The cause of autism is thought to involve a combination of both genetic and environmental factors. One approach to understanding the genetic contribution to autism has been to use large samples to investigate multiple genes associated with the disorder. This approach, known as a genome-wide association study, has resulted in several interesting genetic ‘hits,’ — the discovery of genes that appear to be associated with autism.

The proposed research takes advantage of the resources available at the University of Oxford in the U.K. to validate a new noninvasive magnetic resonance imaging (MRI) biomarker of autism using postmortem imaging. This has enormous potential for subsequent development as a tool for early detection, diagnosis, monitoring and assessment of individuals with autism. Steven Chance and his colleagues seek to better understand the cause of autism by investigating the neuroanatomical basis of the condition. Accurate diagnosis in life is difficult because the detailed changes in the cerebral cortex cannot be seen in brain imaging of living people.

Autism is diagnosed in boys four times more frequently than in girls. Recent genetic research suggests that this difference is due to the fact that girls are protected from autism risk factors rather than boys being subjected to additional risk factors. The nature of this ‘female protective effect’ remains unknown.

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.

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.

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.

David Heeger, André Fenton and Robert Froemke of New York University, in collaboration with Marlene Behrmann of Carnegie Mellon University in Pittsburgh, are investigating the possibility that generic, brain-wide circuit malfunctions lie at the root of autism spectrum disorders. They posit that if we understood these malfunctions better, both diagnosis and intervention might be optimized.

Genetic and neuroimaging studies provide strong evidence that the gene CNTNAP2 (also known as CASPR2) is a critical risk factor for autism spectrum disorders. CNTNAP2 encodes a protein on the surface of neurons that is involved in interactions between neurons and glial cells in axons with a myelin sheath.

Duplication of a small region on chromosome 22, resulting in 22q11.2 duplication syndrome, has been associated with autism, but to date there has not been a large-scale cohort study of this association.

Fragile X syndrome, which is closely associated with autism, is a single-gene disorder caused by the lack of a protein that suppresses protein synthesis. A fragile X mouse model has been shown to exhibit increased protein synthesis in the brain.