Genetics of autism spectrum disorders

Abstract

Characterized by a combination of abnormalities in language, social cognition and mental flexibility, autism is not a single disorder but a neurodevelopmental syndrome commonly referred to as autism spectrum disorder (ASD). Several dozen ASD susceptibility genes have been identified in the past decade, collectively accounting for 10-20% of ASD cases. These findings, although demonstrating that ASD is etiologically heterogeneous, provide important clues about its pathophysiology. Diverse genetic and genomic approaches provide evidence converging on disruption of key biological pathways, many of which are also implicated in other allied neurodevelopmental disorders. Knowing the genes involved in ASD provides us with a crucial tool to probe both the specificity of ASD and the shared neurobiological and cognitive features across what are considered clinically distinct disorders, with the goal of linking gene to brain circuits to cognitive function.

Figure 1. Common and Rare Variants

We usually think of common and rare variants representing two extremes on the allelic spectrum. Single nucleotide polymorphisms (SNPs) with modest effects sizes (gray oval) have been identified through association studies. Rare events that segregate with disease have also been identified through re-sequencing efforts and CNV studies. Less attention has been directed at events not at either extreme, but also likely to modulate risk. Larger studies will permit consideration of lower frequency intermediate effect alleles (ovals with dotted lines). Current data do not support the presence of common alleles of large effect for affection status (bottom right corner). But, it is possible that such associations may be observed in the future when appropriate quantitative endophenotypes are used. Adapted with permission from [87].

Figure 2. Convergence of genes on neural systems

Here we illustrate a working model for how major affect autism risk alleles, such as those shown at the left, might act to lead to autism. Because these Mendelian conditions are not specific for ASD and typically lead to ID, either environmental or genetic factors must modify their affects on brain development. The biological pathways through which such genes are known to act (shown in the middle box) are myriad. Although the gene expression and proteomic studies identify molecular and biological pathways that provide a source of convergence, the ultimate convergence must lie in neural systems. At a neural systems level, the convergent process will likely be disconnection of the circuits outlined in the far right box, since these systems are thought to underlie the core deficits of ASD. Adapted with permission from [88].