Assessing the landscape of STXBP1-related disorders in 534 individuals
Por:
Xian J, Parthasarathy S, Ruggiero SM, Balagura G, Fitch E, Helbig K, Gan J, Ganesan S, Kaufman MC, Ellis CA, Lewis-Smith D, Galer P, Cunningham K, O'Brien M, Cosico M, Baker K, Darling A, Veiga de Goes F, El Achkar CM, Doering JH, Furia F, Garcia-Cazorla A, Gardella E, Geertjens L, Klein C, Kolesnik-Taylor A, Lammertse H, Lee J, Mackie A, Misra-Isrie M, Olson H, Sexton E, Sheidley B, Smith L, Sotero L, Stamberger H, Syrbe S, Thalwitzer KM, van Berkel A, van Haelst M, Yuskaitis C, Weckhuysen S, Prosser B, Son Rigby C, Demarest S, Pierce S, Zhang Y, Møller RS, Bruining H, Poduri A, Zara F, Verhage M, Striano P and Helbig I
Publicada:
3 jun 2022
Ahead of Print:
1 feb 2022
Resumen:
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.
Filiaciones:
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
Garcia-Cazorla A:
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
Green Submitted, gold
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