SCN9A – SCN9A-related Epilepsy

Clinical Validity
SCN9A (Nav1.7) encodes a voltage-gated sodium channel predominantly expressed in peripheral neurons but increasingly implicated in central seizure disorders. Heterozygous missense variants in SCN9A have been reported in multiple patients presenting with focal and generalized epilepsy, suggesting a contributory role in epileptogenesis. The overall gene–disease association is categorized as Moderate based on eight probands across four independent studies, limited segregation data, and concordant mechanistic plausibility in neuronal excitability modulation.

Genetic Evidence
Inheritance is autosomal dominant, with most variants arising de novo or in small families. A recurrent heterozygous variant, c.980G>A (p.Gly327Glu) , was identified in twin sisters with idiopathic focal epilepsy with rolandic spikes ([PMID:30834459]). Two unrelated patients harbouring distinct heterozygous SCN9A mutations exhibited variable epilepsy phenotypes including febrile and focal seizures ([PMID:29500686]). Two further unrelated potentially pathogenic SCN9A variants emerged from a cohort re-analysis of pediatric epilepsy cases ([PMID:39509559]). Moreover, a targeted exome study of 63 Chinese trios found SCN9A among 15 families with pathogenic or likely pathogenic variants in known epilepsy genes ([PMID:28074849]). Despite replication across studies (total 8 probands), segregation beyond sibling pairs remains limited.

Functional Evidence
Although SCN9A mutations are best characterized in pain syndromes, Nav1.7 influences neuronal action potential initiation and firing frequency. Gain-of-function effects documented in DRG neurons imply that analogous variants could hyperexcite cortical or hippocampal networks. However, no direct functional assays in epilepsy-specific neuronal models have been reported.

Conflicting Evidence
No studies to date refute or dispute the association of SCN9A variants with epilepsy phenotypes.

Integration & Conclusion
Heterozygous SCN9A missense mutations contribute to a growing spectrum of epilepsy disorders, likely via altered sodium current dynamics and neuronal hyperexcitability. While functional data from pain models support a gain-of-function mechanism, epilepsy-targeted assays are needed to confirm pathogenicity. SCN9A testing should be considered in epilepsy gene panels, particularly for patients with focal or febrile seizure presentations. Key Take-home: Identification of pathogenic SCN9A variants informs diagnostic evaluation and may guide sodium channel-targeted therapies in epilepsy.

References

• Neurological sciences • 2019 • G327E mutation in SCN9A gene causes idiopathic focal epilepsy with Rolandic spikes: a case report of twin sisters. PMID:30834459
• Neurological sciences • 2018 • Variable epilepsy phenotypes associated with heterozygous mutation in the SCN9A gene: report of two cases. PMID:29500686
• Epilepsia open • 2024 • Previously defined variants of uncertain significance may play an important role in epilepsy and interactions between certain variants may become pathogenic. PMID:39509559
• Scientific reports • 2017 • Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing. PMID:28074849

Evidence Based Scoring (AI generated)