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Understanding the Genetic Basis of Autism Spectrum Disorder


Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction, as well as restricted and repetitive patterns of behavior, interests, or activities. The prevalence of ASD has been steadily increasing in recent years, currently affecting about 1 in 54 children in the United States (Centers for Disease Control and Prevention, 2020). The etiology of ASD is complex and multifactorial, involving both genetic and environmental factors. However, in this paper, we will focus specifically on the genetic basis of ASD.

Genetics of ASD: Common and Rare Variants

Studies investigating the genetic basis of ASD have shown that it is a highly heritable disorder, with estimates of heritability ranging from 50% to 80% (Gaugler et al., 2014; Sandin et al., 2017). One of the key findings is that ASD is a highly heterogeneous disorder, meaning that there are multiple genes involved, each with a small effect size. This is supported by the observation that individuals with ASD often have different combinations of genetic variants, leading to considerable phenotypic heterogeneity within the disorder.

There are two main classes of genetic variants implicated in ASD: common variants and rare variants. Common variants are DNA sequence variations that are present in a significant proportion of the general population. These variants confer a small risk of developing ASD and often have a polygenic effect, meaning that multiple variants collectively contribute to the overall risk. Genome-wide association studies (GWAS) have identified several common variants associated with ASD, such as single nucleotide polymorphisms (SNPs) in genes involved in synaptic function and neuronal development (Gaugler et al., 2014).

Rare variants, on the other hand, are DNA sequence variations that are much less common in the general population. These variants are typically de novo mutations, meaning that they occur spontaneously in the germ cells or early in embryonic development and are not inherited from the parents. Rare variants have been found to have a stronger effect on ASD risk compared to common variants. They often disrupt the function of specific genes or alter their expression levels, leading to abnormal neurodevelopmental processes.

Copy Number Variants

One type of rare variant that has been extensively studied in ASD is copy number variants (CNVs). CNVs are chromosomal abnormalities where certain DNA segments are duplicated or deleted. These genomic rearrangements can range in size from a few kilobases to several megabases and can involve one or multiple genes. CNVs can disrupt gene dosage, leading to abnormal protein expression levels, or affect the structure and function of regulatory elements, resulting in altered gene expression patterns.

Several large-scale studies have shown that individuals with ASD are more likely to have CNVs compared to controls (Sanders et al., 2011; Pinto et al., 2014). These CNVs can be inherited from parents or occur de novo. Furthermore, different CNVs have been associated with specific phenotypic features of ASD. For example, certain CNVs have been linked to intellectual disability or language impairment, whereas others are more strongly associated with repetitive behaviors or sensory abnormalities.

Single Gene Mutations

In addition to CNVs, single gene mutations have also been implicated in ASD. These mutations can be inherited from a parent with a milder form of ASD or occur de novo. Several different types of single gene mutations have been identified, including point mutations, insertions, deletions, and chromosomal rearrangements.

A particularly important class of single gene mutations in ASD is mutations in genes encoding proteins involved in synaptic function. The synapse is the site of communication between neurons, and disruption of synaptic signaling has been implicated in the pathogenesis of ASD. For example, mutations in the SHANK3 gene, which encodes a scaffolding protein involved in the formation and function of synapses, have been found in individuals with Phelan-McDermid syndrome, a rare genetic disorder associated with ASD (Betancur, 2011).