Major progress has been made in understanding the genetic basis of autism spectrum disorders. Rare or de novo mutations throughout the genome are now known to be important factors. These include copy number variations (CNVs) and point mutations that disrupt the protein-coding sequences of genes.
Several loci, or stretches of chromosomal DNA, have been shown to be defective in individuals with autism. These loci each contain more than one gene, so the next step is to identify the specific genes that are disrupted.
Among the many interesting findings emerging from studies of de novo mutations in the Simons Simplex Collection has been the extreme degree of genetic heterogeneity that underlies autism spectrum disorders. In addition, one mutation may be associated with a wide range of distinct psychiatric and neurodevelopmental outcomes. Many of the genes that contribute to autism also demonstrate considerable pleiotropy, playing diverse biological roles at different points in brain development. These factors present important obstacles to translating the rapidly growing understanding of autism genomics into a deeper understanding of autism pathophysiology.
The diverse genetic variations associated with autism are thought to affect molecular networks, which have yet to be identified. Dennis Vitkup and his colleagues at Columbia University in New York have developed an algorithm called NETBAG to search for clusters of genes perturbed by autism-associated genetic variations.
People with autism spectrum disorders have more mutations in their DNA than do their unaffected siblings. The emerging picture is that the genetics of autism is very complex: Dozens or perhaps even hundreds of different mutations may contribute to the disease in each person with autism.
Imprinted genes are an unusual class of genes that preferentially express either the maternally or paternally inherited gene copy in the child. A role for imprinted genes in autism-related behaviors has been established through studies of Angelman syndrome, a disorder characterized by features of autism and resulting from loss of the maternally expressed gene UBE3A[ref]Van Buggenhout G. and J.P. Fryns Eur. J. Hum. Genet. 17, 1367-1373 (2009) PubMed[/ref]. This gene is located in an imprinted gene cluster in the 15q11-13 chromosomal region.
Autism spectrum disorders represent a challenge for geneticists because of the heterogeneity of causes. Still, in a subset of people with autism, certain deleterious gene mutations have been identified, and most are involved in the formation of synapses — the points of contact between neurons. At first, these mutations alone were thought to be sufficient to cause autism, but studies suggest that the inheritance of ‘modifier genes,’ which alter the expression of other genes, might contribute to the wide behavioral variability observed in individuals with autism.
Autism has strong genetic origins, but neither common nor rare gene variants explain the majority of cases. This suggests that less-studied portions of the genome may contribute significantly to the disorder.
Chromosomal microarray (CMA) analysis to detect copy number variations (CNVs) —duplication or deletion of chromosomal regions — is the recommended first-tier diagnostic screen for autism, and studies of structural variation (SV) to date have largely focused on CNV detection and interpretation. Copy-neutral SVs, or balanced chromosomal abnormalities (BCAs), have not been systematically surveyed in autism, suggesting that these rearrangements could represent a potent class of loss-of-function mutations that have not yet been characterized in autism.