Genetics

Autism-Risk Gene Rewires the Brain in a Way That Disrupts Learning and Language Acquisition

Source: 
Medical News Today
Date Published: 
November 3, 2010
Abstract: 

Researchers at UCLA have discovered how an autism-risk gene rewires the brain, which could pave the way for treatments aimed at rebalancing brain circuits during early development. Dr. Geschwind and team examined the variations in brain function and connectivity resulting from two forms of the CNTNAP2 gene - one form of the gene increases the risk of autism. The researchers suspected that CNTNAP2 might have an important impact on brain activity. They used fMRI (functional magnetic resonance imaging) to scan 32 children's brains while they were performing tasks related to learning. Only 16 of them had autism.

The imaging results confirmed their suspicions. All the children with the autism-risk gene showed a disjointed brain, regardless of their diagnosis. Their frontal lobe was over-connected to itself, while connection to the rest of the brain was poor, especially with the back of the brain. There was also a difference between how the left and right sides of the brain connected with each other, depending on which CNTNAP2 version the child carried.

The authors believe their findings could help identify autism risk earlier, and eventually lead to interventions that could enhance connections between the frontal lobe and the left side of the brain.

Link Between Genetic Defect And Brain Changes In Schizophrenia Demonstrated

Source: 
Science Daily
Date Published: 
October 17, 2009
Abstract: 

Researchers at the University of North Carolina at Chapel Hill School of Medicine have found that the 22q11 gene deletion -- a mutation that confers the highest known genetic risk for schizophrenia -- is associated with changes in the development of the brain that ultimately affect how its circuit elements are assembled.

The researchers would now like to figure out how these alterations in the circuitry of the brain affect the behavior of the mouse. They also hope that understanding the "mis-wiring" of the brain in a genetic animal model of schizophrenia would help them understand the causes of the disease in the general population

Utah Researchers Discover Another Genetic Link to Autism

Source: 
Salt Lake Tribune
Date Published: 
October 8, 2009
Abstract: 

An international consortium of researchers, including three from the University of Utah, has discovered yet another genetic link to autism. Studying the genes of more than 1,000 families -- including 150 from Utah -- who have more than one person with the disorder, the researchers found a region on chromosome 5 that is strongly associated with autism.

Genome Wide Study of Autism Published in Nature

Source: 
EurekAlert
Date Published: 
October 7, 2009
Abstract: 

In one of the first studies of its kind, an international team of researchers has uncovered a single-letter change in the genetic code that is associated with autism. The finding, published in the October 8 issue of the journal Nature, implicates a neuronal gene not previously tied to the disorder and more broadly, underscores a role for common DNA variation. In addition, the new research highlights two other regions of the genome, which are likely to contain rare genetic differences that may also influence autism risk.

Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

Source: 
PLOS Genetics, Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, et al.
Date Published: 
June 2009
Year Published: 
2009

The study identified 27 different genetic regions where rare copy number variations - missing or extra copies of DNA segments - were found in the genes of children with autism spectrum disorders, but not in the healthy controls. The researchers, including geneticists from the University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia (CHOP) compared genetic samples of 3,832 individuals from 912 families with multiple autistic children against genetic samples of 1,070 disease-free children. Besides the identification of 27 regions harboring rare variants in children with ASDs, the study also uncovered two novel genes where variations were found, BZRAP1 and MDGA2 - thought to be important in synaptic function and neurological development, respectively. Interestingly, key variants on these genes were passed down in some, but not all, of the affected individuals in families.

High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene

Source: 
Molecular Psychiatry, Strom, Stone, Bosch, Merriman, Cantor, Geschwind, and Nelson
Date Published: 
May 2009
Year Published: 
2009

(From a UCLA press release) UCLA scientists have discovered a variant of a gene called CACNA1G that may increase a child's risk of developing autism, particularly in boys. "We found that a common form of the gene occurs more frequently in the DNA of families that have two or more sons affected by autism, but no affected daughters," explained Dr. Stanley Nelson, professor of human genetics at the David Geffen School of Medicine at UCLA. The researchers traced the genetic markers to CACNA1G, which helps move calcium between the cells. They discovered that the gene has a common variant that appears in the DNA of nearly 40 percent of the population. "This alternate form of CACNA1G consistently increased the correlation to autism spectrum disorder, suggesting that inheriting the gene may heighten a child's risk of developing autism," observed Nelson. How the gene contributes to higher autism risk remains unclear, but Nelson emphasized that it cannot be considered a risk factor on its own. "This variant is a single piece of the puzzle," he said. "We need a larger sample size to identify all of the genes involved in autism and to solve the whole puzzle of this disease." The UCLA team's next step will be to sequence the gene in people who possess the altered variant in order to identify the exact change that increases autism risk. These subtle variations offer potential markers for the real mutation causing greater susceptibility to the disease.

Newly Found Genetic Variation Linked to Autism

Source: 
Nature
Date Published: 
April 2009
Year Published: 
2009

A newly identified genetic variant could account for up to 15 percent of autism cases, say researchers who studied genes that are important in connecting brain cells.  Researchers say the variant is carried by about 65 per cent of people with autism.
 

Recurrent 16p11.2 Microdeletions in Autism

Source: 
Human Molecular Genetics, Kumar, KaraMohamed, et al
Date Published: 
2008
Year Published: 
2008

Autism is a childhood neurodevelopmental disorder with a strong genetic component, yet the identification of autism susceptibility loci remains elusive. We investigated 180 autism probands and 372 control subjects by array comparative genomic hybridization (aCGH) using a 19K whole-genome tiling path bacterial artificial chromosome microarray to identify submicroscopic chromosomal rearrangements specific to autism. We discovered a recurrent 16p11.2 microdeletion in two probands with autism and none in controls. The deletion spans approximately 500-kb and is flanked by approximately 147-kb segmental duplications (SDs) that are >99% identical, a common characteristic of genomic disorders. We assessed the frequency of this new autism genomic disorder by screening an additional 532 probands and 465 controls by quantitative PCR and identified two more patients but no controls with the microdeletion, indicating a combined frequency of 0.6% (4/712 autism versus 0/837 controls; Fisher exact test P = 0.044). We confirmed all 16p11.2 deletions using fluorescence in situ hybridization, microsatellite analyses and aCGH, and mapped the approximate deletion breakpoints to the edges of the flanking SDs using a custom-designed high-density oligonucleotide microarray. Bioinformatic analysis localized 12 of the 25 genes within the microdeletion to nodes in one interaction network. We performed phenotype analyses and found no striking features that distinguish patients with the 16p11.2 microdeletion as a distinct autism subtype. Our work reports the first frequency, breakpoint, bioinformatic and phenotypic analyses of a de novo 16p11.2 microdeletion that represents one of the most common recurrent genomic disorders associated with autism to date.

Stereotypes and Hyperactivity in Rhesus Monkeys Exposed to IgG from Mothers of Children with Autism

Source: 
Brain Behavior Immunology, Martin, Ashwood, Braunschweig, Cabanlit, Van de Water, Amaral
Date Published: 
2008

One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533-537]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics.

Identifying autism Loci and Genes by Tracing Recent Shared Ancestry

Source: 
Science, Morrow, Yoo, et al
Date Published: 
2008

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.