Abstracts

Rationale:
Disease-causing variants in the SCN1A gene are associated with a spectrum of neurogenetic disorders, including Dravet syndrome, generalized epilepsy with febrile seizures+ (GEFS+), and early infantile epileptic encephalopathy (EEIE). Dravet syndrome is a treatment-resistant developmental and epileptic encephalopathy characterized by seizure onset in the first year of life, severe neurodevelopmental decline and behavioral problems. Between 2011 and 2015, the reported average age at molecular diagnosis for patients with SCN1A-related disorders was 6.2 years of age (Lindy et. al 2018). As precision medicine therapies emerge, it is becoming increasingly important to diagnose SCN1A-related disorders before disease progression. To reduce the age at molecular diagnosis, we launched a no-cost, targeted epilepsy gene panel testing program for children suspected to have genetic epilepsy. Here we report the results of 6874 tests through this program and the clinical characteristics of 152 patients diagnosed with SCN1A-related disorders. 
Method:
At testing, eligible participants had a single unprovoked seizure and were 0-48 months of age (from Feb/2019 to Jan/2020) and 0-96 months of age (Jan/2020 to present). Ordering physicians provided brief clinical information that included seizure type (generalized, febrile, focal), family history, language delay, and motor disturbances (ataxia, clumsiness, and/or frequent falls). The sponsored testing program used a multi‐gene, next‐generation sequencing panel with simultaneous sequence and exonic copy number variant detection to investigate up to 186 epilepsy-related genes.
Results:
Out of 6874 patients tested, 152 had a positive molecular diagnosis (PosMD) related to the SCN1A gene, accounting for 2.2% of all patients tested. The average age at molecular diagnosis was 23 months for patients identified with a SCN1A PosMD and the average age of the first seizure was 9.8 months. Most patients presented with generalized seizures (76.3%, n=116) and febrile seizures (65.8%, n=100). Approximately 30% of patients had focal seizures (n=49) and motor disturbances (n=45), while 15% had language delays (n=23). Approximately 6% (n=9) of patients had a family history of epilepsy.
Conclusion:
By providing a no-cost, targeted epilepsy gene panel sponsored testing program, a large cohort of patients with PosMD in the SCN1A gene has been identified. Our results demonstrate a substantial decrease in the average age at molecular diagnosis from over 6 years of age in 2015 to under 2 years of age as of June 2020. Based on the reported clinical findings of the tested participants, we expect most individuals to have a clinical diagnosis of GEFS+ or Dravet syndrome. As precision medicine therapies emerge, rapid and early molecular diagnosis is vital to enable early intervention, before disease has progressed, to ensure transformative outcomes in patients with SCN1A-related disorders.
Funding:
:None