March 15, 2022; 98 (11) Research Article
Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies
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
First published January 24, 2022, DOI: https://doi.org/10.1212/WNL.0000000000200028
Andreas Brunklaus
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Eduardo Pérez-Palma
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Ismael Ghanty
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Ji Xinge
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Eva Brilstra
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Berten Ceulemans
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Nicole Chemaly
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Iris de Lange
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Christel Depienne
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Renzo Guerrini
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Davide Mei
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Rikke S. Møller
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Rima Nabbout
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Brigid M. Regan
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Amy L. Schneider
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Ingrid E. Scheffer
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
An-Sofie Schoonjans
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Joseph D. Symonds
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Sarah Weckhuysen
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Michael W. Kattan
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Sameer M. Zuberi
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Dennis Lal
From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.
Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies
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
Neurology Mar 2022, 98 (11) e1163-e1174; DOI: 10.1212/WNL.0000000000200028
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Abstract
Background and Objectives Pathogenic variants in the neuronal sodium channel α1 subunit gene (SCN1A) are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum, including severe childhood epilepsy; Dravet syndrome, characterized by drug-resistant seizures, intellectual disability, and high mortality; and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome vs GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of SCN1A-related epilepsies.
Methods We performed a retrospective multicenter cohort study comprising data from patients with SCN1A-positive Dravet syndrome and patients with GEFS+ consecutively referred for genetic testing (March 2001–June 2020) including age at seizure onset and a newly developed SCN1A genetic score. A training cohort was used to develop multiple prediction models that were validated using 2 independent blinded cohorts. Primary outcome was the discriminative accuracy of the model predicting Dravet syndrome vs other GEFS+ phenotypes.
Results A total of 1,018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training cohort, 147/203 (72%) in validation cohort 1, and 60/72 (83%) in validation cohort 2. A high SCN1A genetic score (133.4 [SD 78.5] vs 52.0 [SD 57.5]; p < 0.001) and young age at onset (6.0 [SD 3.0] vs 14.8 [SD 11.8] months; p < 0.001) were each associated with Dravet syndrome vs GEFS+. A combined SCN1A genetic score and seizure onset model separated Dravet syndrome from GEFS+ more effectively (area under the curve [AUC] 0.89 [95% CI 0.86–0.92]) and outperformed all other models (AUC 0.79–0.85; p < 0.001). Model performance was replicated in both validation cohorts 1 (AUC 0.94 [95% CI 0.91–0.97]) and 2 (AUC 0.92 [95% CI 0.82–1.00]).
Discussion The prediction model allows objective estimation at disease onset whether a child will develop Dravet syndrome vs GEFS+, assisting clinicians with prognostic counseling and decisions on early institution of precision therapies (http://scn1a-prediction-model.broadinstitute.org/).
Classification of Evidence This study provides Class II evidence that a combined SCN1A genetic score and seizure onset model distinguishes Dravet syndrome from other GEFS+ phenotypes.
Glossary
- AUC=
- area under the curve;
- CADD=
- Combined Annotation Dependent Depletion;
- GEFS+=
- genetic epilepsy with febrile seizures plus;
- IPA=
- index of prediction accuracy;
- NPV=
- negative predictive value;
- PPV=
- positive predictive value;
- PTV=
- protein truncating variant;
- REVEL=
- Rare Exome Variant Ensemble Learner;
- SUDEP=
- sudden unexpected death in epilepsy
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work as co–first authors.
↵† These authors contributed equally to this work as co–senior authors.
Class of Evidence: NPub.org/coe
- Received June 22, 2021.
- Accepted in final form January 3, 2022.
- © 2022 American Academy of Neurology
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