2,286 results on '"Berkovic, Samuel F."'
Search Results
2. Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless
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Wallis, Mathew, Bodek, Simon D., Munro, Jacob, Rafehi, Haloom, Bennett, Mark F., Ye, Zimeng, Schneider, Amy, Gardiner, Fiona, Valente, Giulia, Murdoch, Emma, Uebergang, Eloise, Hunter, Jacquie, Stutterd, Chloe, Huq, Aamira, Salmon, Lucinda, Scheffer, Ingrid, Eratne, Dhamidhu, Meyn, Stephen, Fong, Chun Y., John, Tom, Mullen, Saul, White, Susan M., Brown, Natasha J., McGillivray, George, Chen, Jesse, Richmond, Chris, Hughes, Andrew, Krzesinski, Emma, Fennell, Andrew, Chambers, Brian, Santoreneos, Renee, Le Fevre, Anna, Hildebrand, Michael S., Bahlo, Melanie, Christodoulou, John, Delatycki, Martin, and Berkovic, Samuel F.
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- 2024
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3. Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress
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Knowles, Juliet K, Helbig, Ingo, Metcalf, Cameron S, Lubbers, Laura S, Isom, Lori L, Demarest, Scott, Goldberg, Ethan M, George, Alfred L, Lerche, Holger, Weckhuysen, Sarah, Whittemore, Vicky, Berkovic, Samuel F, and Lowenstein, Daniel H
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Clinical Research ,Brain Disorders ,Neurodegenerative ,Epilepsy ,Neurological ,Good Health and Well Being ,Genetic Testing ,Humans ,Precision Medicine ,Seizures ,Suggestion ,epilepsy ,exome sequencing ,genomic medicine ,personalized medicine ,precision medicine ,Neurology & Neurosurgery ,Clinical sciences - Abstract
The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.
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- 2022
4. RNA variant assessment using transactivation and transdifferentiation
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Azmanov, Dimitar N., Barnett, Christopher P., Barry, Simon C., Baynam, Gareth, Berkovic, Samuel F., Christodoulou, John, Coman, David J., Cooper, Sandra, Corbett, Mark A., Delatycki, Martin, Dudding, Tracy E., Fletcher, Sue, Gardner, Alison E., Gecz, Jozef, Higgins, Megan J., Hildebrand, Michael S., Jolly, Lachlan A., Lister, Ryan, McGaughran, Julie, Pflueger, Christian, Poulton, Cathryn, Roscioli, Tony, Hamish S. Scott, Ingrid Scheffer, Sinclair, Andrew H., Spurdle, Amanda B., Tan, Tiong Y., van Eyk, Clare L., Voineagu, Irina, Nicolas-Martinez, Emmylou C., Robinson, Olivia, Gardner, Alison, Ritchie, Tarin, Kroes, Thessa, Scheffer, Ingrid E., Barnier, Jean-Vianney, Rousseau, Véronique, Genevieve, David, Haushalter, Virginie, Piton, Amélie, Denommé-Pichon, Anne-Sophie, Bruel, Ange-Line, Nambot, Sophie, Isidor, Bertrand, Grigg, John, Gonzalez, Tina, Ghedia, Sondhya, Marchant, Rhett G., Bournazos, Adam, Wong, Wui-Kwan, Webster, Richard I., Evesson, Frances J., Jones, Kristi J., and Cooper, Sandra T.
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- 2024
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5. Somatic mosaicism in focal epilepsies
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Gooley, Samuel, Perucca, Piero, Tubb, Caitlin, Hildebrand, Michael S., and Berkovic, Samuel F.
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- 2024
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6. Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients
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Mole, Sara E, Schulz, Angela, Badoe, Eben, Berkovic, Samuel F, de Los Reyes, Emily C, Dulz, Simon, Gissen, Paul, Guelbert, Norberto, Lourenco, Charles M, Mason, Heather L, Mink, Jonathan W, Murphy, Noreen, Nickel, Miriam, Olaya, Joffre E, Scarpa, Maurizio, Scheffer, Ingrid E, Simonati, Alessandro, Specchio, Nicola, Von Löbbecke, Ina, Wang, Raymond Y, and Williams, Ruth E
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Biological Sciences ,Biomedical and Clinical Sciences ,Clinical Sciences ,Genetics ,Brain Disorders ,Neurodegenerative ,Neurosciences ,Clinical Research ,7.3 Management and decision making ,Management of diseases and conditions ,Good Health and Well Being ,Consensus ,Humans ,Neuronal Ceroid-Lipofuscinoses ,Tripeptidyl-Peptidase 1 ,Expert mapping ,Guideline development program ,CLN2 ,Batten ,Neurodegenerative disorder ,Key Opinion Leader ,Modified-Delphi ,Other Medical and Health Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
BackgroundCLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition.MethodsAn expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria.ResultsTwenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality).ConclusionThis program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available.
