Genetic Contributions to Autism Spectrum Disorder: A Review of Recent Advances

1. Introduction

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication, and restricted and repetitive behavioral patterns [1]. Its global prevalence has been increasing, reaching 2.3% in children in the United States in 2018 [2]. Comorbidities such as neurodevelopmental delay (NDD), intellectual disability (ID), and attention-deficit hyperactivity disorder (ADHD) are widely documented among individuals with ASD, illustrating its clinical heterogeneity [3].

Although the origin of ASD involves both environmental and genetic factors, mutations in specific genes, such as those involved in the regulation of brain development and synaptic function, are associated with distinct manifestations of the disorder [4]. These mutations influence the severity of behavioral traits and the presence of comorbidities, such as epilepsy and mood disorders [2].

Advances in genetic sequencing techniques, such as genome-wide association studies (GWAS) and exome sequencing, have enabled the identification of genetic variants that help map the complexity of the clinical spectrum of ASD [5]. These discoveries reveal a multifaceted network of genes associated with neurodevelopment, neuronal communication, and synaptic plasticity, indicating that ASD is a genetically heterogeneous disorder with a direct impact on the observed clinical manifestations [6].

This integrative review aims to explore the main genes associated with ASD and their relationships with neurodevelopment, highlighting how these factors contribute to the varied clinical manifestations of the disorder, based on recent literature.

2. Materials and Methods

The data were obtained through a search conducted in two electronic databases: US National Library of Medicine (PubMed) and Web of Science. The search terms used were combined as follows: “Autism” OR "Autism Spectrum Disorder" OR “ASD” AND “genes” OR "genetic mutation" OR "gene variant" OR "gene expression" AND “neurodevelopment” OR "brain development" OR "neural development." The descriptors were defined by the guiding research question: “Which genes present in Autism Spectrum Disorder cases are related to neurodevelopment?”. Studies published between January 2020 and April 2024, in Portuguese and English, were included. Duplicated articles, narrative and integrative reviews, as well as studies unrelated to the topic, were excluded. (Figure 1).

The study selection process was carried out in three stages. In the first stage, the studies found were submitted to the Web app Rayyan®, where they underwent a duplicate check. In the second stage, the titles and abstracts of the articles were read to identify potentially relevant studies. In the third and final stage, the articles that passed the initial screening were read in full to confirm their relevance and inclusion in the review. Data extraction was performed after reading the selected articles, identifying genes associated with autism spectrum disorder and neurodevelopment (Figure 2).

3. Results

A total of 292 articles were obtained, distributed as follows: 157 articles from the Web of Science database and 135 articles from the PubMed database. Forty-nine duplicated articles were excluded. After reading the titles and abstracts, 209 articles were excluded, and 34 remained for the next phase. After the full reading of the selected studies, 12 articles proceeded to the data extraction phase (Figure 3).

The results reveal significant findings on the proposed topic. In a clinical case analysis, a deleterious variant in the MYT1L gene was identified, associated with autism and intellectual disability (ID), highlighting the importance of genomic analysis through WGS and the rigorous collection of phenotypic data [7]. Additionally, de novo and inherited variants in the ZNF292 gene were associated with a spectrum of neurodevelopmental characteristics, including ID, ASD, and ADHD [4].

The investigation of genes associated with autism, combined with differential brain expression data, revealed GABRA5, GABRG3, NTM, SNRPN, OTX1, FOXG1, TSHZ3, CDH18, GABRB3, GATM, HTR2A, DHCR7, and NLRP2. All of these genes have associations with the neural system and are linked to autism [8]. (Table 1)

Additionally, genes associated with the production of microRNAs (miRNAs), a class of small non-coding RNAs that play a regulatory role in post-transcriptional gene expression, have been identified. These miRNAs influence various molecular pathways, including those related to neurodevelopment and neuromodulation [9]. Among the key genes highlighted are TUB, SCP2, ONECUT2, OSBP, RBM24, and UGCG, with implications for ASD (Autism Spectrum Disorder) and neurodevelopmental processes. (Table 2)

4. Discussion

The findings of this review reinforce the central role of genetics in understanding Autism Spectrum Disorder (ASD). Genes such as FGFR2 and KMT5B, highlighted by Nicotera et al. [6] and Odak et al. [10], are strongly associated with neurodevelopmental disorders like ASD and ADHD, underscoring their relevance for understanding the genetic basis of these disorders. The association of specific variants, such as the PTEN p.Ile135Leu variant, with alterations in neurogenesis, neural maturation, and synaptic function, as reported by Fu et al. [11] and Park et al. [12], points to the importance of detailed mechanistic studies. These findings suggest that the dysregulation of essential processes such as neurogenesis and gliogenesis may significantly contribute to the clinical variability observed in ASD.

Furthermore, the identification of mutations in the AUTS2 locus and genes like ITSN1 and KDM2B reinforces the complexity of the molecular mechanisms of ASD, linking them not only to neurodevelopment but also to other conditions such as schizophrenia and ADHD [13,14,15,16].The identification of new candidate genes for ASD, especially those related to post-transcriptional regulation, such as microRNAs (TUB, SCP2, UGCG, among others), enhances our understanding of the molecular networks involved. These non-coding RNAs play critical roles in modulating neural differentiation, apoptosis, and neuronal signaling, emerging as potential therapeutic targets [9].

The use of specialized databases was essential for consolidating the findings of this review. OMIM (Online Mendelian Inheritance in Man) is a comprehensive database that gathers information about genes and their relationships to genetic conditions, serving as an indispensable tool for identifying genes associated with ASD. ClinVar, in turn, provides detailed information about the clinical significance of genetic variants, facilitating the correlation between mutations and their clinical impacts. NCBI (National Center for Biotechnology Information) was widely used for genomic sequence consultation and locus analysis, while Decipher proved to be fundamental in investigating rare variants and their associations with specific phenotypes. These resources not only centralize critical information but also enable integrative analyses, contributing to the robustness of the conclusions drawn.

The data presented highlight that specific genetic variants play a central role in the development of ASD, with implications extending beyond diagnosis, offering insights for new therapeutic approaches. The integration of genomic information with emerging technologies, such as cortical organoids and gene-editing studies, may represent a significant advance in the field. The relevance of genes related to neurodevelopment, as well as pathways regulated by miRNAs, emphasizes the need for further exploration of the molecular mechanisms of ASD, focusing on targeted interventions.

5. Conclusions

The presented review demonstrates the genetic complexity of Autism Spectrum Disorder, revealing important genes such as MYT1L, ZNF292, AUTS2, PTEN, and genes related to regulation by microRNAs, all linked to key neurodevelopmental processes such as neurogenesis, synaptogenesis, and neuronal regulation.

The selection of relevant studies, highlighting the diversity of molecular mechanisms contributing to ASD, from specific deleterious variants to dysregulation in gene expression, has expanded the knowledge of genetic factors associated with neurodevelopment. However, the analysis could benefit from greater integration with epigenetic and environmental factors, enhancing the understanding of gene-environment interactions. Despite this, the findings provide a solid foundation for the development of new therapeutic approaches, pointing to genes and molecular pathways as potential targets for personalized clinical strategies, reflecting the relevance of genomics in advancing precision medicine in the field of neurodevelopment.