# Decoding _Scn2a_ Variants: Bridging Genetics and Phenotypes in Autism Spectrum Disorder
## 4 Discussion  
_Analysis of Genotypic and Phenotypic Trends_  
The data analyzed in this study provide significant insights into the genotypic and phenotypic spectrum associated with _SCN2A_ mutations in patients with ASD. Among the 695 patients across 11 studies, 75 (10.8%) were identified as having _SCN2A_ mutations. Of these, 58 cases involved missense mutations, making it the most prevalent mutation type. A missense mutation occurs when single-nucleotide changes result in the substitution of one amino acid for another in the protein sequence, potentially altering its structure and function. This trend aligns with the known impact of missense mutations on the function of the Nav1.2 sodium channel, which plays a critical role in neuronal excitability within the central nervous system. Nav1.2 channels are responsible for initiating and propagating action potentials in neurons, facilitating rapid communication between nerve cells [66]. When these channels are underutilized or their function is depressed, it can lead to reduced neuronal activity, which is associated with developmental delays, intellectual disabilities, and conditions like ASD [50]. Conversely, overactivation of these channels can result in excessive neuronal firing, potentially leading to seizures and other hyperexcitable states, further contributing to the neurological symptoms observed in individuals with _SCN2A_ mutations [66; 67; 68; 69]. Frameshift mutations, which involve insertions or deletions of nucleotides that disrupt the reading frame of the gene, were the next most common, found in 14 patients, followed by 14 cases of nonsense mutations, which introduce a premature stop codon, leading to truncated, nonfunctional proteins. Both typically lead to severe phenotypes, including profound intellectual disability and intractable epilepsy due to the loss of function in the _SCN2A_ protein. Splicing mutations, which affect the normal removal of introns and assembly of exons during RNA processing, were documented in nine patients, highlighting the complexity of _SCN2A_-related disorders and the potential for these mutations to result in abnormal RNA processing. Phenotypically, individuals with _SCN2A_ mutations frequently exhibited a combination of motor impairments and behavioral symptoms characteristic of ASD [41]. Specifically, 19 patients reported difficulties with walking, including unsteady or atax gait, and 29 patients exhibited movement disorders like hypotonia and dystonia. Behavioral symptoms included repetitive actions and delayed speech development, with 22 patients experiencing speech delays and 17 reported as nonverbal. Additionally, seizures and epilepsy were prevalent, affecting 79 and 37 patients, respectively, further underscoring the neurological impact of _SCN2A_ mutations. Previous studies have extensively documented the association between _SCN2A_ mutations and epilepsy, particularly in early-onset cases. For instance, [PERSON] et al. and [PERSON] et al. found that mutations in _SCN2A_ can lead to both gain-of-function and loss-of-function effects in the Nav1.2 sodium channel, contributing to hyperexcitability in neurons and resulting in seizure activity [49; 50]. These studies emphasize that _SCN2A_-related epilepsy often presents within the first few months of life and can be severe, sometimes resistant to standard antiepileptic treatments [41]. The observed phenotypic variability, even among patients with similar genotypic alterations, suggests the influence of other genetic, epigenetic, or environmental factors on clinical presentation. Moreover, the association of _SCN2A_ mutations with early-onset epilepsy and intellectual disability, observed in 79 and 65 patients, respectively, corroborates findings from previous studies such as those by [PERSON] et al. and [PERSON] et al. [44; 50]. The phenotypic variability documented in our data, where some patients exhibit mild forms of ASD while others present with severe neurodevelopmental disorders, mirrors the heterogeneity noted in earlier research [39; 70].