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.

Autism is a complex disorder of many biological causes that results in characteristic behavioral symptoms. However, recent advances in the genetics of autism point to a constellation of genetic causes that converge on a subset of intracellular signaling pathways, including RAS-MAPK and PI3K/AKT, that may all contribute to autism, even if mutations in these pathways on their own may not be sufficient to cause the disorder.

A large number of susceptibility genes for autism and schizophrenia have been identified, although the function of many of these risk factors in regulating neuronal development is not well understood. Copy number variations (CNVs), structural rearrangements of the genome in which entire chromosomal regions may be either deleted or duplicated, produce variability in the expression level of affected genes.

A rapidly increasing number of genes are implicated in autism. While null alleles —those with mutations that eliminate gene function — tightly linked to autism are extremely helpful in identifying causative genes, one can’t predict the in vivo effects of other types of alleles (such as those with mutations that change the function of the gene).

Nerve cells communicate with each other via excitatory and inhibitory signals. Growing evidence supports the hypothesis that a neuronal excitation/inhibition imbalance resulting in increased excitation in certain nerve cells in the brain is sufficient to elicit autism-like symptoms. Uwe Rudolph and his colleagues at McLean Hospital and Harvard Medical School focus on receptors for the major inhibitory neurotransmitter in the central nervous system, gamma-aminobutyric acid (GABA).

Studies have identified a large number of genes that contribute to autism, and many affect communication between neurons, known as synaptic transmission. However, we do not understand the mechanisms responsible for the genes’ effects on synaptic transmission or how these effects give rise to abnormal behavior. To elucidate these mechanisms, Robert Edwards and his group at the University of California, San Francisco plan to study a protein of known biochemical function that has been implicated in autism and determine its role in synaptic physiology and behavior.