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- 2021
7. Shared genetic basis between genetic generalized epilepsy and background electroencephalographic oscillations
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Stevelink, Remi, Luykx, Jurjen J, Lin, Bochao D, Leu, Costin, Lal, Dennis, Smith, Alexander W, Schijven, Dick, Carpay, Johannes A, Rademaker, Koen, Baldez, Roiza A Rodrigues, Devinsky, Orrin, Braun, Kees PJ, Jansen, Floor E, Smit, Dirk JA, Koeleman, Bobby PC, Abou‐Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J, Bast, Thomas, Baum, Larry, Becker, Albert J, Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F, Boysen, Katja E, Bradfield, Jonathan P, Brody, Lawrence C, Buono, Russell J, Campbell, Ellen, Cascino, Gregory D, Catarino, Claudia B, Cavalleri, Gianpiero L, Cherny, Stacey S, Chinthapalli, Krishna, Coffey, Alison J, Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J, de Haan, Gerrit‐Jan, De Jonghe, Peter, de Kovel, Carolien GF, Delanty, Norman, Depondt, Chantal, Dlugos, Dennis J, Doherty, Colin P, Elger, Christian E, Eriksson, Johan G, Ferraro, Thomas N, Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A, Freytag, Saskia, Gaus, Verena, Geller, Eric B, Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B, Gui, Hongsheng, Guo, Youling, Haas, Kevin F, Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L, Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andrés, Jamnadas‐Khoda, Jennifer, Johnson, Michael R, Kälviäinen, Reetta, Kantanen, Anne‐Mari, Kasperavičiūte, Dalia, Trenite, Dorothee Kasteleijn‐Nolst, Kirsch, Heidi E, Knowlton, Robert C, Krause, Roland, Krenn, Martin, Kunz, Wolfram S, Kuzniecky, Ruben, Kwan, Patrick, Lau, Yu‐Lung, Lehesjoki, Anna‐Elina, Lerche, Holger, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D, Lopes‐Cendes, Iscia, Lowenstein, Daniel H, Malovini, Alberto, Marson, Anthony G, Mayer, Thomas, McCormack, Mark, and Mills, James L
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Genetics ,Brain Disorders ,Clinical Research ,Human Genome ,Neurodegenerative ,Epilepsy ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adult ,Algorithms ,Beta Rhythm ,Cohort Studies ,Databases ,Factual ,Electroencephalography ,Epilepsy ,Generalized ,Genome-Wide Association Study ,Humans ,Linkage Disequilibrium ,Mendelian Randomization Analysis ,Risk Assessment ,Theta Rhythm ,beta power ,EEG ,generalized epilepsy ,GGE ,oscillations ,PRS ,International League Against Epilepsy Consortium on Complex Epilepsies ,Epi25 Collaborative ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.
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- 2021
8. Neuropsychological function in psychosis of epilepsy
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Allebone, James, Kanaan, Richard A., Rayner, Genevieve, Maller, Jerome, O’Brien, Terence J., Mullen, Saul A., Cook, Mark, Adams, Sophia J., Vogrin, Simon, Vaughan, David N., Kwan, Patrick, Berkovic, Samuel F., D’Souza, Wendyl J., Jackson, Graeme, Velakoulis, Dennis, and Wilson, Sarah J.
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- 2023
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9. Brain mosaicism of hedgehog signalling and other cilia genes in hypothalamic hamartoma
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Green, Timothy E., Fujita, Atsushi, Ghaderi, Navid, Heinzen, Erin L., Matsumoto, Naomichi, Klein, Karl Martin, Berkovic, Samuel F., and Hildebrand, Michael S.
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- 2023
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10. Quantitative analysis of phenotypic elements augments traditional electroclinical classification of common familial epilepsies
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Abou‐Khalil, Bassel, Afawi, Zaid, Allen, Andrew S, Bautista, Jocelyn F, Bellows, Susannah T, Berkovic, Samuel F, Bluvstein, Judith, Burgess, Rosemary, Cascino, Gregory, Cossette, Patrick, Cristofaro, Sabrina, Crompton, Douglas E, Delanty, Norman, Devinsky, Orrin, Dlugos, Dennis, Ellis, Colin A, Epstein, Michael P, Fountain, Nathan B, Freyer, Catharine, Geller, Eric B, Glauser, Tracy, Glynn, Simon, Goldberg‐Stern, Hadassa, Goldstein, David B, Gravel, Micheline, Haas, Kevin, Haut, Sheryl, Heinzen, Erin L, Kirsch, Heidi E, Kivity, Sara, Knowlton, Robert, Korczyn, Amos D, Kossoff, Eric, Kuzniecky, Ruben, Loeb, Rebecca, Lowenstein, Daniel H, Marson, Anthony G, McCormack, Mark, McKenna, Kevin, Mefford, Heather C, Motika, Paul, Mullen, Saul A, J. O'Brien, Terence, Ottman, Ruth, Paolicchi, Juliann, Parent, Jack M, Paterson, Sarah, Petrou, Steven, Petrovski, Slavé, Owen Pickrell, William, Poduri, Annapurna, Rees, Mark I, Sadleir, Lynette G, Scheffer, Ingrid E, Shih, Jerry, Singh, Rani, Sirven, Joseph, Smith, Michael, Smith, Phil EM, Thio, Liu Lin, Thomas, Rhys H, Venkat, Anu, Vining, Eileen, Von Allmen, Gretchen, Weisenberg, Judith, Widdess‐Walsh, Peter, and Winawer, Melodie R
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Neurodegenerative ,Neurosciences ,Epilepsy ,Clinical Research ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Electroencephalography ,Epileptic Syndromes ,Female ,Humans ,Latent Class Analysis ,Male ,Pedigree ,Phenotype ,epilepsy ,genetics ,latent class analysis ,phenotype ,Epi4K Consortium ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
ObjectiveClassification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks.MethodsWe used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes.ResultsA total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types.SignificanceQuantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.
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- 2019
11. Comorbidities in newly diagnosed epilepsy: Pre-existing health conditions are common and complex across age groups
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McIntosh, Anne M., Carney, Patrick W., Tan, K. Meng, Hakami, Tahir M., Perucca, Piero, Kwan, Patrick, O'Brien, Terence J., and Berkovic, Samuel F.
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- 2023
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12. Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from non-progressors
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Eratne, Dhamidhu, Keem, Michael, Lewis, Courtney, Kang, Matthew, Walterfang, Mark, Farrand, Sarah, Loi, Samantha, Kelso, Wendy, Cadwallader, Claire, Berkovic, Samuel F., Li, Qiao-Xin, Masters, Colin L., Collins, Steven, Santillo, Alexander, and Velakoulis, Dennis
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- 2022
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13. Increased cortical thickness in nodes of the cognitive control and default mode networks in psychosis of epilepsy
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Allebone, James, Wilson, Sarah J, Bradlow, Richard C J, Maller, Jerome, O'Brien, Terry, Mullen, Saul A, Cook, Mark, Adams, Sophia J, Vogrin, Simon, Vaughan, David N, Connelly, Alan, Kwan, Patrick, Berkovic, Samuel F, D'Souza, Wendyl J, Jackson, Graeme, Velakoulis, Dennis, and Kanaan, Richard A
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- 2022
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14. Bi-allelic SMO variants in hypothalamic hamartoma: a recessive cause of Pallister-Hall syndrome
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Green, Timothy E., Schimmel, Mareike, Schubert, Susanna, Lemke, Johannes R., Bennett, Mark F., Hildebrand, Michael S., and Berkovic, Samuel F.
