Abstract
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition with no current treatment available. Although advances in genetics and genomics have identified hundreds of genes associated with ASD, very little is known about the pathophysiology of ASD and the functional contribution of specific genes to ASD phenotypes. Improved understanding of the biological function of ASD-associated genes and how this heterogeneous group of genetic variants leads to the disease is needed in order to develop therapeutic strategies. Here, we review the current state of ASD research related to gene discovery and examples of emerging molecular mechanisms (protein translation and alternative splicing). In addition, we discuss how patient-derived three-dimensional brain organoids might provide an opportunity to model specific genetic variants in order to define molecular and cellular defects that could be amenable for developing and screening personalized therapies related to ASD.
Highlights
Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous neurodevelopmental condition that manifests as deficits in reciprocal social interaction, repetitive behavior patterns, and restricted interests[1]
Environmental factors likely play some role in the etiology of ASD3, family and twin studies show that genetics contribute to the majority of the risk associated with ASD4–9
Genome-wide studies using genotyping microarrays, whole exome sequencing (WES), and whole genome sequencing have identified a rapidly growing number of genes linked to ASD10–21, providing a window into the molecular underpinnings of the disorder
Summary
Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous neurodevelopmental condition that manifests as deficits in reciprocal social interaction, repetitive behavior patterns, and restricted interests[1]. This complexity is underscored by the potential for certain combinations of common genetic variants contributing to ASD by increasing an individual’s susceptibility to pathogenic effects of rare inherited, de novo, or somatic mutations. Patient-specific disease models The high degree of genetic heterogeneity in ASD requires personalized approaches to understand the underlying individual pathogenic mechanisms and develop efficient treatments. Future strategies to develop therapies for ASD should focus on neurons and include all cell types in the brain These data support the promise of using iPSC models from individuals with genetically complex etiologies to narrow the therapeutic search window to common pathogenic mechanisms. Improvements to brain organoid models that include many cell types such as glia and endothelial cells from non-syndromic ASD patients should further facilitate the identification of patient-specific cellular deficits
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