SCN3A – Developmental and Epileptic Encephalopathy

SCN3A encodes the Nav1.3 α-subunit of voltage-gated sodium channels, with emerging evidence linking heterozygous variants to developmental and epileptic encephalopathy (DEE) (MONDO:0100062) and related epilepsy phenotypes. Autosomal dominant de novo missense variants cluster in pore and voltage-sensing regions, consistent with a gain- or loss-of-function disease mechanism.

Genetic screening across multiple cohorts has identified at least 9 unrelated probands with heterozygous SCN3A missense variants associated with early-onset epilepsy and developmental delay ([PMID:18242854]; [PMID:24157691]; [PMID:24990319]; [PMID:28235671]; [PMID:34102392]; [PMID:37935051]). Inheritance is autosomal dominant with de novo occurrence, and no clear segregation in multiplex families (affected_relatives = 0). The variant spectrum is entirely missense, exemplified by c.1060A>C (p.Lys354Gln), which substitutes glutamine for a conserved lysine in the pore domain.

Functional assays in heterologous systems demonstrate convergent pathogenic effects: c.1060A>C (p.Lys354Gln) increases persistent sodium current in NaV1.3 channels ([PMID:18242854]), while the recurrent p.Ile875Thr variant augments slowly inactivating current and induces paroxysmal bursting in patient-derived iPSC neurons ([PMID:37935051]). Mouse hypomorphic Scn3a+/Hyp models exhibit increased electroconvulsive and chemiconvulsive seizure susceptibility, confirming the in vivo relevance of SCN3A loss-of-function ([PMID:28235671]). Electrophysiological characterization of R357Q, D766N, E1111K and M1323V variants further supports a shared hyperexcitability phenotype ([PMID:24157691]).

A broader meta-analysis across sodium channelopathies reveals high biophysical concordance between corresponding SCN variants, suggesting predictive value for uncharacterized SCN3A alleles ([PMID:35037686]). These findings establish a direct genotype-phenotype correlation and mechanistic link between SCN3A dysfunction and DEE.

One report of a 2q24.3 microduplication including SCN3A and neighboring SCN genes in a patient with early infantile DEE did not maintain seizure activity beyond infancy, indicating that gene dosage effects may differ from point mutation pathogenicity ([PMID:35733834]).

Overall, the evidence supports a Moderate ClinGen clinical validity classification for SCN3A in DEE, with multiple probands harboring de novo missense variants and concordant functional data. Key take-home: Heterozygous SCN3A missense variants exert gain- and loss-of-function effects that underlie developmental and epileptic encephalopathy and may guide precision sodium channel–targeted therapy.

References

• Neuroscience letters • 2008 • Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. PMID:18242854
• Neurobiology of disease • 2014 • Novel SCN3A variants associated with focal epilepsy in children. PMID:24157691
• Molecular neurobiology • 2015 • Electrophysiological Differences between the Same Pore Region Mutation in SCN1A and SCN3A. PMID:24990319
• Neurobiology of disease • 2017 • SCN3A deficiency associated with increased seizure susceptibility. PMID:28235671
• Epilepsy research • 2021 • Identification of a novel variant p.Ser606Gly in SCN3A associated with childhood absence epilepsy. PMID:34102392
• Brain : a journal of neurology • 2024 • Targeted blockade of aberrant sodium current in a stem cell-derived neuron model of SCN3A encephalopathy. PMID:37935051
• Epilepsy & behavior reports • 2022 • Long-term course of early onset developmental and epileptic encephalopathy associated with 2q24.3 microduplication. PMID:35733834
• Brain : a journal of neurology • 2022 • Gene variant effects across sodium channelopathies predict function and guide precision therapy. PMID:35037686

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