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Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies

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dc.contributor.authorBrunklaus, Andreas
dc.contributor.authorPérez, Eduardo
dc.contributor.authorGhanty, Ismael
dc.contributor.authorXinge, Ji
dc.contributor.authorBrilstra, Eva
dc.contributor.authorCeulemans, Berten
dc.contributor.authorChemaly, Nicole
dc.contributor.authorDe Lange, Iris
dc.contributor.authorDepienne, Christel
dc.contributor.authorGuerrini, Renzo
dc.contributor.authorMei, Davide
dc.contributor.authorMøller, Rikke
dc.contributor.authorNabbout, Rima
dc.contributor.authorRegan, Brigid
dc.contributor.authorSchneider, Amy
dc.contributor.authorMGenCouns
dc.contributor.authorScheffer, Ingrid
dc.contributor.authorSchoonjans, An
dc.contributor.authorSymonds, Joseph
dc.contributor.authorWeckhuysen, Sarah
dc.contributor.authorKattan, Michael
dc.contributor.authorZuberi, Sameer
dc.contributor.authorLal, Dennis
dc.date.accessioned2023-03-31T16:44:26Z
dc.date.available2023-03-31T16:44:26Z
dc.date.issued2022
dc.description.abstractBackground and objectives: Pathogenic variants in the neuronal sodium channel α1 subunit gene (SCN1A) are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum, including severe childhood epilepsy; Dravet syndrome, characterized by drug-resistant seizures, intellectual disability, and high mortality; and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome vs GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of SCN1A-related epilepsies. Methods: We performed a retrospective multicenter cohort study comprising data from patients with SCN1A-positive Dravet syndrome and patients with GEFS+ consecutively referred for genetic testing (March 2001-June 2020) including age at seizure onset and a newly developed SCN1A genetic score. A training cohort was used to develop multiple prediction models that were validated using 2 independent blinded cohorts. Primary outcome was the discriminative accuracy of the model predicting Dravet syndrome vs other GEFS+ phenotypes. Results: A total of 1,018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training cohort, 147/203 (72%) in validation cohort 1, and 60/72 (83%) in validation cohort 2. A high SCN1A genetic score (133.4 [SD 78.5] vs 52.0 [SD 57.5]; p < 0.001) and young age at onset (6.0 [SD 3.0] vs 14.8 [SD 11.8] months; p < 0.001) were each associated with Dravet syndrome vs GEFS+. A combined SCN1A genetic score and seizure onset model separated Dravet syndrome from GEFS+ more effectively (area under the curve [AUC] 0.89 [95% CI 0.86-0.92]) and outperformed all other models (AUC 0.79-0.85; p < 0.001). Model performance was replicated in both validation cohorts 1 (AUC 0.94 [95% CI 0.91-0.97]) and 2 (AUC 0.92 [95% CI 0.82-1.00]). Discussion: The prediction model allows objective estimation at disease onset whether a child will develop Dravet syndrome vs GEFS+, assisting clinicians with prognostic counseling and decisions on early institution of precision therapies (http://scn1a-prediction-model.broadinstitute.org/). Classification of evidence: This study provides Class II evidence that a combined SCN1A genetic score and seizure onset model distinguishes Dravet syndrome from other GEFS+ phenotypes.
dc.description.versionVersión publicada
dc.identifier.citationBrunklaus A, Pérez-Palma E, Ghanty I, Xinge J, Brilstra E, Ceulemans B, Chemaly N, de Lange I, Depienne C, Guerrini R, Mei D, Møller RS, Nabbout R, Regan BM, Schneider AL, Scheffer IE, Schoonjans AS, Symonds JD, Weckhuysen S, Kattan MW, Zuberi SM, Lal D. Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies. Neurology. 2022 Mar 15;98(11):e1163-e1174. doi: 10.1212/WNL.0000000000200028
dc.identifier.doihttps://doi.org/10.1212/WNL.0000000000200028
dc.identifier.urihttps://repositorio.udd.cl/handle/11447/7222
dc.language.isoen
dc.subjectChild
dc.subjectCohort Studies
dc.subjectEarly Diagnosis
dc.subjectEpilepsies, Myoclonic / diagnosis
dc.subjectEpilepsies, Myoclonic / genetics
dc.subjectEpilepsy / diagnosis
dc.subjectEpilepsy / genetics
dc.subjectNAV1.1 Voltage-Gated Sodium Channel / genetics
dc.subjectMutation
dc.subjectRetrospective Studies
dc.titleDevelopment and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies
dc.typeArticle
dcterms.accessRightsAcceso abierto
dcterms.sourceNeurology
dspace.entity.typePublication

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