Molecular Analysis of SCN1A Gene Variants Associated with Dravet Syndrome: Implications for Diagnosis and Management.
TL;DR
SCN1A-confirmed DS is associated with substantial seizure burden and neurodevelopmental morbidity, and delayed molecular diagnosis may lead to inappropriate treatment exposure and seizure worsening.
Abstract
Objective
SCN1A variants are the primary genetic cause of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy characterized by early-onset prolonged seizures and progressive neurodevelopmental impairment. Early molecular diagnosis may influence treatment decisions and clinical outcomes. To characterize the molecular spectrum of SCN1A variants and describe the associated clinical and therapeutic features in children with suspected DS.
Methods
This retrospective study included children evaluated between 2018 and 2020 with clinical suspicion of DS or febrile seizures with epilepsy who were referred for SCN1A genetic testing. Next-generation sequencing was used to detect sequence variants, complemented by multiplex ligation-dependent probe amplification for copy number analysis. A total of 60 patients were screened, and 18 patients carrying pathogenic or likely pathogenic SCN1A variants and fulfilling clinical criteria for DS were included.
Results
Eighteen patients were identified with heterozygous pathogenic or likely pathogenic SCN1A variants, including 6 novel variants. Segregation analysis demonstrated that all 15 tested patients had de novo variants. Seizure onset ranged from 2.5 to 8 months, predominantly before 6 months of age. Several patients were exposed to sodium channel-blocking agents prior to molecular confirmation, with seizure aggravation and subsequent treatment modification. All patients required multiple anti-seizure medications and showed varying degrees of neurodevelopmental impairment.
Conclusion
SCN1A-confirmed DS is associated with substantial seizure burden and neurodevelopmental morbidity. Delayed molecular diagnosis may lead to inappropriate treatment exposure and seizure worsening. Early genetic testing in infants with early-onset seizures may improve treatment selection and clinical outcomes.