Assessing the landscape of STXBP1-related disorders in 534 individuals.

Electroencephalography Epilepsy / genetics Humans Infant Munc18 Proteins / genetics Retrospective Studies Seizures / genetics Spasms, Infantile / drug therapy
STXBP1 Human Phenotype Ontology developmental and epileptic encephalopathy epilepsy genetics

Journal

Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537

Informations de publication

Date de publication:
03 06 2022
Historique:
received: 30 03 2021
revised: 30 07 2021
accepted: 10 08 2021
pubmed: 23 2 2022
medline: 9 6 2022
entrez: 22 2 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1093/brain/awab327 PMID: 35190816 PMC: PMC9166568
pubmed: 35190816
pii: 6433675
doi: 10.1093/brain/awab327
pmc: PMC9166568
doi:

Substances chimiques

Munc18 Proteins 0
STXBP1 protein, human 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1668-1683

Subventions

Organisme : NINDS NIH HHS
ID : K02 NS112600
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001878
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD105351
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS091008
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD086984
Pays : United States
Organisme : NINDS NIH HHS
ID : K23 NS121520
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00030/3
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00005/16
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : U24 NS120854
Pays : United States

Informations de copyright

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

Références

Genet Med. 2021 Jul;23(7):1263-1272
pubmed: 33731876
Neurology. 2017 Jul 25;89(4):385-394
pubmed: 28667181
Genet Med. 2020 Dec;22(12):2060-2070
pubmed: 32773773
Epilepsy Behav. 2019 Mar;92:121-124
pubmed: 30654231
Brain. 2020 Apr 1;143(4):1099-1105
pubmed: 32168371
Mol Genet Genomic Med. 2017 Jun 20;5(5):495-507
pubmed: 28944233
Epilepsia. 2010 Dec;51(12):2449-52
pubmed: 21204804
Nat Rev Neurosci. 2021 Mar;22(3):152-166
pubmed: 33531663
Am J Hum Genet. 2020 Oct 1;107(4):683-697
pubmed: 32853554
Epilepsia. 2011 Oct;52(10):1828-34
pubmed: 21770924
Nucleic Acids Res. 2021 Jan 8;49(D1):D1207-D1217
pubmed: 33264411
Lancet Neurol. 2005 Nov;4(11):712-7
pubmed: 16239177
Science. 2000 Feb 4;287(5454):864-9
pubmed: 10657302
Neurology. 2016 Mar 8;86(10):954-62
pubmed: 26865513
J Child Neurol. 2006 Mar;21(3):193-8
pubmed: 16901419
Am J Hum Genet. 2018 Apr 5;102(4):557-573
pubmed: 29576218
EMBO Mol Med. 2021 Jan 11;13(1):e12354
pubmed: 33332765
Genet Med. 2021 Apr;23(4):653-660
pubmed: 33299146
Epilepsia. 2021 Jan;62(1):198-216
pubmed: 33368200
Am J Hum Genet. 2008 Nov;83(5):610-5
pubmed: 18950739
Neuropharmacology. 2020 Aug 1;172:107970
pubmed: 32413583
Nat Genet. 2014 Dec;46(12):1327-32
pubmed: 25362483
J Neurochem. 2021 May;157(3):450-466
pubmed: 33259669
Am J Hum Genet. 2019 Jun 6;104(6):1060-1072
pubmed: 31104773
Brain. 2020 Feb 1;143(2):441-451
pubmed: 31855252
J Med Genet. 2016 Mar;53(3):190-9
pubmed: 26740508
Neuron. 2020 Jul 8;107(1):22-37
pubmed: 32559416
Science. 2009 Jan 23;323(5913):474-7
pubmed: 19164740
J Neurochem. 2021 Apr;157(2):165-178
pubmed: 32643187
Am J Hum Genet. 2019 Apr 4;104(4):721-730
pubmed: 30929742
Brain. 2018 May 1;141(5):1350-1374
pubmed: 29538625
Neurology. 2010 Sep 28;75(13):1159-65
pubmed: 20876469
J Neurodev Disord. 2019 Aug 6;11(1):17
pubmed: 31387522
Nat Genet. 2008 Jun;40(6):782-8
pubmed: 18469812
Nature. 2012 Oct 11;490(7419):201-7
pubmed: 23060190
Neurology. 2014 Apr 8;82(14):1245-53
pubmed: 24623842
Nat Commun. 2018 Sep 28;9(1):3986
pubmed: 30266908
N Engl J Med. 2018 Oct 11;379(15):1452-1462
pubmed: 30304648

Auteurs

Julie 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.
ORCID: 0000-0002-0205-0648

Shridhar 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.

