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Variants in the SCN2A gene that disrupt the encoded neuronal sodium channel Na_V1.2 are important risk factors for autism spectrum disorder (ASD), developmental delay, and infantile seizures. Variants observed in infantile seizures are predominantly missense, leading to a gain of function and increased neuronal excitability. How variants associated with ASD affect Na_V1.2 function and neuronal excitability are unclear.

We examined the properties of 11 ASD-associated SCN2A variants in heterologous expression systems using whole-cell voltage-clamp electrophysiology and immunohistochemistry. Resultant data were incorporated into computational models of developing and mature cortical pyramidal cells that express Na_V1.2.

In contrast to gain of function variants that contribute to seizure, we found that all ASD-associated variants dampened or eliminated channel function …