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- 2022
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15. Functional correlates of clinical phenotype and severity in recurrent SCN2A variants
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Berecki, Géza, Howell, Katherine B., Heighway, Jacqueline, Olivier, Nelson, Rodda, Jill, Overmars, Isabella, Vlaskamp, Danique R. M., Ware, Tyson L., Ardern-Holmes, Simone, Lesca, Gaetan, Alber, Michael, Veggiotti, Pierangelo, Scheffer, Ingrid E., Berkovic, Samuel F., Wolff, Markus, and Petrou, Steven
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- 2022
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16. Diagnostic delay in focal epilepsy: Association with brain pathology and age
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Yang, Mengjiazhi, Tan, K. Meng, Carney, Patrick, Kwan, Patrick, O'Brien, Terence J., Berkovic, Samuel F., Perucca, Piero, and McIntosh, Anne M.
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- 2022
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17. Familial aggregation of seizure outcomes in four familial epilepsy cohorts.
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Ellis, Colin A., Tu, Danni, Oliver, Karen L., Mefford, Heather C., Hauser, W. Allen, Buchhalter, Jeffrey, Epstein, Michael P., Cao, Quy, Berkovic, Samuel F., and Ottman, Ruth
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EPILEPSY ,SEIZURES (Medicine) ,INTRACLASS correlation ,PEOPLE with epilepsy - Abstract
Objective: To assess the possible effects of genetics on seizure outcome by estimating the familial aggregation of three outcome measures: seizure remission, history of ≥4 tonic–clonic seizures, and seizure control for individuals taking antiseizure medication. Methods: We analyzed families containing multiple persons with epilepsy in four previously collected retrospective cohorts. Seizure remission was defined as being 5 and 10 years seizure‐free at last observation. Total number of tonic–clonic seizures was dichotomized at <4 and ≥4 seizures. Seizure control in patients taking antiseizure medication was defined as no seizures for 1, 2, and 3 years. We used Bayesian generalized linear mixed‐effects model (GLMM) to estimate the intraclass correlation coefficient (ICC) of the family‐specific random effect, controlling for epilepsy type, age at epilepsy onset, and age at last data collection as fixed effects. We analyzed each cohort separately and performed meta‐analysis using GLMMs. Results: The combined cohorts included 3644 individuals with epilepsy from 1463 families. A history of ≥4 tonic–clonic seizures showed strong familial aggregation in three separate cohorts and meta‐analysis (ICC.28, 95% confidence interval [CI].21–.35, Bayes factor 8 × 1016). Meta‐analyses did not reveal significant familial aggregation of seizure remission (ICC.08, 95% CI.01–.17, Bayes factor 1.46) or seizure control for individuals taking antiseizure medication (ICC.13, 95% CI 0–.35, Bayes factor 0.94), with heterogeneity among cohorts. Significance: A history of ≥4 tonic–clonic seizures aggregated strongly in families, suggesting a genetic influence, whereas seizure remission and seizure control for individuals taking antiseizure medications did not aggregate consistently in families. Different seizure outcomes may have different underlying biology and risk factors. These findings should inform the future molecular genetic studies of seizure outcomes. [ABSTRACT FROM AUTHOR]
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- 2024
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18. De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures.
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Myers, Candace T, Stong, Nicholas, Mountier, Emily I, Helbig, Katherine L, Freytag, Saskia, Sullivan, Joseph E, Ben Zeev, Bruria, Nissenkorn, Andreea, Tzadok, Michal, Heimer, Gali, Shinde, Deepali N, Rezazadeh, Arezoo, Regan, Brigid M, Oliver, Karen L, Ernst, Michelle E, Lippa, Natalie C, Mulhern, Maureen S, Ren, Zhong, Poduri, Annapurna, Andrade, Danielle M, Bird, Lynne M, Bahlo, Melanie, Berkovic, Samuel F, Lowenstein, Daniel H, Scheffer, Ingrid E, Sadleir, Lynette G, Goldstein, David B, Mefford, Heather C, and Heinzen, Erin L
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Humans ,Epilepsy ,Spasms ,Infantile ,Calcineurin ,Severity of Illness Index ,Cohort Studies ,Sequence Analysis ,DNA ,Synaptic Transmission ,Mutation ,Adolescent ,Adult ,Child ,Child ,Preschool ,Infant ,Infant ,Newborn ,Female ,Male ,Young Adult ,Exome ,Lennox Gastaut Syndrome ,Neurodevelopmental Disorders ,PPP3CA ,calcineurin ,de novo mutation ,developmental and epileptic encephalopathy ,epilepsy ,Brain Disorders ,Neurodegenerative ,Pediatric ,Genetics ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Good Health and Well Being ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10-8) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.
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- 2017
19. What is the motor vehicle crash risk for drivers with epilepsy? A systematic review
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Koppel, Sjaan, Di Stefano, Marilyn, Dimech-Betancourt, Bleydy, Aburumman, Mohammed, Osborne, Rachel, Peiris, Sujanie, Williams, Gabrielle, McInnes, Aaron, Stephens, Amanda, Odell, Morris, Darzins, Peteris, Carney, Patrick, Cook, Mark, Berkovic, Samuel F., Rapoport, Mark J., Dow, Jamie, O'Neill, Des, and Charlton, Judith L.
