Dosage-sensitive genes in autism spectrum disorders: From neurobiology to therapy.

Abstract Autism spectrum disorders (ASDs) are a group of heterogenous neurodevelopmental disorders affecting 1 in 59 children. Syndromic ASDs are commonly associated with chromosomal rearrangements or dosage imbalance involving a single gene. Many of these genes are dosage-sensitive and regulate transcription, protein homeostasis, and synaptic function in the brain. Despite vastly different molecular perturbations, syndromic ASDs share core symptoms including social dysfunction and repetitive behavior. However, each ASD subtype has a unique pathogenic mechanism and combination of comorbidities that require individual attention. We have learned a great deal about how these dosage-sensitive genes control brain development and behaviors from genetically-engineered mice. Here we describe the clinical features of eight monogenic neurodevelopmental disorders caused by dosage imbalance of four genes, as well as recent advances in using genetic mouse models to understand their pathogenic mechanisms and develop intervention strategies. We propose that applying newly developed quantitative molecular and neuroscience technologies will advance our understanding of the unique neurobiology of each disorder and enable the development of personalized therapy.