# Decoding _Scn2a_ Variants: Bridging Genetics and Phenotypes in Autism Spectrum Disorder
## 4 Discussion
This variability is particularly evident in the context of gender,where the impact of _SCN2A_ mutations appears to differ between males and females, a pattern that has been reported in other genetic studies on ASD [3; 35; 66]. An important aspect of the data concerns the gender distribution of patients with _SCN2A_ mutations. Among the 201 patients for whom gender data were available, there were 114 males and 87 females, indicating a slight male predominance. While this cohort demonstrated a slight male predominance, the distribution of males and females in the cohort was skewed away from the typical 4:1 ratio of males to females [71]. This may indicate _SCN2A_ affecting a female population more than other known ASD genetic mutations [72]. The higher prevalence of _SCN2A_ mutations in males may reflect this broader epidemiological pattern, suggesting that males may be more susceptible to the neurodevelopmental impacts of _SCN2A_ mutations. The reason for this male predominance in ASD and related genetic conditions like those involving _SCN2A_ is not fully understood, but it is thought to involve a combination of genetic, hormonal, and possibly environmental factors [73]. Some researchers have proposed that females might have a higher threshold for developing ASD, meaning that they require a greater mutational burden or additional genetic and environmental risk factors to exhibit ASD symptoms compared to males [43; 71; 74]. This could explain why the females in this cohort, although fewer in number, might present with more severe phenotypes, though this hypothesis requires further investigation. There is also a thought that females may display a differing array of symptoms, which can be more subtle than in their male counterparts [71]. The current diagnostic understanding of ASD is based largely on studies and observations in males, possibly allowing affected females to be missed by current diagnostic criteria [32; 33]. Although this review documents gender distribution and reports genotype-phenotype associations, a detailed statistical analysis of the most frequent SCN2A variants among individuals with comorbid ASD and epilepsy, as well as formal testing of gender-specific trends, was not performed. These analyses are important and could yield meaningful insights, but they were beyond the scope of this study. Future investigations using harmonized datasets and larger cohorts may be better positioned to explore these relationships more robustly. The trends observed in this study align with findings from previous research on _SCN2A_-related disorders. Prior studies have consistently identified _SCN2A_ as a significant contributor to ASD, with a strong correlation between _SCN2A_ mutations and severe neurological phenotypes [5; 39]. For instance, the predominance of missense mutations (58 cases) aligns with reports from [PERSON] et al. and [PERSON] et al., which highlight the role of these mutations in disrupting Nav1.2 channel function, leading to neurological symptoms associated with ASD and related conditions [41; 49]. While the overall trends in this study align with the existing literature, our analysis contributes to the growing body of knowledge by providing a more detailed examination of specific genotypic and phenotypic correlations within a larger cohort of patients. The documentation of specific mutations, such as the novel splicing mutation c.2919+4 deIT, and their corresponding clinical manifestations adds valuable information to the understanding of _SCN2A_-related disorders. One of the novel aspects of this study is the detailed examination of specific _SCN2A_ mutations and their precise phenotypic outcomes, including a focus on gender differences. While previous studies have identified the general association between _SCN2A_ and ASD, this study goes further by cataloging exact mutations and linking them to specific clinical presentations, such as low-functioning autism and dystonic movement disorder associated with the c.2919+4 delT splicing mutation.