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- 2021
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20. Applying the ILAE diagnostic criteria for Lennox‐Gastaut syndrome in the real‐world setting: A multicenter retrospective cohort study
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Nightscales, Russell, primary, Chen, Zhibin, additional, Barnard, Sarah, additional, Auvrez, Clarissa, additional, Tao, Gerard, additional, Sivathamboo, Shobi, additional, Bennett, Caitlin, additional, Rychkova, Maria, additional, D'Souza, Wendyl, additional, Berkovic, Samuel F., additional, Nicolo, John‐Paul, additional, O'Brien, Terence J., additional, Perucca, Piero, additional, Scheffer, Ingrid E., additional, and Kwan, Patrick, additional
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- 2024
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21. Are Germline Mosaic TSC1/2 Variants Present in Controls? Implications for Diagnosis
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Ye, Zimeng, primary, Lin, Sufang, additional, Zhao, Xia, additional, Wallis, Mathew, additional, Gao, Xinyi, additional, Sun, Li, additional, Wu, Jiarui, additional, Duan, Jing, additional, Yao, Yi, additional, Li, Lin, additional, Chen, Li, additional, Cao, Dezhi, additional, Hu, Zhanqi, additional, Zhang, Victor W., additional, Berkovic, Samuel F., additional, Scheffer, Ingrid E., additional, Liao, Jianxiang, additional, and Hildebrand, Michael S., additional
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- 2024
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22. GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons
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Bryson, Alexander, Hatch, Robert John, Zandt, Bas-Jan, Rossert, Christian, Berkovic, Samuel F., Reid, Christopher A., Grayden, David B., Hill, Sean L., and Petrou, Steven
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- 2020
23. Somatic Mosaic Pathogenic Variant Gradient Detected in Trace Brain Tissue From Stereo-EEG Depth Electrodes
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Ye, Zimeng, Bennett, Mark F., Neal, Andrew, Laing, Joshua A., Hunn, Martin K., Wittayacharoenpong, Thanomporn, Todaro, Marian, Patel, Sheila K., Bahlo, Melanie, Kwan, Patrick, OʼBrien, Terence J., Scheffer, Ingrid E., Berkovic, Samuel F., Perucca, Piero, and Hildebrand, Michael S.
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- 2022
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24. Contribution of rare genetic variants to drug response in absence epilepsy
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Myers, Kenneth A., Bennett, Mark F., Grinton, Bronwyn E., Dabscheck, Gabriel, Chan, Eunice K., Bello-Espinosa, Luis E., Sadleir, Lynette G., D’Alfonso, Sabrina, Schneider, Amy L., Damiano, John A., Hildebrand, Michael S., Bahlo, Melanie, Berkovic, Samuel F., Buchhalter, Jeffrey, and Scheffer, Ingrid E.
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- 2021
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25. The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective
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Eratne, Dhamidhu, Schneider, Amy, Lynch, Ella, Martyn, Melissa, Velakoulis, Dennis, Fahey, Michael, Kwan, Patrick, Leventer, Richard, Rafehi, Haloom, Chong, Belinda, Stark, Zornitza, Lunke, Sebastian, Phelan, Dean G., O'Keefe, Melanie, Siemering, Kirby, West, Kirsty, Sexton, Adrienne, Jarmolowicz, Anna, Taylor, Jessica A., Schultz, Joshua, Purvis, Rebecca, Uebergang, Eloise, Chalinor, Heather, Creighton, Belinda, Gelfand, Nikki, Saks, Tamar, Prawer, Yael, Smagarinsky, Yana, Pan, Tianxin, Goranitis, Ilias, Ademi, Zanfina, Gaff, Clara, Huq, Aamira, Walsh, Maie, James, Paul A., Krzesinski, Emma I., Wallis, Mathew, Stutterd, Chloe A., Bahlo, Melanie, Delatycki, Martin B., and Berkovic, Samuel F.
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- 2021
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26. Phenotypic analysis of 303 multiplex families with common epilepsies.
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Abou-Khalil, Bassel, Afawi, Zaid, Allen, Andrew S, Bautista, Jocelyn F, Bellows, Susannah T, Berkovic, Samuel F, Bluvstein, Judith, Burgess, Rosemary, Cascino, Gregory, Cops, Elisa J, Cossette, Patrick, Cristofaro, Sabrina, Crompton, Douglas E, Delanty, Norman, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P, Fountain, Nathan B, Freyer, Catharine, Garry, Sarah I, Geller, Eric B, Glauser, Tracy, Glynn, Simon, Goldberg-Stern, Hadassa, Goldstein, David B, Gravel, Micheline, Haas, Kevin, Haut, Sheryl, Heinzen, Erin L, Kirsch, Heidi E, Kivity, Sara, Knowlton, Robert, Korczyn, Amos D, Kossoff, Eric, Kuzniecky, Ruben, Loeb, Rebecca, Lowenstein, Daniel H, Marson, Anthony G, McCormack, Mark, McKenna, Kevin, Mefford, Heather C, Motika, Paul, Mullen, Saul A, O'Brien, Terence J, Ottman, Ruth, Paolicchi, Juliann, Parent, Jack M, Paterson, Sarah, Petrovski, Slave, Pickrell, William Owen, Poduri, Annapurna, Rees, Mark I, Sadleir, Lynette G, Scheffer, Ingrid E, Shih, Jerry, Singh, Rani, Sirven, Joseph, Smith, Michael, Smith, Phil EM, Thio, Liu Lin, Thomas, Rhys H, Venkat, Anu, Vining, Eileen, Von Allmen, Gretchen, Weisenberg, Judith, Widdess-Walsh, Peter, and Winawer, Melodie R
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Genetics ,Clinical Research ,Brain Disorders ,Pediatric ,Neurosciences ,Epilepsy ,Neurodegenerative ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adolescent ,Age of Onset ,Child ,Child ,Preschool ,Epilepsy ,Generalized ,Family Health ,Female ,Humans ,Male ,Pedigree ,Phenotype ,Sex Factors ,Young Adult ,epilepsy ,multiplex families ,phenotype ,genetics ,Epi4K Consortium ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one-third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and inter-relationships of the common epilepsy syndromes.
