Development and Validation of a Prediction Model for Early Diagnosis of SCN1A -Related Epilepsies - Sorbonne Université
Journal Articles Neurology Year : 2022

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

Andreas Brunklaus
  • Function : Author
Eduardo Pérez-Palma
  • Function : Author
Ismael Ghanty
  • Function : Author
Ji Xinge
  • Function : Author
Eva Brilstra
  • Function : Author
Berten Ceulemans
  • Function : Author
Nicole Chemaly
  • Function : Author
Iris de Lange
  • Function : Author
Renzo Guerrini
  • Function : Author
Davide Mei
  • Function : Author
Rikke Møller
  • Function : Author
Rima Nabbout
  • Function : Author
Brigid Regan
  • Function : Author
Amy Schneider
  • Function : Author
Ingrid Scheffer
  • Function : Author
An-Sofie Schoonjans
  • Function : Author
Joseph Symonds
  • Function : Author
Sarah Weckhuysen
  • Function : Author
Michael Kattan
  • Function : Author
Sameer Zuberi
  • Function : Author
Dennis Lal
  • Function : Author

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 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/).

Dates and versions

hal-04577902 , version 1 (16-05-2024)

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Cite

Andreas Brunklaus, Eduardo Pérez-Palma, Ismael Ghanty, Ji Xinge, Eva Brilstra, et al.. Development and Validation of a Prediction Model for Early Diagnosis of SCN1A -Related Epilepsies. Neurology, 2022, 98 (11), pp.e1163-e1174. ⟨10.1212/WNL.0000000000200028⟩. ⟨hal-04577902⟩
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