A Neurodevelopmental Perspective for Autism-Associated Gene Function.

Abstract

Large-scale genetic sequencing studies have identified a wealth of genes in which mutations are associated with autism spectrum disorder (ASD). Understanding the biological function of these genes sheds light onto the neurodevelopmental basis of ASD. To this end, we defined functional categories representing brain development – (1) Cell Division and Survival, (2) Cell Migration and Differentiation, (3) Neuronal Morphological Elaboration, (4) Development and Regulation of Cellular Excitability, and (5) Synapse Formation and Function – and place 100 high confidence ASD-associated genes yielding at least 50 published PubMed articles into these categories based on keyword searches. We compare the categorization of ASD genes to genes associated with developmental delay (DD) and systematically review the published literature on the function of these genes. We find evidence that ASD-associated genes have important functions that span the neurodevelopmental continuum. Further, examining the temporal expression pattern of these genes using the BrainSpan Atlas of the Developing Human Brain supports their function across development. Thus, our analyses and review of literature on ASD gene function support a model whereby differences in brain development – from very early stages of macroarchitectural patterning to late stages of activity-dependent sculpting of synaptic connectivity – may lead to ASD. It will be important to keep investigating potential points of mechanistic convergence which could explain a common pathophysiological basis of ASD behind this disparate array of genes.