Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (n = 2), GNAO1 (n = 1), STXBP1 (n = 1), SLC35A2 (n = 1), TBL1XR1 (n = 1), and KIF1A (n = 1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder.

Child Neurology Department 2nd Faculty of Medicine Charles University and University Hospital Motol Prague 150 06 Czech Republic

Danish Epilepsy Centre Dianalund 4293 Denmark; Institute for Regional Health research University of Southern Denmark Odense 5230 Denmark

Department of Clinical Neurosciences and Pediatric Neurology Clinic Carol Davila University of Medicine Al Obregia Hospital Bucharest 050474 Romania; Pediatric Neurology Clinic Alexandru Obregia Hospital Bucharest Romania

Department of Medical Genetics Institute of Mother and Child Warsaw Poland; Institute of Genetics and Biotechnology Warsaw University Warsaw Poland

Department of Neurology Neurology Lab and Epilepsy Unit IIS Fundación Jiménez Díaz UAM and CIBERER Madrid 28040 Spain

Department of Neuropediatrics Christian Albrechts University Kiel and University Hospital Schleswig Holstein Campus Kiel 24105 Germany; Northern German Epilepsy Center for Children and Adolescents Schwentinental Raisdorf 24223 Germany

Division of Genetic Medicine Department of Pediatrics University of Washington Seattle WA 98195 USA

Division of Neurology Children's Hospital of Philadelphia Philadelphia PA 19104 USA; Department of Neuropediatrics Christian Albrechts University Kiel and University Hospital Schleswig Holstein Campus Kiel 24105 Germany

Folkhälsan Research Center and Medical Faculty University of Helsinki Helsinki 00290 Finland

Neurogenetics Group Center for Molecular Neurology VIB University of Antwerp Antwerp 2610 Belgium; Institute Born Bunge University of Antwerp Antwerp 2610 Belgium; Department of Neurology Antwerp University Hospital Antwerp 2650 Belgium

Pediatric Neurology and Muscular Diseases Unit IRCCS Istituto G Gaslini Genova 16147 Italy; Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genova Genova 16132 Italy

Pediatric Neurology Neurogenetics and Neurobiology Unit and Laboratories A Meyer Children's Hospital University of Florence Florence 50139 Italy

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Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood

Radiprodil, a NR2B negative allosteric modulator, from bench to bedside in infantile spasm syndrome