Decoding the genetic landscape of autism: A comprehensive review

Abstract

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings. Recent advancements in genetic and epigenetic research have provided insights into the intricate mechanisms contributing to ASD, influencing both diagnosis and therapeutic strategies.

Aim: To explore the genetic architecture of ASD, elucidate mechanistic insights into genetic mutations, and examine gene-environment interactions.

Methods: A comprehensive systematic review was conducted, integrating findings from studies on genetic variations, epigenetic mechanisms (such as DNA methylation and histone modifications), and emerging technologies [including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 and single-cell RNA sequencing]. Relevant articles were identified through systematic searches of databases such as PubMed and Google Scholar.

Results: Genetic studies have identified numerous risk genes and mutations associated with ASD, yet many cases remain unexplained by known factors, suggesting undiscovered genetic components. Mechanistic insights into how these genetic mutations impact neural development and brain connectivity are still evolving. Epigenetic modifications, particularly DNA methylation and non-coding RNAs, also play significant roles in ASD pathogenesis. Emerging technologies like CRISPR-Cas9 and advanced bioinformatics are advancing our understanding by enabling precise genetic editing and analysis of complex genomic data.

Conclusion: Continued research into the genetic and epigenetic underpinnings of ASD is crucial for developing personalized and effective treatments. Collaborative efforts integrating multidisciplinary expertise and international collaborations are essential to address the complexity of ASD and translate genetic discoveries into clinical practice. Addressing unresolved questions and ethical considerations surrounding genetic research will pave the way for improved diagnostic tools and targeted therapies, ultimately enhancing outcomes for individuals affected by ASD.

Keywords: Autism spectrum disorder; Clustered Regularly Interspaced Short Palindromic Repeats-Cas9; Epigenetics; Gene-environment interactions; Genetics; Personalized medicine.

Figure 1

The main clinical manifestations of autism spectrum disorder.

Figure 2

The study flow chart.

Figure 3

Simple diagrammatic presentation of the genetic architecture of autism.

Figure 4

Genetic mutations in autism spectrum disorder: Functions and localizations of representative molecules. This figure provides an overview of representative molecules and their roles in synaptic function, focusing on the structure of a synapse, including the presynaptic terminal (containing neurotransmitter vesicles), the postsynaptic density (containing receptors and signaling proteins), and the synaptic cleft (space between presynaptic and postsynaptic terminals). Key molecules include CHD8 (chromatin remodeling, gene expression regulation; nucleus; mutations disrupt gene expression, affecting synaptic development), SHANK3 (postsynaptic scaffold protein; postsynaptic density; mutations affect synaptic signaling and plasticity), MECP2 (DNA methylation regulation, transcriptional repression; nucleus; mutations affect neuronal function), FMR1 (regulates synaptic protein synthesis; cytoplasm, dendrites; mutations affect synaptic strength and plasticity), NRXN1 (cell adhesion, synaptic transmission; presynaptic terminal; mutations impair synaptic adhesion and neurotransmitter release), NLGN4X (cell adhesion molecule; postsynaptic membrane; mutations disrupt synaptic signaling and connectivity, especially in males), NLGN4Y [similar to NLGN4X; postsynaptic membrane; variations contribute to sex differences in autism spectrum disorder (ASD)], and PTCHD1 (involved in the Hedgehog signaling pathway; cell membrane and cytoplasm; mutations linked to ASD and intellectual disabilities, more pronounced in males). The synaptic diagram illustrates the overall structure with labeled components, and molecule annotations place symbols representing each molecule at their respective localizations within the synapse, using arrows or lines to indicate their functional roles and the impact of mutations. Additional notes include color coding for different molecules to distinguish their roles and localizations and a legend explaining the symbols, colors, and impact of mutations. This figure underscores the importance of synaptic proteins and pathways in maintaining proper signaling and plasticity, with genetic mutations leading to impaired synaptic function central to ASD pathology.