, Gordon, additional, Aiba, Isamu, additional, and Noebels, Jeffrey L., additional

Published
2017
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33. Contributors

Author

Aiba, Isamu, primary, Andrade, Pedro, additional, Angamo, Eskedar A., additional, Aronica, Eleonora, additional, Auvin, Stéphane, additional, Baines, Richard A., additional, Balosso, Silvia, additional, Barker-Haliski, Melissa, additional, Bartolomei, Fabrice, additional, Bastar, Jeffrey, additional, Battaglia, Giorgio, additional, Benke, Tim, additional, Berdichevsky, Yevgeny, additional, Bernard, Christophe, additional, Bertoglio, Daniele, additional, Bertram, Edward H., additional, Buchanan, Gordon, additional, Buckmaster, Paul S., additional, Calas, Guilhem, additional, Carlen, Peter L., additional, Carmant, Lionel, additional, Cepeda, Carlos, additional, Cho, Frances S., additional, Clemente, Alexandra, additional, Cloyd, James C., additional, Colciaghi, Francesca, additional, Coles, Lisa D., additional, Conti, Valerio, additional, Copmans, Daniëlle, additional, Coulter, Douglas A., additional, Dal Bo, Gregory, additional, Dang, Louis T., additional, de Curtis, Marco, additional, de Witte, Peter A.M., additional, Dedeurwaerdere, Stefanie, additional, Deleye, Steven, additional, Dengler, Nora, additional, Depaulis, Antoine, additional, Deransart, Colin, additional, Dorandeu, Frederic, additional, Dudek, F. Edward, additional, Dulla, Chris G., additional, Dzhala, Volodya, additional, Ekstrand, Jeffrey, additional, Estrada-Sánchez, Ana M., additional, Eubanks, James H., additional, Faingold, Carl, additional, Fares, Raafat, additional, Ferland, R.J., additional, Ferraro, T.N., additional, Finardi, Adele, additional, Friedman, Alon, additional, Gabriel, Siegrun, additional, Galanopoulou, Aristea S., additional, Giachello, Carlo N.G., additional, Glykys, Joseph, additional, Gnatkovsky, Vadym, additional, Goldman, Alica M., additional, Goodman, Jeffrey, additional, Gorter, Jan A., additional, Gröhn, Olli, additional, Guerrini, Renzo, additional, Guillemain, Isabelle, additional, Halasz, Peter, additional, Heinemann, Uwe, additional, Henshall, David C., additional, Holden, Stephanie, additional, Holmes, Gregory L., additional, Hovens, Chris, additional, Ivanov, Anton I., additional, Jansen, Laura A., additional, Jarre, Guillaume, additional, Jarvis, Paul R., additional, Jefferys, John G.R., additional, Jensen, Frances E., additional, Jeong, Anna, additional, Jin, Xiaoming, additional, Jin, Yishi, additional, Köhling, Rüdiger, additional, Kadam, Shilpa D., additional, Kaufer, Daniela, additional, Kelly, Kevin M., additional, Kelly, Mary E., additional, Klang, Andrea, additional, Klitgaard, Henrik, additional, Kneissl, Sibylle, additional, Kostopoulos, George K., additional, Kotloski, Robert J., additional, Kuker, Marie, additional, Kyyriäinen, Jenni, additional, Löscher, Wolfgang, additional, Lau, Lauren A., additional, Lehmann, Thomas-Nicolas, additional, Leppik, Ilo E., additional, Levine, Michael S., additional, Librizzi, Laura, additional, Lillis, Kyle, additional, Lin, Dean D., additional, Lin, Wei-Hsiang, additional, Mühlebner, Angelika, additional, Marchi, Nicola, additional, Mazarati, Andrey M., additional, Milikovsky, Dan Z., additional, Modolo, Julien, additional, Moshé, Solomon L., additional, N’Gouemo, Prosper, additional, Ndode-Ekane, Xavier Ekolle, additional, Nehlig, Astrid, additional, Newton, Jamila, additional, Nobili, Paola, additional, Noebels, Jeffrey L., additional, O’Brien, Terence J., additional, O’Leary, Heather, additional, Pakozdy, Akos, additional, Parent, Jack M., additional, Pasanen, Lotta, additional, Patel, Dipan C., additional, Patterson, Edward N., additional, Paz, Jeanne T., additional, Petrou, Steve, additional, Ping, Xingjie, additional, Pitkänen, Asla, additional, Potschka, Heidrun, additional, Raikov, Ivan, additional, Ravizza, Teresa, additional, Reddy, Doodipala S., additional, Richards, Kay L., additional, Roper, Steven N., additional, Salar, Seda, additional, Salinas, Felipe S., additional, Sanon, Nathalie T., additional, Shakarjian, Michael P., additional, Shaker, Tarek, additional, Shultz, Sandy, additional, Siekierska, Aleksandra, additional, Soltesz, Ivan, additional, Spampanato, Jay G., additional, Staley, Kevin J., additional, Stewart, Mark, additional, Sun, Hongyu, additional, Sutula, Thomas P., additional, Szabó, Charles Á., additional, Takayanagi-Kiya, Seika, additional, Tanila, Heikki, additional, Tannenbaum, Jerrold, additional, Tupal, Srinivasan, additional, Uva, Laura, additional, van Vliet, Erwin A., additional, Velíšek, Libor, additional, Velíšková, Jana, additional, Walker, Matthew C., additional, Wendling, Fabrice, additional, White, H. Steve, additional, Wilcox, Karen S., additional, Wong, Michael, additional, Wykes, Robert C., additional, Zayachkivsky, Andrew, additional, Zhang, Liang, additional, and Zheng, Ping, additional

