Autism spectrum disorders (ASDs) are highly heritable but have a complex genetic architecture. There is significant locus heterogeneity for ASD and distinct subgroups, including syndromic and nonsyndromic cases. Whole-exome sequencing (WES) has emerged as an important tool in understanding ASD. WES studies have revealed an increased burden of de novo variants in people with ASD compared with unaffected individuals. However, due to variants in thousands of different genes — many of which are poorly characterized — interpreting the disease relevance of individual variants has been difficult.

Human genetic studies have identified hundreds of genes with variants associated with autism. However, the significance of most of these variants is unknown. At least half of the genes are present in all animals and thus can be studied in genetic model organisms that allow rapid, rigorous genetic analysis.

A major challenge that researchers face in attempting to understand the molecular mechanisms underlying autism spectrum disorders (ASD) is that thousands of gene mutations have been linked to the disease. Adding to this complexity is that, for many of the implicated genes, different variants have been found in distinct individuals with ASD. Assessing this complexity has proven difficult using traditional low-throughput methods, resulting in a wealth of ASD gene variants without functional phenotyping. To address this issue, Kurt Haas and his colleagues at the University of British Columbia will use a combined approach taking advantage of both high- and low-throughput assays to identify ASD gene variants with strong phenotypes, and to provide information on physiological roles for many poorly characterized ASD-associated genes.

The hallmarks of autism spectrum disorder (ASD) are deficits in social communication and interaction, but a coherent underlying etiological mechanism for ASD is yet unknown. New sequencing technologies have revealed thousands of unique mutations in individuals with ASD, but not in their unaffected parents. Dubbed de novo mutations, the majority alter only a single amino acid in the protein the gene encodes. Some of these mutations impact protein function; many others do not. Currently there are no good methods to study the functional relevance of this large set of de novo missense mutations, and for this reason they have yet to reveal much about the underlying etiology of ASD.

The brain is an exquisitely complex network, and the precise development of neuronal connections into the appropriate circuitry is crucial in determining brain function. Malformation of these connections during prenatal and early postnatal development can lead to neurological deficits, including intellectual disability, autism and schizophrenia. While inappropriate circuit formation has been suggested to be a critical deficit in autism, precisely whether and how various autism-related gene mutations lead to such defects remains unclear.