Abstracts

Rationale: SCN1A encodes the NaV1.1 voltage-gated sodium channel (NaV1.1) α subunit. Pathogenic variants cause a spectrum of neurological disorders, including recurrent febrile seizures, GEFS+, Dravet Syndrome, and a recently described early-onset severe form of Dravet-like syndrome. The cause for high clinical variability in SCN1A-related disorders despite similar or identical causative SCN1A variants is unclear, necessitating the combination of deep phenotypic reconstruction with genomic strategies.

Methods: We performed an analysis of 55 individuals with SCN1A-related disorders from our local cohort, utilizing the standardized biomedical dictionary provided by the Human Phenotype Ontology (HPO) to accurately extract clinical features. Seizure types, medication histories, and neurological features were reconstructed in monthly increments and compared to similarly reconstructed datasets for other severe, infantile-onset genetic epilepsies caused by disease-causing variants in STXBP1, SYNGAP1, and SCN2/8A.

Results: We reconstructed 315 patient years of seizure, developmental, and intervention histories. The mean age of onset of seizures was 6.9 months. Febrile seizures were documented as present in 75% of individuals, and 84% had at least one episode of status epilepticus. Convulsive status epilepticus was present in 53% of individuals, and 40% of all episodes of status epilepticus occurred in the setting of fever. Common seizure types in the cohort included bilateral tonic-clonic seizures (89%) followed by hemiclonic seizures (51%) and seizures without significant motor involvement (49%). During most of the reconstructed time periods, individuals had either monthly seizures or multiple seizures per day. Most individuals in our cohort had neurodevelopmental delay (73%), most often presenting as expressive language or global developmental delay. Age of seizure onset was significantly associated with the age of onset of developmental delay (p< 0.001, R=0.88). In a sub-cohort of individuals with gain-of-function (GOF) variants (n=6), seizure onset was significantly earlier (1 vs. 6.9 months p< 0.001) when compared to the loss-of-function cohort. Finally, congenital anomalies of the male genitalia (GOF cohort vs. total cohort, p< 0.001) were present in the GOF cohort, which represents a novel finding within the spectrum of SCN1A-related disorders.

Conclusions: SCN1A-related epilepsies demonstrate a broad variability in seizure frequencies and neurodevelopmental features that can be delineated through phenotype reconstruction techniques in a scalable manner. We demonstrate that pertinent clinical hallmarks of Dravet Syndrome identified in smaller prospective natural history studies can be replicated in and complemented by real-world datasets. In addition, our findings highlight that up to 25% of individuals with Dravet Syndrome present atypically and that the trajectory of Dravet Syndrome is clearly distinct from SCN1A-related epilepsies due to gain-of-function variants.

Funding: Dravet Syndrome Foundation and the National Institute for Neurological Disorders and Stroke (R01 NS127830-01A1, R01 NS131512-01 and K02 NS112600).