Abstract
SCN2A encodes for the alpha subunit of the voltage-gated sodium channel Na(V)1.2, which is involved in action potential initiation and backpropagation in excitatory neurons. Currently, it is one of the highest monogenetic risk factors for both epilepsy and autism spectrum disorder. However, SCN2A-related disorders manifest in a broad clinical neuropsychiatric spectrum, including distinct neurological and psychiatric disorders. This clinical heterogeneity presents challenges for mechanistic understanding and treatment development. SCN2A mutations are generally classified as either gain-of-function (GOF) or loss-of-function (LOF); however, many mutations do not perfectly align to this binary framework. SCN2A dysfunction alters neuronal excitability, channel kinetics, and synaptic transmission in various ways, resulting in multiple electrophysiological effects and both seizure and behavioral phenotypes that are influenced by developmental stage, brain region, genetic background, and sex. Although early lethality in GOF models limits behavioral characterization, LOF models broadly show patterns of learning impairments, altered sociability, and disrupted sensory processing. Still, behavioral and seizure phenotypes are often inconsistent even across models with similar or identical variants, suggesting that genetic modifiers, such as potassium channels, play a role in shaping disease outcomes. Overall, these findings suggest that SCN2A-related disorders involve complex gene-gene and gene-environment interactions, rather than only channel biophysics. Current therapeutic strategies include Clustered Regularly Interspaced Short Palindromic Repeat-mediated transcriptional activation (CRISPRa), antisense oligonucleotides, and deep brain stimulation; however, they are limited due to variant specificity or age of intervention. This review highlights areas of convergence and conflict across models, emphasizing knowledge gaps, such as the limited availability of data on early development. Ultimately, it emphasizes the importance of investigating models across different developmental stages, using diverse genetic background strains, among other approaches, to encourage therapeutic innovation and enhance care for patients. We hope this work contributes to the emerging unifying framework that looks beyond the GOF and LOF binary in SCN2A-related disorders.