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- 2017
27. A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations
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Zhu, Xiaolin, Padmanabhan, Raghavendra, Copeland, Brett, Bridgers, Joshua, Ren, Zhong, Kamalakaran, Sitharthan, O'Driscoll-Collins, Ailbhe, Berkovic, Samuel F, Scheffer, Ingrid E, Poduri, Annapurna, Mei, Davide, Guerrini, Renzo, Lowenstein, Daniel H, Allen, Andrew S, Heinzen, Erin L, and Goldstein, David B
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Biological Sciences ,Genetics ,Neurodegenerative ,Biotechnology ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Case-Control Studies ,DNA Mutational Analysis ,Epilepsy ,Female ,Genes ,Dominant ,Genome-Wide Association Study ,Humans ,Male ,Munc18 Proteins ,Mutation ,NAV1.2 Voltage-Gated Sodium Channel ,Nerve Tissue Proteins ,Potassium Channels ,Potassium Channels ,Sodium-Activated ,Exome Sequencing ,Developmental Biology - Abstract
Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants. Despite modest sample size, three known EE genes (KCNT1, SCN2A, and STXBP1) achieved genome-wide significance (p
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- 2017
28. The use of Spect in Focal Epilepsy
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Berkovic, Samuel F., primary and Rowe, Christopher C., additional
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- 2021
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29. Enlarged hippocampal fissure in psychosis of epilepsy
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Allebone, James, Kanaan, Richard A., Maller, Jerome J., O'Brien, Terrence, Mullen, Saul, Cook, Mark, Adams, Sophie, Vogrin, Simon, Vaughan, David, Connelly, Alan, Kwan, Patrick, Berkovic, Samuel F., D'Souza, Wendyl, Jackson, Graeme, Velakoulis, Dennis, and Wilson, Sarah J.
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- 2020
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30. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns
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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.
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- 2021
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31. EXOME REPORT: Novel mutation in ATP6V1B2 segregating with autosomal dominant epilepsy, intellectual disability and mild gingival and nail abnormalities
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Shaw, Marie, Winczewska-Wiktor, Anna, Badura-Stronka, Magdalena, Koirala, Sunita, Gardner, Alison, Kuszel, Łukasz, Kowal, Piotr, Steinborn, Barbara, Starczewska, Monika, Garry, Sarah, Scheffer, Ingrid E., Berkovic, Samuel F., and Gecz, Jozef
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- 2020
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32. Epilepsy genetics: clinical impacts and biological insights
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Ellis, Colin A, Petrovski, Slavé, and Berkovic, Samuel F
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- 2020
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33. De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies
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Consortium, Epi4K, Myers, Candace T, McMahon, Jacinta M, Schneider, Amy L, Petrovski, Slavé, Allen, Andrew S, Carvill, Gemma L, Zemel, Matthew, Saykally, Julia E, LaCroix, Amy J, Heinzen, Erin L, Hollingsworth, Georgina, Nikanorova, Marina, Corbett, Mark, Gecz, Jozef, Coman, David, Freeman, Jeremy, Calvert, Sophie, Gill, Deepak, Carney, Patrick, Lerman-Sagie, Tally, Sampaio, Hugo, Cossette, Patrick, Delanty, Norman, Dlugos, Dennis, Eichler, Evan E, Epstein, Michael P, Glauser, Tracy, Johnson, Michael R, Kuzniecky, Ruben, Marson, Anthony G, O’Brien, Terence J, Ottman, Ruth, Petrou, Stephen, Poduri, Annapurna, Pickrell, William O, Chung, Seo-Kyung, Rees, Mark I, Sherr, Elliott, Sadleir, Lynette G, Goldstein, David B, Lowenstein, Daniel H, Møller, Rikke S, Berkovic, Samuel F, Scheffer, Ingrid E, and Mefford, Heather C
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Human Genome ,Brain Disorders ,Pediatric ,Prevention ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Adolescent ,Adult ,Alleles ,Calcium Channels ,Child ,Preschool ,Cohort Studies ,Epilepsy ,Excitatory Amino Acid Transporter 2 ,Female ,GTP-Binding Protein alpha Subunits ,Gi-Go ,Glutamate Plasma Membrane Transport Proteins ,Guanine Nucleotide Exchange Factors ,Humans ,Infant ,Infant ,Newborn ,Male ,Mosaicism ,Mutation ,N-Acetylglucosaminyltransferases ,Receptors ,GABA-A ,Seizures ,Epi4K Consortium ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Epileptic encephalopathies (EEs) are the most clinically important group of severe early-onset epilepsies. Next-generation sequencing has highlighted the crucial contribution of de novo mutations to the genetic architecture of EEs as well as to their underlying genetic heterogeneity. Our previous whole-exome sequencing study of 264 parent-child trios revealed more than 290 candidate genes in which only a single individual had a de novo variant. We sought to identify additional pathogenic variants in a subset (n = 27) of these genes via targeted sequencing in an unsolved cohort of 531 individuals with a diverse range of EEs. We report 17 individuals with pathogenic variants in seven of the 27 genes, defining a genetic etiology in 3.2% of this unsolved cohort. Our results provide definitive evidence that de novo mutations in SLC1A2 and CACNA1A cause specific EEs and expand the compendium of clinically relevant genotypes for GABRB3. We also identified EEs caused by genetic variants in ALG13, DNM1, and GNAO1 and report a mutation in IQSEC2. Notably, recurrent mutations accounted for 7/17 of the pathogenic variants identified. As a result of high-depth coverage, parental mosaicism was identified in two out of 14 cases tested with mutant allelic fractions of 5%-6% in the unaffected parents, carrying significant reproductive counseling implications. These results confirm that dysregulation in diverse cellular neuronal pathways causes EEs, and they will inform the diagnosis and management of individuals with these devastating disorders.