Published
2017
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42. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Motelow, Joshua E., primary, Povysil, Gundula, additional, Dhindsa, Ryan S., additional, Stanley, Kate E., additional, Allen, Andrew S., additional, Feng, Yen-Chen Anne, additional, Howrigan, Daniel P., additional, Abbott, Liam E., additional, Tashman, Katherine, additional, Cerrato, Felecia, additional, Cusick, Caroline, additional, Singh, Tarjinder, additional, Heyne, Henrike, additional, Byrnes, Andrea E., additional, Churchhouse, Claire, additional, Watts, Nick, additional, Solomonson, Matthew, additional, Lal, Dennis, additional, Gupta, Namrata, additional, Neale, Benjamin M., additional, Cavalleri, Gianpiero L., additional, Cossette, Patrick, additional, Cotsapas, Chris, additional, De Jonghe, Peter, additional, Dixon-Salazar, Tracy, additional, Guerrini, Renzo, additional, Hakonarson, Hakon, additional, Heinzen, Erin L., additional, Helbig, Ingo, additional, Kwan, Patrick, additional, Marson, Anthony G., additional, Petrovski, Slavé, additional, Kamalakaran, Sitharthan, additional, Sisodiya, Sanjay M., additional, Stewart, Randy, additional, Weckhuysen, Sarah, additional, Depondt, Chantal, additional, Dlugos, Dennis J., additional, Scheffer, Ingrid E., additional, Striano, Pasquale, additional, Freyer, Catharine, additional, Krause, Roland, additional, May, Patrick, additional, McKenna, Kevin, additional, Regan, Brigid M., additional, Bennett, Caitlin A., additional, Leu, Costin, additional, Leech, Stephanie L., additional, O’Brien, Terence J., additional, Todaro, Marian, additional, Stamberger, Hannah, additional, Andrade, Danielle M., additional, Ali, Quratulain Zulfiqar, additional, Sadoway, Tara R., additional, Krestel, Heinz, additional, Schaller, André, additional, Papacostas, Savvas S., additional, Kousiappa, Ioanna, additional, Tanteles, George A., additional, Christou, Yiolanda, additional, Štěrbová, Katalin, additional, Vlčková, Markéta, additional, Sedláčková, Lucie, additional, Laššuthová, Petra, additional, Klein, Karl Martin, additional, Rosenow, Felix, additional, Reif, Philipp S., additional, Knake, Susanne, additional, Neubauer, Bernd A., additional, Zimprich, Friedrich, additional, Feucht, Martha, additional, Reinthaler, Eva M., additional, Kunz, Wolfram S., additional, Zsurka, Gábor, additional, Surges, Rainer, additional, Baumgartner, Tobias, additional, von Wrede, Randi, additional, Pendziwiat, Manuela, additional, Muhle, Hiltrud, additional, Rademacher, Annika, additional, van Baalen, Andreas, additional, von Spiczak, Sarah, additional, Stephani, Ulrich, additional, Afawi, Zaid, additional, Korczyn, Amos D., additional, Kanaan, Moien, additional, Canavati, Christina, additional, Kurlemann, Gerhard, additional, Müller-Schlüter, Karen, additional, Kluger, Gerhard, additional, Häusler, Martin, additional, Blatt, Ilan, additional, Lemke, Johannes R., additional, Krey, Ilona, additional, Weber, Yvonne G., additional, Wolking, Stefan, additional, Becker, Felicitas, additional, Lauxmann, Stephan, additional, Boßelmann, Christian, additional, Kegele, Josua, additional, Hengsbach, Christian, additional, Rau, Sarah, additional, Steinhoff, Bernhard J., additional, Schulze-Bonhage, Andreas, additional, Borggräfe, Ingo, additional, Schankin, Christoph J., additional, Schubert-Bast, Susanne, additional, Schreiber, Herbert, additional, Mayer, Thomas, additional, Korinthenberg, Rudolf, additional, Brockmann, Knut, additional, Wolff, Markus, additional, Dennig, Dieter, additional, Madeleyn, Rene, additional, Kälviäinen, Reetta, additional, Saarela, Anni, additional, Timonen, Oskari, additional, Linnankivi, Tarja, additional, Lehesjoki, Anna-Elina, additional, Rheims, Sylvain, additional, Lesca, Gaetan, additional, Ryvlin, Philippe, additional, Maillard, Louis, additional, Valton, Luc, additional, Derambure, Philippe, additional, Bartolomei, Fabrice, additional, Hirsch, Edouard, additional, Michel, Véronique, additional, Chassoux, Francine, additional, Rees, Mark