# Decoding _Scn2a_ Variants: Bridging Genetics and Phenotypes in Autism Spectrum Disorder
## 1 Introduction
A designation of 1-3 is given, where 1 indicates a gene with significant implication in ASD with at least 3 reported likely de novo gene-disrupting mutations. Each of those signifies meeting a threshold false discovery rate of <0.1. A designation of 2 is given to genes with two reported gene-disrupting de novomutations, and a designation of 3 is given to genes with one. Genes with a designation of syndromic (S) can be assigned if genes carry a considerably high risk for ASD. In order to establish a causative relationship between a gene and ASD diagnosis, an Evaluation of Autism gene Link Evidence (EAGLE) score can be utilized, where increased scores indicate a greater likelihood of causation of ASD [[https://gene.sfari.org/](https://gene.sfari.org/)]([https://gene.sfari.org/](https://gene.sfari.org/)) (accessed on 4 November 2024. Among the numerous genes identified as being significant for contributing to the development of ASD, _SCN2A_ has been identified as a category 1 gene, with the second highest EAGLE score of 109.3. Several studies have identified _SCN2A_ as a key genetic contributor to ASD development [3; 17; 34; 35; 36; 37; 38; 39; 40; 41; 42]. _SCN2A_ mutations in ASD significantly impair the initiation and propagation of neuronal action potentials, as well as axonal excitability, which are critical for proper early neurodevelopment. These disruptions compromise dendritic and synaptic functions, resulting in diminished synaptic plasticity and strength, key processes essential for effective neuronal communication and cognitive function (Figure 1) [43]. In fact, a 2018 study identified that 0.3% of children with ASD have the _SCN2A_ variant [44]. The gene is located on the positive strand of chromosome 2 (2q24.3), contains 27 exons, and encodes for the 2005 amino acid voltage-gated sodium channel Na\({}_{\text{v}}\)1.2 [41]. The structure of the voltage-gated sodium channel (NaV) highlights its intricate architecture, comprising a pore-forming alpha subunit with four domains and an external IG-fold domain of the beta subunit. The key features include the selectivity filter (DEKA box), the tetrodotoxin (TTX) binding site, and the allosteric coupling enabled by the domain-swapped architecture, which facilitates NaV gating and modulation by blockers such as GX-936 at the voltage-sensor domain (Figure 2) [45]. Na\({}_{\text{v}}\)1.2 functions to initiate and propagate action potentials, and de novo truncation or loss of function missense mutations have been recognized as contributing to depression in channel function [46]. This depression has consequently been associated with increased development of ASD and intellectual disability (ID) [41]. Na\({}_{\text{v}}\)1.2 is also broadly located throughout the central nervous system but not the peripheral nervous system [47]. These findings explain, in part, why children with this genotypic variant tend to present with delayed motor skills, unsteady/ataxic gait, clumsiness, repetitive actions, and hypotonia [34; 46; 48]. Studies have established the therapeutic potential of _SCN2A_ as a pharmacological target in mitigating the severity of diseases associated with dysfunction of the Na\({}_{\text{v}}\)1.2 channel, such as epilepsy, seizures, and ASD/ID [41; 49; 50]. Brain MRIs from patients with _SCN2A_ variants consistently demonstrated structural abnormalities, including agenesis of the corpus callosum, delayed white matter myelination, frontotemporal lobe dysplasia, and enlarged lateral ventricles (Figure 3) [51]. These findings provide critical insights into the neurological impact of _SCN2A_ mutations, enhancing our understanding of their role in brain development and predisposition to ASD. The objective of this manuscript is to systematically review and analyze the genotypic and phenotypic relationships between _SCN2A_ gene mutations and ASD, with a focus on elucidating the diverse spectrum of clinical presentations.