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

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/).

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.

• Authors: Andreas Brunklaus, Eduardo Pérez-Palma, Ismael Ghanty, Ji Xinge, Eva Brilstra, Berten Ceulemans, Nicole Chemaly, Iris de Lange, Christel Depienne, Renzo Guerrini, Davide Mei, Rikke S Møller, Rima Nabbout, Brigid M Regan, Amy L Schneider, Ingrid E Scheffer, An-Sofie Schoonjans, Joseph D Symonds, Sarah Weckhuysen, Michael W Kattan, Sameer M Zuberi, Dennis Lal
• Journal: Neurology (Neurology) Vol. 98 Issue 11 Pg. e1163-e1174 (03 15 2022) ISSN: 1526-632X [Electronic] United States
• PMID: 35074891 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 American Academy of Neurology.

Chemical References

• NAV1.1 Voltage-Gated Sodium Channel
• SCN1A protein, human

Topics

• Child
• Cohort Studies
• Early Diagnosis
• Epilepsies, Myoclonic (diagnosis, genetics)
• Epilepsy (diagnosis, genetics)
• Humans
• Mutation
• NAV1.1 Voltage-Gated Sodium Channel (genetics)
• Retrospective Studies