Copy number variants (CNVs) are the regions of the human genome that represent significant genetic risk factors for autism and other neurodevelopmental disorders. One such CNV located on chromosome 16, called 16p11.2, confers a high risk for developing autism and intellectual disability when deleted, and autism, schizophrenia, bipolar disorder and intellectual disability when duplicated. Even more intriguingly, 16p11.2 deletions are associated with increased head and brain size in the carriers (macrocephaly), whereas 16p11.2 duplications are associated with the decreased head and brain size (microcephaly). However, the exact mechanism by which this CNV influences brain size is unknown.

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.

Many of the social and cognitive behavioral impairments associated with autism spectrum disorders (ASDs) are likely caused by changes in early brain development that alter the formation of neural circuits, and in particular, the neural circuitry of the cerebral cortex. Because early brain development is completed long before the onset of any identifiable behavioral changes, most studies of the developmental origins of autism have focused on animal models of genetic syndromes or rare single-gene mutations that lead to ASD-like behaviors. It is not clear how these different syndromes may be related to one another, or how these distinct genetic changes can each lead to similar behavioral outcomes.

Microglia — the brain’s resident immune cells — have many roles in normal brain development that neuroscience is just beginning to ascertain. It has long been known that microglia rapidly transform from a homeostatic to an ‘activated’ state following injury or disease and are recruited to sites of damage. A recent and increasing body of work now indicates that microglia also perform important roles in the normal development of the nervous system. For example, microglia sculpt neuronal circuits by removing under-utilized synapses. Microglia also appear to regulate synaptic maturation and plasticity and can impact behavior.

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.

One of the most critical challenges in the identification of new medications to treat autism spectrum disorders (ASDs) is our limited understanding of the biological mechanisms underlying these disorders. In recent years, there have been considerable advances in the genetics of ASD, with a resulting rapidly accumulating pool of reliable ASD risk genes. Currently, we need systems that will allow us to progress from gene discovery to the illumination of relevant biological pathways and novel therapeutics.

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.

Although 16p11.2 copy number variants (CNVs) make a significant contribution to the risk of autism spectrum disorder (ASD) and are becoming well described at the clinical level, the biological mechanisms underlying pathogenesis are not yet understood. MAPK3, MVP and KCTD13 — three of the genes in the 16p11.2 chromosomal region — are involved in RAS/MAPK signaling, a ubiquitous signaling pathway important for proliferation, differentiation and apoptosis across development. Interestingly, there is overlap between clinical and neuroimaging presentation in individuals with a 16p11.2 CNV and those with classic RASopathy syndromes, which are caused by dominant mutations activating RAS/MAPK signaling. There is also phenotypic overlap between 16p11.2 syndrome and RASopathy model organisms. Combined, these data suggest that alterations in RAS/MAPK signaling play an important role in the 16p11.2 CNV syndrome phenotype.

Recent advances in sequencing analysis of individuals with autism have revealed a large number of genetic variations that are associated with autism. However, the causal role and mechanisms of these mutations are not known.

Mutations in the autism susceptibility candidate 2 gene (AUTS2) have long been linked with autism spectrum disorder (ASD) and several neurodevelopmental abnormalities. However, the molecular mechanisms by which AUTS2 functions in normal brain development and how it goes awry in ASD has remained elusive.