We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

'L Sacco' Department of Biomedical and Clinical Sciences University of Milan 20157 Milan Italy

1 M Sechenov 1st Moscow State Medical University 100000 Moscow Russia

Academic Center for Epileptology Kempenhaeghe Maastricht University Medical Center 5591 Heeze The Netherlands

Analytic and Translational Genetics Unit Massachusetts General Hospital Boston MA 02108 USA

Center for Pediatric Neurology Cleveland Clinic Cleveland OH 44102 USA

Center for Rare Diseases Department of Pediatrics and Department of Clinical Genetics Copenhagen University Hospital Rigshospitalet 2200 Copenhagen Denmark

Child Neurology and Clinical Neurophysiology Unit Padova University Hospital 35100 Padova Italy

Child Neurology and Psychiatry Unit Children's Hospital G Salesi 60121 Ancona Italy

Child Neurology Center for Pediatric and Teenage Health Care 53757 Sankt Augustin Germany

Child Neuropsychiatric Unit Civilian Hospital 25100 Brescia Italy

Children's Department Swiss Epilepsy Centre Clinic Lengg 8001 Zurich Switzerland

Clinic for Neuropediatrics and Neurorehabilitation Epilepsy Center for Children and Adolescents Schön Klinik 83569 Vogtareuth Germany

Clinique de Génétique Guy Fontaine CHU Lille 59000 Lille France

Cologne Center for Genomics University of Cologne 50667 Cologne Germany

Comprehensive Epilepsy Center Ludwig Maximilian University of Munich 80331 Munich Germany

Département de Neuropédiatrie INSERM CHU Montpellier 34000 Montpellier France

Department of Biomedical and Health Informatics Children's Hospital of Philadelphia Philadelphia PA 19104USA

Department of Child Neurology 2nd Faculty of Medicine Charles University and University Hospital Motol 10000 Prague Czech Republic

Department of Child Neurology 5 Buzzi Children's Hospital 20125 Milan Italy

Department of Clinical Diagnostics Ambry Genetics Aliso Viejo CA 92637 USA

Department of Clinical Genetics Amsterdam Reproduction and Development Research Institute Amsterdam UMC University of Amsterdam 1019 Amsterdam Netherlands

Department of Clinical Medicine University of Copenhagen 2200 Copenhagen Denmark

Department of Diagnostics and Technology Fondazione IRCCS Istituto Neurologio Carlo Besta 20125 Milan Italy

Department of Epilepsy Genetics and Personalized Treatment The Danish Epilepsy Center 4293 Dianalund Denmark

Department of Genetics Boston Children's Hospital Boston MA 02108 USA

Department of Genetics University Medical Center Utrecht Utrecht University 3553 Utrecht The Netherlands

Department of Medical Genetics Alberta Children's Hospital Research Institute University of Calgary AB T6G 2T4 Canada

Department of Medical Genetics Groupement Hospitalier Est and ERN EpiCARE University Hospitals of Lyon 69001 Lyon France

Department of Medical Genetics Institute of Mother and Child 00 034 Warsaw Poland

Department of Neurology Aarhus University Hospital 8000 Aarhus Denmark

Department of Neurology and Epileptology Hertie Institute for Clinical Brain Research University of Tuebingen 72072 Tuebingen Germany

Department of Neurology Boston Children's Hospital and Harvard Medical School Boston MA 02108 USA

Department of Neurology Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104USA

Department of Neuropediatrics Children's Hospital University Hospital Carl Gustav Carus Technical University 1099 Dresden Germany

Department of Neuropediatrics Kiel University 24105 Kiel Germany

Department of Neuropediatrics Klinikum Weiden Kliniken Nordoberpfalz AG 92637 Weiden Germany

Department of Neuropediatrics Universitätsklinikum Schleswig Holstein Campus Kiel 24106 Kiel Germany

Department of Neuropediatrics University Hospital Bonn 53229 Bonn Germany

Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genoa 16121 Genova Italy

Department of Pediatric Neurology Amalia Children's Hospital Radboud University Medical Center 6525 Nijmegen The Netherlands

Department of Pediatric Neurology and Developmental Medicine University Children's Hospital 72072 Tuebingen Germany

Department of Pediatric Neurology Hospital Italiano de Buenos Aires C1428 Buenos Aires Argentina

Department of Pediatrics and Pediatric Neurology Antwerp University Hospital University of Antwerp 2650 Edegem Belgium

Department of Pediatrics Copenhagen University Hospital Rigshospitalet 2200 Copenhagen Denmark

Department of Pediatrics Division of Pediatric Neurology Gent University Hospital 9042 Gent Belgium

Department of Pediatrics Oestfold Hospital 1712 Graalum Norway

Department of Pediatrics St Jacques Hospital 25000 Besançon France

Department of Pediatrics University of Melbourne Royal Children's Hospital 3052 Parkville Australia

Department of Surgical Sciences Dentistry Gynecology and Pediatrics University of Verona 37121 Verona Italy

Department of Woman's and Child's Health Padova University Hospital 35100 Padova Italy

Departments of Clinical Neurosciences Medical Genetics and Community Health Sciences Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute Cumming School of Medicine University of Calgary Calgary AB T2P 0A1 Canada

