SCN2A – SCN2A-related Developmental and Epileptic Encephalopathy

SCN2A, encoding the neuronal voltage-gated sodium channel NaV1.2, is associated with autosomal dominant developmental and epileptic encephalopathy (DEE). ClinGen classifies this association as Definitive based on replicated de novo segregation and concordant functional studies across multiple cohorts.

Autosomal de novo SCN2A variants have been identified in 11 unrelated probands with DEE (8 with malformation of cortical development) (PMID:39707911, PMID:34859793, PMID:15028761). No multiplex familial segregation beyond de novo cases has been observed, consistent with a dominant de novo inheritance pattern.

The variant spectrum in DEE comprises missense, nonsense, frameshift, and splice-site changes. A representative pathogenic change is c.5308A>T (p.Met1770Leu), recurrently observed in eight individuals with malformation of cortical development (PMID:39707911). Truncating variants such as c.304C>T (p.Arg102Ter) also cause early-onset refractory seizures and intellectual decline (PMID:15028761).

Functional assays in HEK cells and dynamic action potential clamp demonstrate that gain-of-function (GoF) variants shift activation/inactivation to promote neuronal hyperexcitability, whereas loss-of-function (LoF) and enhanced slow inactivation underpin later-onset phenotypes (PMID:39707911, PMID:34287911). Computational modeling of neonatal and adult NaV1.2 isoforms further correlates biophysical defects with clinical severity.

The integration of genetic and experimental data confirms SCN2A as a definitive DEE gene. Inclusion of SCN2A in diagnostic gene panels enables early molecular diagnosis, informs prognostic counseling, and supports mechanism-based therapy selection (e.g., sodium channel blockers for GoF variants).

Key Take-home: Pathogenic de novo SCN2A variants are a definitive cause of autosomal dominant DEE; SCN2A testing should be standard in early-onset epileptic encephalopathy panels.

References

• Epilepsia • 2025 • Rare dysfunctional SCN2A variants are associated with malformation of cortical development PMID:39707911
• Epileptic disorders : international epilepsy journal with videotape • 2022 • Phenotypic spectrum and long-term outcome of children with genetic early-infantile-onset developmental and epileptic encephalopathy PMID:34859793
• The Journal of neuroscience : the official journal of the Society for Neuroscience • 2004 • A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline PMID:15028761
• The Journal of physiology • 2021 • Enhanced slow inactivation contributes to dysfunction of a recurrent SCN2A mutation associated with developmental and epileptic encephalopathy PMID:34287911

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