Abstracts

Rationale: SCN2A-related developmental and epileptic encephalopathy (DEE) comprises a subset of rare neurodevelopmental genetic disorders associated with a broad epilepsy phenotype, developmental impairments, intellectual disability, and autism. As a rare condition with significant heterogeneity, comprehensive understanding of disease burden and progression is limited. We aimed to explore the burden of SCN2A-DEE on patients and caregivers using clinical data generated via a novel, patient-consented, real-world data platform.

Methods: Real-world clinical data were extracted from patients with an SCN2A variant using Invitae’s Ciitizen platform (www.ciitizen.com), which employs a proprietary approach combining machine learning and expert human review to streamline generation of research-grade data from unstructured health records spanning ~10 years. Extracted data, including seizure history, medication use, comorbidities, and developmental milestones, were classified by phenotype based on age at seizure onset, type of seizure at initial presentation, variant type, and variant functional characterization using dynamic action potential clamp analysis. SCN2A variants producing increased or decreased action potential relative to wild type were classified as probable gain-of-function or loss-of-function, respectively.

Results: Of 49 enrolled patients, 45 had data available for analyses. Four emergent phenotypes (Table 1) were identified across three groups: early onset epilepsy (EO, 33.5%), late onset epilepsy (LO, 42%), and autism without epilepsy (AO, 24.5%). The LO group contained two distinct phenotypes based on age and type of seizure at onset: the first, characterized by initial seizure presentation with infantile spasms (LOIS, 20%); the second characterized by seizures other than infantile spasms and presenting later in life (LO, 22%). The AO group was characterized by developmental delay and autism without epilepsy. Mean patient age across cohorts was 8 years (range 0.8-23.3), with similar percentages of male and female patients. Mean age at seizure onset was 5.1 (1-44) days for those classified as EO. Fifty-three percent of patients with seizures experienced status epilepticus at least once. Mean number of medications prescribed over the lifetime of each patient was 18.1 (0-58). Patients had multiple comorbidities, with global developmental delay reported in almost all patients (97%), and hypotonia, GERD, autism, and sleep disorders reported in >50%. Greater than 60% of patients had not achieved age-appropriate physical developmental milestones.

Conclusions: Using a novel real-world data platform and functional variant characterization, we provide unprecedented insight into clinical phenotypes, disease burden and treatment patterns in SCN2A. We demonstrate that symptoms are diverse and extend beyond epilepsy, with patient burden compounded by comorbidities, treatment use, and procedural interventions. Our findings are anticipated to aid development of more effective and targeted therapies for better outcomes in SCN2A.

Funding: Praxis Precision Medicines