Julie Xian (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA / Children's Hospital of Philadelphia. Department of Biomedical and Health Informatics. Philadelphia, PA, USA / University of Pennsylvania. Neuroscience Program. Philadelphia, PA, USA.); Shridhar Parthasarathy (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA / Children's Hospital of Philadelphia. Department of Biomedical and Health Informatics. Philadelphia, PA, USA / The College of New Jersey. Department of Biology. Ewing Township, NJ, USA.); Sarah M. Ruggiero (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA.); Ganna Balagura (University of Genoa. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health. Genoa, Italy / L'istituto Giannina Gaslini è Istituto di Ricovero e Cura Pediatrico a Carattere Scientifico. Pediatric Neurology and Muscular Diseases Unit. Genoa, Italy.); Eryn Fitch (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA.); Katherine Helbig (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA / Children's Hospital of Philadelphia. Department of Biomedical and Health Informatics. Philadelphia, PA, USA.) / Jing Gan (Sichuan University. West China Second University Hospital. Department of Pediatrics. Chengdu, China / Ministry of Education. Sichuan University. Key Laboratory of Birth Defects and Related Diseases of Women and Children. Chengdu, China.); Shiva Ganesan (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA / Children's Hospital of Philadelphia. Department of Biomedical and Health Informatics. Philadelphia, PA, USA.); Michael C. Kaufman (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA / Children's Hospital of Philadelphia. Department of Biomedical and Health Informatics. Philadelphia, PA, USA.); Colin A. Ellis(Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA / Children's Hospital of Philadelphia. Department of Biomedical and Health Informatics. Philadelphia, PA, USA / Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA.); David Lewis-Smith (Newcastle University. Translational and Clinical Research Institute. Newcastle-upon-Tyne, UK / Royal Victoria Infirmary. Newcastle-upon-Tyne, UK); Peter Galer (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA / Children's Hospital of Philadelphia. Department of Biomedical and Health Informatics. Philadelphia, PA, USA / University of Pennsylvania. Center for Neuroengineering and Therapeutics. Philadelphia, PA, USA.); Kristin Cunningham (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA.); Margaret O'Brien (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA , USA / Temple University. Lewis Katz School of Medicine. Philadelphia, PA, USA.); Mahgenn Cosico (Children's Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA.); Kate Baker (University of Cambridge. MRC Cognition and Brain Sciences Unit. Cambridge, UK.); Alejandra Darling (University of Barcelona. Hospital Sant Joan de Déu. Pediatric Neurology Department. Barcelona, Spain.); Fernanda Veiga de Goes (Fundação Oswaldo Cruz. Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira. Departamento de Pediatria. Laboratório de Neurologia Pediátrica. Rio de Janeiro, RJ, Brasil.); Christelle M. El Achkar (Boston Children's Hospital. Department of Neurology. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program. Boston, MA, USA.); Jan Henje Doering (University Hospital Heidelberg. Centre for Pediatric and Adolescent Medicine. Division of Pediatric Epileptology. Heidelberg, Germany); Francesca Furia (Danish Epilepsy Center Filadelfia. Department of Clinical Neurophysiology. Dianalund, Denmark.); Ángeles García-Cazorla (University of Barcelona. Hospital Sant Joan de Déu. Pediatric Neurology Department. Barcelona, Spain.); Elena Gardella (Danish Epilepsy Center Filadelfia. Department of Clinical Neurophysiology. Dianalund, Denmark.); Lisa Geertjens (University of Amsterdam. Amsterdam UMC. Department of Child and Adolescent Psychiatry. Amsterdam, The Netherlands.); Courtney Klein (Children's Hospital Colorado. Departments of Pediatrics and Neurology. Aurora, CO, USA.); Anna Kolesnik-Taylor (University of Cambridge. MRC Cognition and Brain Sciences Unit. Cambridge, UK.); Hanna Lammertse (Amsterdam University Medical Center. Center for Neurogenomics and Cognitive Research. Department of Human Genetics. de Boelelaan, Amsterdam, The Netherlands.); Jeehun Lee (Sungkyunkwan University. School of Medicine. Samsung Medical Center. Department of Pediatrics. Seoul, Republic of Korea.); Alexandra Mackie (Children's Hospital Colorado. Departments of Pediatrics and Neurology. Aurora, CO, USA.); Mala Misra-Isrie (Amsterdam University Medical Center. Center for Neurogenomics and Cognitive Research. Department of Human Genetics. de Boelelaan, Amsterdam, The Netherlands.); Heather Olson (Boston Children's Hospital. Department of Neurology. