Andreas Brunklaus1,2, Juanjiangmeng Du3, Felix Steckler1,2, Ismael I Ghanty1,2, Katrine M Johannesen4,5, Christina Dühring Fenger4,6, Stephanie Schorge7,8, David Baez-Nieto9, Hao-Ran Wang9, Andrew Allen9, Jen Q Pan9, Holger Lerche10, Henrike Heyne9,11,12, Joseph D Symonds1,2, Sameer M Zuberi1,2, Stephan Sanders13, Beth R Sheidley14, Dana Craiu15,16, Heather E Olson14, Sarah Weckhuysen17,18,19, Peter DeJonge17,18,19, Ingo Helbig20,21,22,23,24, Hilde Van Esch25, Tiffany Busa26, Matthieu Milh27,28, Bertrand Isidor29, Christel Depienne30,31, Annapurna Poduri14,32, Arthur J Campbell8, Jordane Dimidschstein9, Rikke S Møller4,5, Dennis Lal3,9,11,33,34. 1. Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK. 2. School of Medicine, University of Glasgow, Glasgow, UK. 3. Cologne Center for Genomics, University of Cologne, University Hospital Cologne, Cologne, Germany. 4. Deparment of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center Filadelfia, Dianalund, Denmark. 5. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark. 6. Amplexa Genetics, Odense, Denmark. 7. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK. 8. School of Pharmacy, University College London, London, UK. 9. Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts. 10. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany. 11. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts. 12. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. 13. Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California. 14. Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts. 15. Carol Davila University of Medicine, Department of Clinical Neurosciences, Pediatric Neurology Discipline, Bucharest, Romania. 16. Alexandru Obregia Hospital, Pediatric Neurology Clinic, Bucharest, Romania. 17. Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium. 18. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. 19. Department of Neurology, University Hospital Antwerp, Antwerp, Belgium. 20. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 21. Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 22. Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 23. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 24. Department of Neuropediatrics, University of Kiel, Kiel, Germany. 25. Department of Human Genetics and Center for Human Genetics, Laboratory for Genetics of Cognition, University Hospitals Leuven, Leuven, Belgium. 26. Genetics Department, Timone Enfants University Hospital Center, Public Assistance-Marseille Hospitals, Marseille, France. 27. Medical Genetics and Functional Genomics, National Institute of Health and Medical Research, Mixed Unit of Research S910, Aix-Marseille University, Marseille, France. 28. Hematology Laboratory, Le Mans Hospital Center, Le Mans, France. 29. Medical Genetics Department, Nantes University Hospital Center, Nantes, France. 30. Institute of Human Genetics, Essen University Hospital, Essen, Germany. 31. Brain and Spinal Cord Institute, National Institute of Health and Medical Research, Unit 1127, National Center for Scientific Research, Mixed Unit of Research 7225, Sorbonne Universities, Pierre and Marie Curie University, Mixed Unit of Research S 1127, Brain & Spine Institute, Paris, France. 32. Harvard Medical School, Boston, Massachusetts. 33. Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio. 34. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Abstract
OBJECTIVE: Voltage-gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain-expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN-related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone. METHODS: We analyzed genotype-phenotype correlations in large SCN-patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders. RESULTS: Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy-associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain-of-function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed. SIGNIFICANCE: Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered. Wiley Periodicals, Inc.
OBJECTIVE: Voltage-gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain-expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN-related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone. METHODS: We analyzed genotype-phenotype correlations in large SCN-patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of humanSCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders. RESULTS: Comparing 865 epilepsypatients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy-associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain-of-function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed. SIGNIFICANCE: Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered. Wiley Periodicals, Inc.
Authors: Andreas Brunklaus; Eduardo Pérez-Palma; Ismael Ghanty; Ji Xinge; Eva Brilstra; Berten Ceulemans; Nicole Chemaly; Iris de Lange; Christel Depienne; Renzo Guerrini; Davide Mei; Rikke S Møller; Rima Nabbout; Brigid M Regan; Amy L Schneider; Ingrid E Scheffer; An-Sofie Schoonjans; Joseph D Symonds; Sarah Weckhuysen; Michael W Kattan; Sameer M Zuberi; Dennis Lal Journal: Neurology Date: 2022-01-24 Impact factor: 11.800
Authors: Anne M Rochtus; Richard D Goldstein; Ingrid A Holm; Catherine A Brownstein; Eduardo Pérez-Palma; Robin Haynes; Dennis Lal; Annapurna H Poduri Journal: Mol Genet Genomic Med Date: 2020-05-25 Impact factor: 2.183
Authors: Scott K Adney; John J Millichap; Jean-Marc DeKeyser; Tatiana Abramova; Christopher H Thompson; Alfred L George Journal: Ann Clin Transl Neurol Date: 2020-08-04 Impact factor: 4.511
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