학술논문

Assessing the landscape of STXBP1-related disorders in 534 individuals.
Document Type
Academic Journal
Author
Xian J; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA.; Neuroscience Program, University of Pennsylvania, Philadelphia, PA 19104, USA.; Parthasarathy S; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA.; Department of Biology, The College of New Jersey, Ewing Township, NJ 08618, USA.; Ruggiero SM; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Balagura G; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Italy.; Pediatric Neurology and Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, Genoa, Italy.; Fitch E; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Helbig K; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA.; Gan J; Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.; Ganesan S; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA.; Kaufman MC; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA.; Ellis CA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA.; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.; Lewis-Smith D; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK.; Royal Victoria Infirmary, Newcastle-upon-Tyne NE1 4LP, UK.; Galer P; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA.; Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.; Cunningham K; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; O'Brien M; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.; Cosico M; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Baker K; MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.; Darling A; Pediatric Neurology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.; Veiga de Goes F; Department of Pediatrics and Pediatric Neurology Laboratory, Instituto Fernandes Figueira, Rio de Janeiro 22250-020, Brazil.; El Achkar CM; Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.; Doering JH; Division of Pediatric Epileptology, Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.; Furia F; Department of Clinical Neurophysiology, Danish Epilepsy Center Filadelfia, Dianalund 4293, Denmark.; García-Cazorla Á; Pediatric Neurology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.; Gardella E; Department of Clinical Neurophysiology, Danish Epilepsy Center Filadelfia, Dianalund 4293, Denmark.; Geertjens L; Department of Child and Adolescent Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Klein C; Departments of Pediatrics and Neurology, Children's Hospital Colorado, Aurora, CO 80045, USA.; Kolesnik-Taylor A; MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.; Lammertse H; Department of Human Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam University Medical Center, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.; Lee J; Department of Pediatrics, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea.; Mackie A; Departments of Pediatrics and Neurology, Children's Hospital Colorado, Aurora, CO 80045, USA.; Misra-Isrie M; Department of Human Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam University Medical Center, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.; Olson H; Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.; Sexton E; Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.; Sheidley B; Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.; Smith L; Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.; Sotero L; Department of Pediatrics and Pediatric Neurology Laboratory, Instituto Fernandes Figueira, Rio de Janeiro 22250-020, Brazil.; Stamberger H; Division of Neurology, University Hospital Antwerp, Antwerp, Belgium.; Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.; Syrbe S; Division of Pediatric Epileptology, Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.; Thalwitzer KM; Division of Pediatric Epileptology, Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.; van Berkel A; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.; van Haelst M; Department of Human Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam University Medical Center, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.; Yuskaitis C; Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.; Weckhuysen S; Division of Neurology, University Hospital Antwerp, Antwerp, Belgium.; Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.; Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium.; Prosser B; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.; Son Rigby C; STXBP1 Foundation, Apex, NC 27539, USA.; Demarest S; Departments of Pediatrics and Neurology, Children's Hospital Colorado, Aurora, CO 80045, USA.; Pierce S; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Zhang Y; Department of Pediatrics, Beijing University First Hospital, Beijing, China.; Møller RS; Department of Clinical Neurophysiology, Danish Epilepsy Center Filadelfia, Dianalund 4293, Denmark.; Bruining H; Department of Child and Adolescent Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Poduri A; Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.; Zara F; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Italy.; Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy.; Verhage M; Department of Human Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam University Medical Center, de Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.; Striano P; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Italy.; Pediatric Neurology and Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, Genoa, Italy.; Helbig I; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA.; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Source
Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE
Subject
Language
English
Abstract
Disease-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.
(© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)