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program. Boston, MA, USA.); Emma Sexton (Boston Children's Hospital. Department of Neurology. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program. Boston, MA, USA.); Beth Sheidley (Boston Children's Hospital. Department of Neurology. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program. Boston, MA, USA.); Lacey Smith (Boston Children's Hospital. Department of Neurology. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program. Boston, MA, USA.); Luiza Sotero (Fundação Oswaldo Cruz. Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira. Departamento de Pediatria. Laboratório de Neurologia Pediátrica. Rio de Janeiro, RJ, Brasil.); Hannah Stamberger (University Hospital Antwerp. Division of Neurology. Antwerp, Belgium / VIB Center for Molecular Neurology. Applied & Translational Neurogenomics Group. Antwerp, Belgium.); Steffen Syrbe (University Hospital Heidelberg. Centre for Pediatric and Adolescent Medicine. Division of Pediatric Epileptology. Heidelberg, Germany.); Kim Marie Thalwitzer (University Hospital Heidelberg. Centre for Pediatric and Adolescent Medicine. Division of Pediatric Epileptology. Heidelberg, Germany.); Annemiek van Berkel (VU University Amsterdam. Center for Neurogenomics and Cognitive Research. Department of Functional Genomics. De Boelelaan, Amsterdam, The Netherlands.); Mieke van Haelst (Amsterdam University Medical Center. Center for Neurogenomics and Cognitive Research. Department of Human Genetics. De Boelelaan, Amsterdam, The Netherlands.); Christopher Yuskaitis (Boston Children's Hospital. Department of Neurology. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program. Boston, MA, USA.); Sarah Weckhuysen (University Hospital Antwerp. Division of Neurology. Antwerp, Belgium / VIB Center for Molecular Neurology. Applied & Translational Neurogenomics Group. Antwerp, Belgium / University of AntwerpFaculty of Medicine and Health Science. Translational Neurosciences. Antwerp, Belgium.); Ben Prosser (University of Pennsylvania. Perelman School of Medicine. Department of Physiology. Philadelphia, PA, USA.); Charlene Son Rigby (STXBP1 Foundation. Apex, NC, USA.); Scott Demarest (Children's Hospital Colorado. Departments of Pediatrics and Neurology. Aurora, CO, USA.); Samuel Pierce (Children’s Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA.); Yuehua Zhang (Beijing University First Hospital. Department of Pediatrics. Beijing, China.); Rikke S. Møller (Danish Epilepsy Center Filadelfia. Department of Clinical Neurophysiology. Dianalund, Denmark.); Hilgo Bruining (University of Amsterdam. Amsterdam UMC. Department of Child and Adolescent Psychiatry. Amsterdam, The Netherlands.); Annapurna Poduri (Boston Children's Hospital. Department of Neurology. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program. Boston, MA, USA.); Federico Zara (University of Genoa. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health. Genoa, Italy.); Matthijs Verhage (Amsterdam University Medical Center. Center for Neurogenomics and Cognitive Research. Department of Human Genetics. De Boelelaan, Amsterdam, The Netherlands / VU University Amsterdam. Center for Neurogenomics and Cognitive Research. Department of Functional Genomics. De Boelelaan, Amsterdam, The Netherlands.); Pasquale Striano (University of Genoa. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health. Genoa, Italy.); Ingo Helbig (Children’s Hospital of Philadelphia. Division of Neurology. Philadelphia, PA, USA / Children's Hospital of Philadelphia. The Epilepsy NeuroGenetics Initiative. Philadelphia, PA, USA / Children’s Hospital of Philadelphia. Department of Biomedical and Health Informatics. Philadelphia, PA, USA / University of Pennsylvania. Perelman School of Medicine. Department of Neurology. Philadelphia, PA, USA.).K23 NS121520/NS/NINDS NIH HHS/United States MC_UU_00005/16/MRC_/Medical Research Council/United Kingdom K02 NS112600/NS/NINDS NIH HHS/United States U54 HD086984/HD/NICHD NIH HHS/United States WT_/Wellcome Trust/United KingdomDisease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.