Understanding how genetic defects that cause autism lead to abnormal neurodevelopment is critical to developing mechanism-based treatments. One particularly important question is whether different genetic defects produce autism traits in completely different ways, or whether alterations in different genes trigger a cascade of cellular changes that overlap and ultimately lead to autism by the same biochemical mechanism. JamesGusella and his colleagues at Massachusetts General Hospital aim to explore this question by using cutting-edge genome modification techniques to compare the effects of different autism-linked genetic traits in cultured human stem cells and neurons.

Illness or infections during early pregnancy are associated with increased incidence of autism. In pregnant mice, exposure to viral or bacterial agents alters fetal brain development, and pups show behavioral changes that are analogous to features seen in autism.

Immune‐related genes and immune responses to environmental stimuli are receiving attention due to their potential involvement in several neurodevelopmental disorders, including autism. Immune‐related genes have been associated with autism and maternal infection has been found to be the most compelling environmental risk factor for the disorder. Additionally, immune molecules have been shown to play many roles throughout brain development, including the initial establishment of synaptic connections, as well as synaptic plasticity.

Anatomic and molecular features observed in the brains of individuals with autism suggest that abnormalities in early embryonic development underlie the development of autism. Mutations in a gene called CHD8 are the most commonly identified mutations associated with autism. How CHD8 influences the disorder remains unknown, but observations that children with autism and CHD8 mutations have abnormally large heads (macrocephaly) support the possibility that CHD8 functions in regulating brain growth during development.

Mutations in hundreds of genes may predispose individuals to autism, but no common feature characterizes these genes, little is known about the functions of many of them and it remains unclear how mutations in these genes promote autism pathogenesis. Multiple autism-associated mutations have been identified in genes encoding neuroligins — cell-adhesion molecules that are essential for the organization of synapses, or the junctions between neurons, and for synapse property specification, during which neuroligins contribute to organizing synapse properties.

Children with the rare genetic disorder Prader-Willi syndrome have a high rate of autism spectrum disorders, with features including restricted and repetitive, compulsive and self-injurious behaviors. They also typically present with neonatal feeding difficulties, developmental delay, endocrine dysfunction and obesity. Prader-Willi syndrome is usually caused by the inactivation of a group of genes on chromosome 15. Spontaneous, or de novo, inactivating mutations in one of those genes, MAGEL2, have been identified in four children who have autism and other features of Prader-Willi syndrome. Loss of MAGEL2 function is likely to be responsible for autism predisposition in children with Prader-Willi syndrome.

Fragile X syndrome is the most common cause of inherited autism and results from loss of function of a single gene: FMR1. Most research into the pathogenesis of fragile X syndrome has focused on the role of FMRP, the protein encoded by FMR1, in neuronal health and function. However, recent work in cultured cells suggests that loss of FMR1 in astrocytes, star-shaped brain cells that help support neurons at their junctions (synapses), can contribute to the abnormal dendritic morphology and synapse development seen in fragile X. In addition, over the past decade, increasing evidence has demonstrated that glia — support cells in the brain — such as astrocytes play important roles in regulating neuronal synaptic development, plasticity and communication. These are activities that, if altered, may contribute to fragile X syndrome and autism.

Efforts to find genetic causes of autism have identified hundreds of rare mutations in individuals with the disorder, and this list is anticipated to grow steadily in the next few years. A pressing question is which of the mutations are responsible for conferring a disease risk. A small number of the mutations appear likely to disrupt the function of the affected genes, and individuals with autism have a higher burden of these mutations, suggesting a causative link to the disorder. However, the majority of mutations change only a single amino acid of the protein product or are ‘silent’ according to the genetic code. These mutations occur at similar frequencies in individuals with autism and unaffected siblings, implying that most of them are probably benign.

There is growing support for the idea that both genetic and environmental risk factors contribute to autism. One environmental risk is maternal infection, as validated by large epidemiological studies showing links between infection during pregnancy and autism in the child. Similar associations were found with elevated immune responses in maternal serum or amniotic fluid. Also consistent with an immune pathophysiology are findings of activated microglia — immune cells within the brain — in people with autism, as well as dysregulation of immune-related genes in the brain, cerebral spinal fluid and periphery.

A major goal of autism research is to understand the relationships among genetic etiology, altered developmental trajectory, aberrant neural circuits and behavioral symptoms characteristic of this disorder. Understanding how the functional activity of neural circuits is altered with cell-type resolution is likely to lead to more effective and targeted therapies. Among the neural circuits implicated in autism are ones involving the striatum, a structure buried deep within the brain that contributes to the evaluation and selection of behavior. Additionally, one gene associated with autism is SHANK3, which is important for the connections between neurons, including those within the striatum.