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

Neurology

From the Pediatric Neurosciences Research Group (A.B., I.G., J.D.S., S.M.Z.), Royal Hospital for Children, Glasgow; Institute of Health and Wellbeing (A.B., I.G., J.D.S., S.M.Z.), University of Glasgow, UK; Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana (E.P.-P.), Universidad del Desarrollo, Santiago, Chile; Genomic Medicine Institute, Lerner Research Institute (E.P.-P., D.L.), Department of Quantitative Health Sciences (J.X., M.W.K.), and Epilepsy Center, Neurological Institute (D.L.), Cleveland Clinic, OH; Department of Genetics (E.B., I.d.L.), University Medical Centre, Utrecht, the Netherlands; Department of Child Neurology (B.C., A.-S.S.), University Hospital Antwerp, Belgium; Reference Centre for Rare Epilepsies, Department of Pediatric Neurology (N.C., R.N.), Hôpital Necker-Enfants Malades, Université de Paris, France; Institute of Human Genetics (C.D.), University Hospital Essen, University of Duisburg-Essen, Germany; Neuroscience Department (R.G., D.M.), Children's Hospital A. Meyer-University of Florence, Italy; The Danish Epilepsy Centre (R.S.M.), Dianalund, Denmark; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Medicine, Epilepsy Research Centre, Austin Health (B.M.R., A.L.S., I.E.S.), and Florey and Murdoch Children's Research Institutes, Royal Children's Hospital (I.E.S.), University of Melbourne, Australia; Applied and Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology, VIB, Antwerp; Neurology Department (S.W.), University Hospital Antwerp; Institute Born-Bunge (S.W.), University of Antwerp, Belgium; Cologne Center for Genomics (D.L.), University of Cologne, Germany; and Stanley Center for Psychiatric Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge, MA.

Published: March 2022

Pathogenic variants in the sodium channel gene are the leading genetic cause of epilepsy, with varying severity in conditions like Dravet syndrome, which has severe outcomes, and the milder GEFS+, which allows for normal cognitive function.
The study involved analyzing data from over 1,000 patients with known genetic variations related to these conditions to develop a prediction model identifying the likelihood of a patient having Dravet syndrome versus GEFS+.
Results showed that a high genetic score and early seizure onset are strongly linked to Dravet syndrome, with the combined model achieving a high accuracy (AUC 0.89) in distinguishing Dravet from GEFS+, outperforming other predictive strategies.

Background And Objectives: Pathogenic variants in the neuronal sodium channel α1 subunit gene () 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 -related epilepsies.

Methods: We performed a retrospective multicenter cohort study comprising data from patients with -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 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 genetic score (133.4 [SD 78.5] vs 52.0 [SD 57.5]; < 0.001) and young age at onset (6.0 [SD 3.0] vs 14.8 [SD 11.8] months; < 0.001) were each associated with Dravet syndrome vs GEFS+. A combined 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; < 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 genetic score and seizure onset model distinguishes Dravet syndrome from other GEFS+ phenotypes.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8935441	PMC
http://dx.doi.org/10.1212/WNL.0000000000200028	DOI Listing

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