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dc.contributor.authorXian, Julie
dc.contributor.authorParthasarathy, Shridhar
dc.contributor.authorRuggiero, Sarah M
dc.contributor.authorBalagura, Ganna
dc.contributor.authorFitch, Eryn
dc.contributor.authorHelbig, Katherine
dc.contributor.authorGan, Jing
dc.contributor.authorGanesan, Shiva
dc.contributor.authorKaufman, Michael C
dc.contributor.authorEllis, Colin A
dc.contributor.authorLewis-Smith, David
dc.contributor.authorGaler, Peter
dc.contributor.authorCunningham, Kristin
dc.contributor.authorO'Brien, Margaret
dc.contributor.authorCosico, Mahgenn
dc.contributor.authorBaker, Kate
dc.contributor.authorDarling, Alejandra
dc.contributor.authorVeiga de Goes, Fernanda
dc.contributor.authorEl Achkar, Christelle M
dc.contributor.authorDoering, Jan Henje
dc.contributor.authorFuria, Francesca
dc.contributor.authorGarcía-Cazorla, Ángeles
dc.contributor.authorGardella, Elena
dc.contributor.authorGeertjens, Lisa
dc.contributor.authorKlein, Courtney
dc.contributor.authorKolesnik-Taylor, Anna
dc.contributor.authorLammertse, Hanna
dc.contributor.authorLee, Jeehun
dc.contributor.authorMackie, Alexandra
dc.contributor.authorMisra-Isrie, Mala
dc.contributor.authorOlson, Heather
dc.contributor.authorSexton, Emma
dc.contributor.authorSheidley, Beth
dc.contributor.authorSmith, Lacey
dc.contributor.authorSotero, Luiza
dc.contributor.authorStamberger, Hannah
dc.contributor.authorSyrbe, Steffen
dc.contributor.authorThalwitzer, Kim Marie
dc.contributor.authorvan Berkel, Annemiek
dc.contributor.authorvan Haelst, Mieke
dc.contributor.authorYuskaitis, Christopher
dc.contributor.authorWeckhuysen, Sarah
dc.contributor.authorProsser, Ben
dc.contributor.authorSon Rigby, Charlene
dc.contributor.authorDemarest, Scott
dc.contributor.authorPierce, Samuel
dc.contributor.authorZhang, Yuehua
dc.contributor.authorMøller, Rikke S
dc.contributor.authorBruining, Hilgo
dc.contributor.authorPoduri, Annapurna
dc.contributor.authorZara, Federico
dc.contributor.authorVerhage, Matthijs
dc.contributor.authorStriano, Pasquale
dc.contributor.authorHelbig, Ingo
dc.description.abstractDisease-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.
dc.publisherOxford University Press (OUP)
dc.rightsAttribution 4.0 International
dc.subjectHuman Phenotype Ontology
dc.subjectdevelopmental and epileptic encephalopathy
dc.subjectMunc18 Proteins
dc.subjectRetrospective Studies
dc.subjectSpasms, Infantile
dc.titleAssessing the landscape of STXBP1-related disorders in 534 individuals.
dc.publisher.departmentMrc Cognition And Brain Sciences Unit
dc.contributor.orcidXian, Julie [0000-0002-0205-0648]
dc.contributor.orcidRuggiero, Sarah M [0000-0002-0834-0750]
dc.contributor.orcidBalagura, Ganna [0000-0003-0212-8318]
dc.contributor.orcidHelbig, Katherine [0000-0001-8249-0549]
dc.contributor.orcidKaufman, Michael C [0000-0003-2718-296X]
dc.contributor.orcidLewis-Smith, David [0000-0002-1735-8178]
dc.contributor.orcidGardella, Elena [0000-0002-7138-6022]
dc.contributor.orcidOlson, Heather [0000-0002-5385-0119]
dc.contributor.orcidWeckhuysen, Sarah [0000-0003-2878-1147]
dc.contributor.orcidVerhage, Matthijs [0000-0002-5452-5000]
dc.contributor.orcidHelbig, Ingo [0000-0001-8486-0558]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_UU_00005/16)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International