Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy

Significance SCN2A , encoding the voltage-gated sodium channel Na v 1.2, has emerged as a major gene implicated in neonatal-, infantile-, and even childhood-onset epilepsies. Many of these epilepsies are also associated with cognitive and behavioral impairments that range in type and severity. The biophysical, neurophysiological, and clinical impacts of SCN2A mutations are poorly understood. Here, we use clinical evaluation and biophysical analyses to explore the mechanisms underpinning distinctive phenotypes produced by SCN2A variants associated with mild familial or severe de novo forms of epilepsy. We show that dynamic clamp analysis provides clear benefits over conventional voltage clamp for a rapid and definitive prediction of neuron-scale phenotypic consequences, and is well positioned to impact diagnosis and drug discovery in genetic epilepsy.