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- 2016
34. Identifying individuals with rare disease variants by inferring shared ancestral haplotypes from SNP array data
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Robertson, Erandee, primary, Grinton, Bronwyn E, additional, Oliver, Karen L, additional, Fearnley, Liam G, additional, Hildebrand, Michael S, additional, Sadleir, Lynette G, additional, Scheffer, Ingrid E, additional, Berkovic, Samuel F, additional, Bennett, Mark F, additional, and Bahlo, Melanie, additional
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- 2023
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35. Exploring individual fixel-based white matter abnormalities in epilepsy
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Mito, Remika, primary, Pedersen, Mangor, additional, Pardoe, Heath, additional, Parker, Donna, additional, Smith, Robert E, additional, Cameron, Jillian, additional, Scheffer, Ingrid E, additional, Berkovic, Samuel F, additional, Vaughan, David N, additional, and Jackson, Graeme D, additional
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- 2023
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36. Atenolol reduces cardiac-mediated mortality in a genetic mouse model of sudden unexpected death in epilepsy
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Soh, Ming S., primary, Kuanyshbek, Alibek, additional, Syazwan, Erlina S. Mohamed, additional, Lee, Hian M., additional, McKenzie, Chaseley E., additional, Phillips, A. Marie, additional, Hu, Amanda, additional, Scheffer, Ingrid E., additional, Semsarian, Christopher, additional, Berkovic, Samuel F., additional, and Reid, Christopher A., additional
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- 2023
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37. Hypothalamic Hamartomas: Evolving Understanding and Management
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Cohen, Nathan T., Cross, J. Helen, Arzimanoglou, Alexis, Berkovic, Samuel F., Kerrigan, John F., Miller, Ilene Penn, Webster, Erica, Soeby, Lisa, Cukiert, Arthur, Hesdorffer, Dale K., Kroner, Barbara L., Saper, Clifford B., Schulze-Bonhage, Andreas, and Gaillard, William D.
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- 2021
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38. Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy
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Bennett, Mark F., Hildebrand, Michael S., Kayumi, Sayaka, Corbett, Mark A., Gupta, Sachin, Ye, Zimeng, Krivanek, Michael, Burgess, Rosemary, Henry, Olivia J., Damiano, John A., Boys, Amber, Gécz, Jozef, Bahlo, Melanie, Scheffer, Ingrid E., and Berkovic, Samuel F.
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- 2022
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39. Familial adult myoclonic epilepsy type 1 SAMD12 TTTCA repeat expansion arose 17,000 years ago and is present in Sri Lankan and Indian families
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Bennett, Mark F., Oliver, Karen L., Regan, Brigid M., Bellows, Susannah T., Schneider, Amy L., Rafehi, Haloom, Sikta, Neblina, Crompton, Douglas E., Coleman, Matthew, Hildebrand, Michael S., Corbett, Mark A., Kroes, Thessa, Gecz, Jozef, Scheffer, Ingrid E., Berkovic, Samuel F., and Bahlo, Melanie
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- 2020
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40. Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy
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Allen, Andrew S, Berkovic, Samuel F, Coe, Bradley P, Cook, Joseph, Cossette, Patrick, Delanty, Norman, Dlugos, Dennis, Eichler, Evan E, Epstein, Michael P, Glauser, Tracy, Goldstein, David B, Heinzen, Erin L, Johnson, Michael R, Krumm, Nik, Kuzniecky, Ruben, Lowenstein, Daniel H, Marson, Anthony G, Mefford, Heather C, Nelson, Ben, Esmaeeli Nieh, Sahar, O'Brien, Terence J, Ottman, Ruth, Petrou, Stephen, Petrovski, Slavé, Poduri, Annapurna, Raja, Archana, Ruzzo, Elizabeth K, Scheffer, Ingrid E, Sherr, Elliott, Abou‐Khalil, Bassel, Alldredge, Brian K, Andermann, Eva, Andermann, Frederick, Amron, Dina, Bautista, Jocelyn F, Boro, Alex, Cascino, Gregory, Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Fiol, Miguel, Fountain, Nathan B, French, Jacqueline, Friedman, Daniel, Geller, Eric B, Glynn, Simon, Haut, Sheryl R, Hayward, Jean, Helmers, Sandra L, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E, Knowlton, Robert C, Kossoff, Eric H, Kuperman, Rachel, McGuire, Shannon M, Motika, Paul V, Novotny, Edward J, Paolicchi, Juliann M, Parent, Jack, Park, Kristen, Shellhaas, Renée A, Shih, Jerry J, Singh, Rani, Sirven, Joseph, Smith, Michael C, Sullivan, Joe, Thio, Liu Lin, Venkat, Anu, Vining, Eileen PG, Von Allmen, Gretchen K, Weisenberg, Judith L, Widdess‐Walsh, Peter, and Winawer, Melodie R
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Neurodegenerative ,Genetics ,Intellectual and Developmental Disabilities (IDD) ,Epilepsy ,Pediatric ,Clinical Research ,Brain Disorders ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Adult ,Child ,Preschool ,Cohort Studies ,DNA Copy Number Variations ,Exome ,Female ,Humans ,Infant ,Infant ,Newborn ,Lennox Gastaut Syndrome ,Male ,Parents ,Sequence Analysis ,DNA ,Spasms ,Infantile ,Epilepsy Phenome/Genome Project Epi4K Consortium ,Neurology & Neurosurgery ,Clinical sciences - Abstract
Infantile spasms (IS) and Lennox-Gastaut syndrome (LGS) are epileptic encephalopathies characterized by early onset, intractable seizures, and poor developmental outcomes. De novo sequence mutations and copy number variants (CNVs) are causative in a subset of cases. We used exome sequence data in 349 trios with IS or LGS to identify putative de novo CNVs. We confirm 18 de novo CNVs in 17 patients (4.8%), 10 of which are likely pathogenic, giving a firm genetic diagnosis for 2.9% of patients. Confirmation of exome-predicted CNVs by array-based methods is still required due to false-positive rates of prediction algorithms. Our exome-based results are consistent with recent array-based studies in similar cohorts and highlight novel candidate genes for IS and LGS.
