Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies
Brunklaus, Andreas; Pérez-Palma, Eduardo; Ghanty, Ismael; Xinge, Ji; Brilstra, Eva; Ceulemans, Berten; Chemaly, Nicole; de Lange, Iris; Depienne, Christel; Guerrini, Renzo; Mei, Davide; Møller, Rikke S; Nabbout, Rima; Regan, Brigid M; Schneider, Amy L; Scheffer, Ingrid E; Schoonjans, An-Sofie; Symonds, Joseph D; Weckhuysen, Sarah; Kattan, Michael W; Zuberi, Sameer M; Lal, Dennis
(2022) Neurology, volume 98, issue 11, pp. e1163 - e1174
(Article)
Abstract
Background 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
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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-predictionmodel.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.
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Keywords: Child, Cohort Studies, Early Diagnosis, Epilepsies, Myoclonic/diagnosis, Epilepsy/diagnosis, Humans, Mutation, NAV1.1 Voltage-Gated Sodium Channel/genetics, Retrospective Studies, Clinical Neurology, Research Support, Non-U.S. Gov't, Multicenter Study, Journal Article, Research Support, N.I.H., Extramural
ISSN: 0028-3878
Publisher: Lippincott Williams and Wilkins
Note: Funding Information: D.L. was supported by funds from the Dravet Syndrome Foundation (grant 272016), BMBF (Treat-ION grant 01GM1907), and NIH NINDS (Channelopathy-Associated Epilepsy Research Center, 5-U54-NS108874). A.B. and S.M.Z. received a grant from Dravet Syndrome UK for the Glasgow SCN1A database (grant 16GLW00). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Funding Information: D.L. was supported by funds from the Dravet Syndrome Foundation (grant 272016), BMBF (Treat-ION grant 01GM1907), and NIH NINDS (Channelopathy-Associated Epilepsy Research Center, 5-U54-NS108874). A.B. and S.M.Z. received a grant from Dravet Syndrome UK for the Glasgow SCN1A database (grant 16GLW00). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: Copyright © 2022 American Academy of Neurology.
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