Sarah M 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.
ORCID: 0000-0002-0834-0750

Ganna 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.
ORCID: 0000-0003-0212-8318

Eryn 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.

Katherine 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.
ORCID: 0000-0001-8249-0549

Jing 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.

Shiva 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.

Michael C 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.
ORCID: 0000-0003-2718-296X

Colin A 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.

David 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.
ORCID: 0000-0002-1735-8178

Peter 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.

Kristin 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.

Margaret 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.

Mahgenn 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.

Kate Baker (K)

MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.

Alejandra Darling (A)

Pediatric Neurology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.

Fernanda Veiga de Goes (F)

Department of Pediatrics and Pediatric Neurology Laboratory, Instituto Fernandes Figueira, Rio de Janeiro 22250-020, Brazil.

Christelle M El Achkar (CM)

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Jan Henje Doering (JH)

Division of Pediatric Epileptology, Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.

Francesca Furia (F)

Department of Clinical Neurophysiology, Danish Epilepsy Center Filadelfia, Dianalund 4293, Denmark.

Ángeles García-Cazorla (Á)

Pediatric Neurology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.

Elena Gardella (E)

Department of Clinical Neurophysiology, Danish Epilepsy Center Filadelfia, Dianalund 4293, Denmark.
ORCID: 0000-0002-7138-6022

Lisa Geertjens (L)

Department of Child and Adolescent Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Courtney Klein (C)

Departments of Pediatrics and Neurology, Children's Hospital Colorado, Aurora, CO 80045, USA.

Anna Kolesnik-Taylor (A)

MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.

Hanna 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.

Jeehun Lee (J)

Department of Pediatrics, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea.

Alexandra Mackie (A)

Departments of Pediatrics and Neurology, Children's Hospital Colorado, Aurora, CO 80045, USA.

Mala 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.

Heather Olson (H)

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
ORCID: 0000-0002-5385-0119

Emma Sexton (E)

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Beth Sheidley (B)

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Lacey Smith (L)

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Luiza Sotero (L)

Department of Pediatrics and Pediatric Neurology Laboratory, Instituto Fernandes Figueira, Rio de Janeiro 22250-020, Brazil.

Hannah Stamberger (H)

Division of Neurology, University Hospital Antwerp, Antwerp, Belgium.
Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.

Steffen Syrbe (S)

Division of Pediatric Epileptology, Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.

Kim Marie Thalwitzer (KM)

Division of Pediatric Epileptology, Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.

Annemiek 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.

Mieke 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.

Christopher Yuskaitis (C)

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Sarah 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.
ORCID: 0000-0003-2878-1147

Ben Prosser (B)

Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

Charlene Son Rigby (C)

STXBP1 Foundation, Apex, NC 27539, USA.

Scott Demarest (S)

Departments of Pediatrics and Neurology, Children's Hospital Colorado, Aurora, CO 80045, USA.

Samuel 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.

Yuehua Zhang (Y)

Department of Pediatrics, Beijing University First Hospital, Beijing, China.

Rikke S Møller (RS)

Department of Clinical Neurophysiology, Danish Epilepsy Center Filadelfia, Dianalund 4293, Denmark.

Hilgo Bruining (H)

Department of Child and Adolescent Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Annapurna Poduri (A)

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Federico 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.

Matthijs 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.
ORCID: 0000-0002-5452-5000

Pasquale 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.

Ingo 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.
ORCID: 0000-0001-8486-0558

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Électrodiagnostic › Électroencéphalographie › Assessing the landscape of STXBP1-related...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Épilepsie › Assessing the landscape of STXBP1-related...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Assessing the landscape of STXBP1-related...
questionsmedicales.fr › Personnes › Tranches d'âge › Nourrisson › Assessing the landscape of STXBP1-related...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines du transport vésiculaire › Protéines Munc18 › Assessing the landscape of STXBP1-related...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études rétrospectives › Assessing the landscape of STXBP1-related...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Crises épileptiques › Assessing the landscape of STXBP1-related...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Épilepsie › Syndromes épileptiques › Spasmes infantiles › Assessing the landscape of STXBP1-related...