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- 2015
41. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
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Appenzeller, Silke, Balling, Rudi, Barisic, Nina, Baulac, Stéphanie, Caglayan, Hande, Craiu, Dana, De Jonghe, Peter, Depienne, Christel, Dimova, Petia, Djémié, Tania, Gormley, Padhraig, Guerrini, Renzo, Helbig, Ingo, Hjalgrim, Helle, Hoffman-Zacharska, Dorota, Jähn, Johanna, Klein, Karl Martin, Koeleman, Bobby, Komarek, Vladimir, Krause, Roland, Kuhlenbäumer, Gregor, Leguern, Eric, Lehesjoki, Anna-Elina, Lemke, Johannes R, Lerche, Holger, Linnankivi, Tarja, Marini, Carla, May, Patrick, Møller, Rikke S, Muhle, Hiltrud, Pal, Deb, Palotie, Aarno, Pendziwiat, Manuela, Robbiano, Angela, Roelens, Filip, Rosenow, Felix, Selmer, Kaja, Serratosa, Jose M, Sisodiya, Sanjay, Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Suls, Arvid, Talvik, Tiina, von Spiczak, Sarah, Weber, Yvonne, Weckhuysen, Sarah, Zara, Federico, Abou-Khalil, Bassel, Alldredge, Brian K, Andermann, Eva, Andermann, Frederick, Amron, Dina, Bautista, Jocelyn F, Berkovic, Samuel F, Bluvstein, Judith, Boro, Alex, Cascino, Gregory, Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P, Fiol, Miguel, Fountain, Nathan B, French, Jacqueline, Friedman, Daniel, Geller, Eric B, Glauser, Tracy, Glynn, Simon, Haas, Kevin, Haut, Sheryl R, Hayward, Jean, Helmers, Sandra L, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E, Knowlton, Robert C, Kossoff, Eric H, Kuperman, Rachel, Kuzniecky, Ruben, Lowenstein, Daniel H, McGuire, Shannon M, Motika, Paul V, Novotny, Edward J, Ottman, Ruth, Paolicchi, Juliann M, Parent, Jack, Park, Kristen, Poduri, Annapurna, Sadleir, Lynette, Scheffer, Ingrid E, Shellhaas, Renée A, Sherr, Elliott, Shih, Jerry J, Singh, Rani, Sirven, Joseph, Smith, Michael C, Sullivan, Joe, and Thio, Liu Lin
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Genetics ,Pediatric ,Neurosciences ,Epilepsy ,Brain Disorders ,Neurodegenerative ,2.1 Biological and endogenous factors ,Aetiology ,Cohort Studies ,Dynamin I ,Exome ,Fatty Acid Synthase ,Type I ,Female ,Gene Regulatory Networks ,Humans ,Infant ,Newborn ,Lennox Gastaut Syndrome ,Male ,Mutation ,Protein Interaction Maps ,Receptors ,GABA-B ,Ryanodine Receptor Calcium Release Channel ,Spasms ,Infantile ,Synaptic Transmission ,EuroEPINOMICS-RES Consortium ,Epilepsy Phenome/Genome Project ,Epi4K Consortium ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.
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- 2014
42. Somatic mutation: The hidden genetics of brain malformations and focal epilepsies
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Ye, Zimeng, McQuillan, Lara, Poduri, Annapurna, Green, Timothy E., Matsumoto, Naomichi, Mefford, Heather C., Scheffer, Ingrid E., Berkovic, Samuel F., and Hildebrand, Michael S.
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- 2019
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43. Predominantly nocturnal seizures post temporal lobectomy: Characteristics of an unusual outcome group
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Samarasekera, Shanika R., Wynd, Alex W., McIntosh, Anne M., and Berkovic, Samuel F.
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- 2019
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44. Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis
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Mole, Sara E, Anderson, Glenn, Band, Heather A, Berkovic, Samuel F, Cooper, Jonathan D, Kleine Holthaus, Sophia-Martha, McKay, Tristan R, Medina, Diego L, Rahim, Ahad A, Schulz, Angela, and Smith, Alexander J
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- 2019
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45. Association of Short-term Heart Rate Variability and Sudden Unexpected Death in Epilepsy
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Sivathamboo, Shobi, Friedman, Daniel, Laze, Juliana, Nightscales, Russell, Chen, Zhibin, Kuhlmann, Levin, Devore, Sasha, Macefield, Vaughan, Kwan, Patrick, DʼSouza, Wendyl, Berkovic, Samuel F., Perucca, Piero, OʼBrien, Terence J., Devinsky, Orrin, Faroque, Pue, Hesdorffer, Dale C., EdM, Sylwia Misiewicz, Moseley, Brian D., Mendoza, Lucy, Bergey, Gregory, Johnson, Emily L., McIntosh, Anne, Barnard, Rodrigo Sarah, Zuniga, Alberto Rocamora, Enr´ıquez, Carmen P´erez-, and P´erez, Eva Suzana
- Published
- 2021
- Full Text
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46. Progressive Myoclonus Epilepsies: Diagnostic Yield With Next-Generation Sequencing in Previously Unsolved Cases
- Author
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Canafoglia, Laura, Franceschetti, Silvana, Gambardella, Antonio, Striano, Pasquale, Giallonardo, Anna Teresa, Tinuper, Paolo, Di Bonaventura, Carlo, Michelucci, Roberto, Ferlazzo, Edoardo, Granata, Tiziana, Magaudda, Adriana, Licchetta, Laura, Filla, Alessandro, La Neve, Angela, Riguzzi, Patrizia, Cantisani, Teresa Anna, Fanella, Martina, CASTELLOTTI, BARBARA, Gellera, Cinzia, Bahlo, Melanie, Zara, Federico, Courage, Carolina, Lehesjoki, Anna-Elina, Oliver, Karen L., and Berkovic, Samuel F.