I., additional, Chung, Seo-Kyung, additional, Pickrell, William O., additional, Powell, Robert, additional, Baker, Mark D., additional, Fonferko-Shadrach, Beata, additional, Lawthom, Charlotte, additional, Anderson, Joseph, additional, Schneider, Natascha, additional, Balestrini, Simona, additional, Zagaglia, Sara, additional, Braatz, Vera, additional, Johnson, Michael R., additional, Auce, Pauls, additional, Sills, Graeme J., additional, Baum, Larry W., additional, Sham, Pak C., additional, Cherny, Stacey S., additional, Lui, Colin H.T., additional, Delanty, Norman, additional, Doherty, Colin P., additional, Shukralla, Arif, additional, El-Naggar, Hany, additional, Widdess-Walsh, Peter, additional, Barišić, Nina, additional, Canafoglia, Laura, additional, Franceschetti, Silvana, additional, Castellotti, Barbara, additional, Granata, Tiziana, additional, Ragona, Francesca, additional, Zara, Federico, additional, Iacomino, Michele, additional, Riva, Antonella, additional, Madia, Francesca, additional, Vari, Maria Stella, additional, Salpietro, Vincenzo, additional, Scala, Marcello, additional, Mancardi, Maria Margherita, additional, Nobili, Lino, additional, Amadori, Elisabetta, additional, Giacomini, Thea, additional, Bisulli, Francesca, additional, Pippucci, Tommaso, additional, Licchetta, Laura, additional, Minardi, Raffaella, additional, Tinuper, Paolo, additional, Muccioli, Lorenzo, additional, Mostacci, Barbara, additional, Gambardella, Antonio, additional, Labate, Angelo, additional, Annesi, Grazia, additional, Manna, Lorella, additional, Gagliardi, Monica, additional, Parrini, Elena, additional, Mei, Davide, additional, Vetro, Annalisa, additional, Bianchini, Claudia, additional, Montomoli, Martino, additional, Doccini, Viola, additional, Barba, Carmen, additional, Hirose, Shinichi, additional, Ishii, Atsushi, additional, Suzuki, Toshimitsu, additional, Inoue, Yushi, additional, Yamakawa, Kazuhiro, additional, Beydoun, Ahmad, additional, Nasreddine, Wassim, additional, Khoueiry Zgheib, Nathalie, additional, Tumiene, Birute, additional, Utkus, Algirdas, additional, Sadleir, Lynette G., additional, King, Chontelle, additional, Caglayan, S. Hande, additional, Arslan, Mutluay, additional, Yapıcı, Zuhal, additional, Topaloglu, Pınar, additional, Kara, Bulent, additional, Yis, Uluc, additional, Turkdogan, Dilsad, additional, Gundogdu-Eken, Aslı, additional, Bebek, Nerses, additional, Uğur-İşeri, Sibel, additional, Baykan, Betül, additional, Salman, Barış, additional, Haryanyan, Garen, additional, Yücesan, Emrah, additional, Kesim, Yeşim, additional, Özkara, Çiğdem, additional, Tsai, Meng-Han, additional, Ho, Chen-Jui, additional, Lin, Chih-Hsiang, additional, Lin, Kuang-Lin, additional, Chou, I-Jun, additional, Poduri, Annapurna, additional, Shiedley, Beth R., additional, Shain, Catherine, additional, Noebels, Jeffrey L., additional, Goldman, Alicia, additional, Busch, Robyn M., additional, Jehi, Lara, additional, Najm, Imad M., additional, Ferguson, Lisa, additional, Khoury, Jean, additional, Glauser, Tracy A., additional, Clark, Peggy O., additional, Buono, Russell J., additional, Ferraro, Thomas N., additional, Sperling, Michael R., additional, Lo, Warren, additional, Privitera, Michael, additional, French, Jacqueline A., additional, Schachter, Steven, additional, Kuzniecky, Ruben I., additional, Devinsky, Orrin, additional, Hegde, Manu, additional, Greenberg, David A., additional, Ellis, Colin A., additional, Goldberg, Ethan, additional, Helbig, Katherine L., additional, Cosico, Mahgenn, additional, Vaidiswaran, Priya, additional, Fitch, Eryn, additional, Berkovic, Samuel F., additional, Lerche, Holger, additional, Lowenstein, Daniel H., additional, and Goldstein, David B., additional

Published
2021
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47. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., Goldstein, David B., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., and Goldstein, David B.

Abstract

Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

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