Division of Neurology Children's Hospital of Philadelphia Philadelphia PA 19104 USA

Division of Pediatric Neurology Developmental Medicine and Social Pediatrics Department of Pediatrics Dr von Haunersches Children's Hospital Ludwig Maximilian University of Munich 80331 Munich Germany

Epilepsy Center for Children University Hospital Neuruppin Brandenburg Medical School 16816 Neuruppin Germany

Epilepsy Center Kleinwachau 01454 Dresden Radeberg Germany

Epilepsy Center Neurological Institute Cleveland Clinic Cleveland OH 44102 USA

Epilepsy Genetics Program Boston Children's Hospital Boston MA 02108 USA

Finnish Institute for Molecular Medicine University of Helsinki 320 Helsinki Finland

Geisinger Autism and Developmental Medicine Institute Lewisburg PA 17837 USA

Genetics Department CHRU Strasbourg 67000 Strasbourg France

Genetics Department CHU Côte de Nacre 14118 Caen France

Genomed Ltd 100000 Moscow Russia

Genomic Medicine Institute Lerner Research Institute Cleveland Clinic Cleveland OH 44102 USA

Institut Neuromyogène CNRS UMR 5310 INSERM U1217 Université de Lyon Université Claude Bernard Lyon 1 69001 Lyon France

Institute for Molecular and Behavioral Neuroscience University of Cologne 50667 Cologne Germany

Institute for Neurobiology University of Tuebingen 72072 Tuebingen Germany

Institute for Pathology and Genetics 6040 Gosselies Belgium

Institute for Regional Health Services University of Southern Denmark 5230 Odense Denmark

Institute of Clinical Molecular Biology Kiel University 24105 Kiel Germany

Institute of Human Genetics University Clinic Heinrich Heine University 40210 Düsseldorf Germany

Institute of Human Genetics University of Leipzig Hospitals and Clinics 4275 Leipzig Germany

IRCCS 'G Gaslini' Institute 16121 Genoa Italy

IRCCS Stella Maris 56121 Pisa Italy

Justin Neurosciences Center Cook Children's Medical Center Fort Worth TX 76101 USA

Laboratory of Genome Diagnostics Department of Clinical Genetics Amsterdam UMC University of Amsterdam 1019 Amsterdam Netherlands

Luxembourg Centre for Systems Biomedicine University Luxembourg L 4243 Esch sur Alzette Luxembourg

McLaughlin Centre and Department of Molecular Genetics University of Toronto Toronto ON 66777 Canada

Murdoch Children's Research Institute 3052 Parkville Australia

National Centre for Rare Epilepsy Related Disorders Oslo University Hospital 0001 Oslo Norway

Neurology Department The Royal Children's Hospital Melbourne 3002 Melbourne Australia

Pediatric Neurology and Development Center Shamir Medical Center Be'er Ya'akov Israel

Pediatric Neurology and Neurorehabilitation Unit Woman Mother Child Department Lausanne University Hospital 1000 Lausanne Switzerland

Pediatric Neurology Marie Curie Hospital CHU Charleroi 6032 Charleroi Belgium

Pediatric Neurology Neurogenetics and Neurobiology Unit and Laboratories Meyer Children's Hospital University of Florence 50131 Florence Italy

Pediatric Neurology Unit Cliniques Universitaires Saint Luc Université Catholique de Louvain 1000 Brussels Belgium

Pediatric Neurology Unit Department of Pediatrics Centre Hospitalier de Luxembourg 1313 Luxembourg Luxembourg

Pediatric Neurology Unit Department of Pediatrics Universitair Ziekenhuis Brussel Vrije Universiteit Brussel 1050 Brussels Belgium

Pediatric Neurology Unit Vittore Buzzi Hospital ASST Fatebenefratelli Sacco 20100 Milan Italy

Program for Medical and Population Genetics Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge MA 02138 USA

Research Centre for Medical Genetics 115522 Moscow Russia

Research Institute 'Rehabilitation Transition Palliation' PMU Salzburg 5020 Salzburg Austria

Russian Medical Academy of Continuous Professional Education 100000 Moscow Russia

Sackler Faculty of Medicine Tel Aviv University 5296001 Tel Aviv Israel

Section of Pediatric Neurology Alberta Children's Hospital Cumming School of Medicine University of Calgary Calgary AB T2P 0A1 Canada

Service de Génétique Centre Hospitalier Universitaire de Poitiers 86021 Poitiers France

Service de Génétique Médicale CHU Nantes 44093 Nantes France

Stanley Center for Psychiatric Research Broad Institute of Harvard and M 1 T Cambridge MA 02138 USA

Svt Luka's Institute of Child Neurology and Epilepsy 100000 Moscow Russia

The Centre for Applied Genomics and Department of Genetics and Genome Biology The Hospital for Sick Children Toronto ON 66777 Canada

The Epilepsy Neurogenetics Initiative Children's Hospital of Philadelphia Philadelphia PA 19104 USA

University of Copenhagen 2200 Copenhagen Denmark

University of Lausanne 1000 Lausanne Switzerland

Veltischev Research and Clinical Institute for Pediatrics Pirogov Russian National Research Medical University 125412 Moscow Russia

Vestische Kinder und Jugendklinik 45711 Datteln Germany

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