Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation.
Berkel S, Marshall CR, Weiss B, Howe J, Roeth R, Moog U, Endris V, Roberts W, Szatmari P, Pinto D, Bonin M, Riess A, Engels H, Sprengel R, Scherer SW, Rappold GA. Nat Genet. 2010 Jun;42(6):489-91.

Researchers discovered that mutations to SHANK2, a gene believed to play a role in maintaining the inner structure of the synapse, were present in people with ASD, as well as those with intellectual impairment. Without proper structure at the postsynapse – the receiving end of cellular communication – neural impulses cannot be properly sent. A gene in the same family, SHANK3, has previously been linked with ASD. The researchers sequenced SHANK2 in 396 people with ASD, 184 people with mental retardation, and 659 typically developing individuals. They found instances of copy number variations (CNVs), submicroscopic deletions and insertions of DNA, in two people with ASD. The CNVs were de novo, meaning they had arisen spontaneously and were not inherited from a parent. Seven inherited changes in SHANK2 were also found in people with ASD or intellectual impairment – the fact that their parents were carriers of these variants but did not show signs of atypical development suggests that a certain threshold of mutation must be reached to result in a disorder. A single nonsense de novo mutation (a type of mutation that usually results in a nonfunctional protein product) was also found. Overall, the study is notable because it identified additional examples of overlapping genes associated with both ASD (with and without cognitive impairment) and intellectual disability.

Blood mercury concentrations in CHARGE Study children with and without autism.
Hertz-Picciotto I, Green PG, Delwiche L, Hansen R, Walker C, Pessah IN. Environ Health Perspect. 2010 Jan;118(1):161-6.

A study found that children with ASD have similar levels of mercury in their blood as typically developing children, after controlling for other factors that impact mercury levels. The greatest predictor of blood mercury levels was the amount of fish in the child's diet. Almost all fish contain a trace amount of mercury and some larger predatory fish like swordfish and tuna may contain high levels. (The study adjusted for the fact that children with ASD generally ate less fish than their peers.) Researchers measured mercury levels in three groups of children ranging from 2 to 5 years of age: those with ASD, those with another developmental disorder, and those developing typically. The children were all enrolled in a study investigating factors that may contribute to ASD called the Childhood Autism Risk from Genetics and Environment (CHARGE) study. The children's mothers were interviewed to determine ways in which the child could have been exposed to mercury, including fish consumption, personal care products like nasal sprays that may contain mercury, and silver-colored mercury-based amalgam fillings. Vaccine information was collected from the children's medical records and was not found to have any association with blood mercury levels. Overall, children with ASD had similar blood mercury levels to that of the general population. Children with developmental disabilities other than ASD consistently showed lower levels than the other groups. Apart from fish consumption, tooth-grinding and gum-chewing with mercury-based amalgam fillings was also linked to higher mercury levels. The authors caution that the study did not investigate whether mercury exposure in either the prenatal or early postnatal period plays a role in causing ASD because blood measures were taken from children who had already been diagnosed with the disorder.

Functional impact of global rare copy number variation in autism spectrum disorder.
Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, et al. Nature. 2010 Jul 15;466(7304):368-72.

Researchers studying the genetics of ASD have identified a set of rare genetic variations that may confer risk for the disorder. While ASD is known to have a strong genetic component, (studies of identical twins have shown a 90 percent likelihood that both siblings are affected, compared to a 10 percent rate for non-identical twins), the exact genetic causes of ASD are still under investigation. All known genetic causes of ASD account for only 5 to 15 percent of cases, leaving the majority unexplained. Previous studies have implicated mutations in several genes that relate to proper functioning at the synapse, the junction between neurons where cell signaling takes place, and other genes involved in neural development. In the study, researchers conducted in-depth genetic analyses to compare the genomes of 996 people with ASD to 1,287 typically developing individuals. They found that people with ASD had 19 percent more rare copy number variations (CNVs) – abnormalities in the number of copies of one or more sections of DNA. When taken individually, each CNV was found in less than 1 percent of people with ASD. These CNVs were most likely to occur in genes that had previously been linked to ASD and/or intellectual disability. By further investigating the genes where the majority of the CNVs occurred in people with ASD, the researchers identified four genes that had never before been associated with ASD. These genes, as well as others implicated in previous studies, seem to be involved in similar biochemical pathways in the brain – those involved in cognitive development or cell signaling and communication. The authors are hopeful that better understanding of pathways linked to ASD will eventually lead to targets for pharmaceutical treatments.

Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2.
Scott-Van Zeeland AA, Abrahams BS, Alvarez-Retuerto AI, Sonnenblick LI, Rudie JD, Ghahremani D, Mumford JA, Poldrack RA, Dapretto M, Geschwind DH, Bookheimer SY. Sci Transl Med. 2010 Nov 3;2(56)56ra80.

Researchers have found that certain forms of the autism risk gene CNTNAP2 are linked to wiring issues in the brain that could explain problems with language acquisition and learning associated with the disorder. Using functional imaging scans to capture brain activity during a learning task, the researchers discovered that children with the risk gene had too many connections within the frontal lobe, the portion of the brain involved in learning and other higher-level mental functions, and too few connections between the frontal lobe and other parts of the brain. Long-range connections to the back of the brain were particularly weakened. Investigators looked at two variations of CNTNAP2 – one which conferred risk for ASD and another common variant of the gene which did not. In addition to connectivity issues between the front and the back of the brain, children with the risk gene also showed atypical connection patterns between the right and left hemispheres. Those without the risk gene generally had communication pathways in the frontal lobe that connected more strongly to the left side of the brain. Alternatively, children with the risk gene showed equal distribution between right and left hemispheres, suggesting that the variant rearranges the brain's circuitry and could interfere with language skills. Children with the risk gene showed these abnormal activation patterns regardless of whether they were diagnosed with ASD. The findings suggest that CNTNAP2 plays an important role in wiring neurons in the frontal lobe and that mutations to the gene could disturb this process. This theory builds on earlier findings showing that CNTNAP2 is most active during development of the frontal lobe. In the future, understanding how genes can affect brain function and behavior could improve ASD diagnosis and potentially lead to interventions that aim to strengthen necessary connections within the brain. The finding may also apply to other disorders associated with CNTNAP2 variants, including speech and language impairments, attention deficit hyperactivity disorder (ADHD), Tourette syndrome, and schizophrenia.