- Published
- 2021
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47. Association Between Psychiatric Comorbidities and Mortality in Epilepsy
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Tao, Gerard, Auvrez, Clarissa, Nightscales, Russell, Barnard, Sarah, McCartney, Lara, Malpas, Charles B., Perucca, Piero, Chen, Zhibin, Adams, Sophia, McIntosh, Anne, Ignatiadis, Sophia, OʼBrien, Patrick, Cook, Mark J., Kwan, Patrick, Berkovic, Samuel F., DʼSouza, Wendyl, Velakoulis, Dennis, and OʼBrien, Terence J.
- Published
- 2021
- Full Text
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48. Somatic Mutations in Cerebral Cortical Malformations
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Jamuar, Saumya S, Lam, Anh-Thu N, Kircher, Martin, D'Gama, Alissa M, Wang, Jian, Barry, Brenda J, Zhang, Xiaochang, Hill, Robert Sean, Partlow, Jennifer N, Rozzo, Aldo, Servattalab, Sarah, Mehta, Bhaven K, Topcu, Meral, Amrom, Dina, Andermann, Eva, Dan, Bernard, Parrini, Elena, Guerrini, Renzo, Scheffer, Ingrid E, Berkovic, Samuel F, Leventer, Richard J, Shen, Yiping, Wu, Bai Lin, Barkovich, A James, Sahin, Mustafa, Chang, Bernard S, Bamshad, Michael, Nickerson, Deborah A, Shendure, Jay, Poduri, Annapurna, Yu, Timothy W, and Walsh, Christopher A
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Genetics ,Intellectual and Developmental Disabilities (IDD) ,Mental Health ,Human Genome ,Genetic Testing ,Neurosciences ,Brain Disorders ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Cerebral Cortex ,Classical Lissencephalies and Subcortical Band Heterotopias ,DNA Mutational Analysis ,Humans ,Lissencephaly ,Magnetic Resonance Imaging ,Malformations of Cortical Development ,Mutation ,Periventricular Nodular Heterotopia ,Medical and Health Sciences ,General & Internal Medicine - Abstract
BackgroundAlthough there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated.MethodsUsing a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.ResultsValidated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.ConclusionsTargeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).
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- 2014
49. The role of copy number variants in the genetic architecture of common familial epilepsies.
- Author
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Almanza Fuerte, Edith P., Nguyen, John, Mehaffey, Michelle, Sulovari, Arvis, Wang, Tianyun, Galey, Miranda, Miller, Danny E., Eichler, Evan E., Mefford, Heather C., Abou‐Khalil, Bassel, Afawi, Zaid Afawi, Allen, Andrew S., Amrom, Dina, Andermann, Eva, Bautista, Jocelyn F., Bellows, Susannah T., Berkovic, Samuel F., Bluvstein, Judith, Boro, Alexis, and Burgess, Rosemary
- Subjects
EPILEPSY ,DNA copy number variations ,CHROMOSOME duplication ,GENETIC variation ,PARTIAL epilepsy ,GENETIC testing - Abstract
Objective: Copy number variants (CNVs) contribute to genetic risk and genetic etiology of both rare and common epilepsies. Whereas many studies have explored the role of CNVs in sporadic or severe cases, fewer have been done in familial generalized and focal epilepsies. Methods: We analyzed exome sequence data from 267 multiplex families and 859 first‐degree relative pairs with a diagnosis of genetic generalized epilepsies or nonacquired focal epilepsies to predict CNVs. Validation and segregation studies were performed using an orthogonal method when possible. Results: We identified CNVs likely to contribute to epilepsy risk or etiology in the probands of 43 of 1116 (3.9%) families, including known recurrent CNVs (16p13.11 deletion, 15q13.3 deletion, 15q11.2 deletion, 16p11.2 duplication, 1q21.1 duplication, and 5‐Mb duplication of 15q11q13). We also identified CNVs affecting monogenic epilepsy genes, including four families with CNVs disrupting the DEPDC5 gene, and a de novo deletion of HNRNPU in one affected individual from a multiplex family. Several large CNVs (>500 kb) of uncertain clinical significance were identified, including a deletion in 18q, a large duplication encompassing the SCN1A gene, and a 15q13.3 duplication (BP4‐BP5). Significance: The overall CNV landscape in common familial epilepsies is similar to that of sporadic epilepsies, with large recurrent deletions at 15q11, 15q13, and 16p13 contributing in 2.5%–3% of families. CNVs that interrupt known epilepsy genes and rare, large CNVs were also identified. Multiple etiologies were found in a subset of families, emphasizing the importance of genetic testing for multiple affected family members. Rare CNVs found in a single proband remain difficult to interpret and require larger cohorts to confirm their potential role in disease. Overall, our work indicates that CNVs contribute to the complex genetic architecture of familial generalized and focal epilepsies, supporting the role for clinical testing in affected individuals. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
50. Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders.
- Author
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Kang, Matthew J. Y., Eratne, Dhamidhu, Dobson, Hannah, Malpas, Charles B., Keem, Michael, Lewis, Courtney, Grewal, Jasleen, Tsoukra, Vivian, Dang, Christa, Mocellin, Ramon, Kalincik, Tomas, Santillo, Alexander F., Zetterberg, Henrik, Blennow, Kaj, Stehmann, Christiane, Varghese, Shiji, Li, Qiao-Xin, Masters, Colin L., Collins, Steven, and Berkovic, Samuel F.
- Subjects
PEOPLE with mental illness ,CEREBROSPINAL fluid ,CYTOPLASMIC filaments ,DELAYED diagnosis ,MILD cognitive impairment - Abstract
Objective: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. Methods: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. Results: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. Conclusions: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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