From the analysis of exomes to the functional characterization of Autism Spectrum Disorder genes through the aid of new technologies

The progress of Next Generation Sequencing (NGS) technologies and the consequent increasingly widespread use of large-scale whole-exome sequencing (WES) studies, allowed to increase our knowledge on the genetic basis of neurodevelopmental disorders. Particular effort have been directed toward the understanding of autism spectrum disorder (ASD), which is characterized by impaired social interaction and verbal/non-verbal communication, narrow interests, and repetitive behaviors. Among ASD risk factors, the genetic component play an important role, and can be divided into highly penetrant single gene forms with classical Mendelian inheritance, and polygenic component. The identification of ASD-associated genes is just at its beginning, but is already possible to identify some frequently impaired pathways, as the ones mediating brain development and synaptic plasticity. Among the most important findings, the identification of de novo variants associated with ASD highlighted the role of high impact mutations associated with severe phenotypes. The number of novel genes, revealed the need of in depth functional studies which are initially required to corroborate their association with the disorder and later pave the way for treatments. To this extent, in vitro models which can recapitulate the pathology are needed. These methods are becoming highly reproducible, and allow a detailed characterization of the variants found overcoming both practical and ethical issues. Currently, human induced pluripotent stem cells derived neurons, brain organoids and brain-on-chip systems are the most promising technologies to model ASD avoiding animal models.