Genetics

Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study

Source: 
Pediatrics, Ozonoff et al.
Date Published: 
August 2011
Year Published: 
2011

A study published August 15, 2011 in the journal Pediatrics found that infants with an older autistic sibling have a near 19 percent risk that they too will develop the disorder. The study is considered the largest autism study to follow infants for sibling recurrence.

Exome Sequencing in Sporadic Autism Spectrum Disorders Identifies Severe De Novo Mutations

Source: 
Nature Genetics
Date Published: 
June 2011
Year Published: 
2011

 

Another study of spontaneous mutations identified four genes that are likely to play a causal role in the development of autism. Instead of searching more broadly for copy number variants throughout the genome, researchers focused exclusively on the protein-coding region of the genome called the exome. This approach has a greater potential to identify single candidate genes for ASD. The study sequenced the exomes of 20 people with autism and their parents and identified 21 spontaneous or de novomutations. Of the 21 mutations, four were determined to be potentially causative (FOXP1, GRIN2B, SCN1A, and LAMC3). Of note, the four participants carrying these mutations were profoundly affected by autism. Three of the four genes identified in the study had previously been associated with autism, intellectual disability without autism, and epilepsy. The fourth mutation, LAMC3, had never before been linked to autism and represents a potential new avenue of research. Within the study, two of the four children had been hit with a "genetic double-whammy" – both inheriting a harmful gene mutation from his parent and having a de novo mutation. For example, the child with a FOXP1 mutation also inherited a defective copy of CNTNAP2, believed to be involved in language development. This child had severe autism and the most profound language deficits of any participant. Another child with autism and epilepsy had both an inherited deletion putting him at risk for epilepsy and a de novo mutation of a gene associated with epilepsy, SCN1A. These two cases support the 'multi-hit' theory of autism – that a combination of mutations in the same pathway is necessary to cause severe autism or related disorders. The authors note that the study supports the role of de novo mutations as a major genetic contributor to autism and demonstrates the great potential of whole exome sequencing to identify candidate genes.

--IACC 2011 Summary of Advances in ASD Research

 

Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders

Source: 
Neuron
Date Published: 
June 9, 2011
Year Published: 
2011

A study of the genetic causes of autism confirmed that spontaneous or de novo mutations are present in a substantial number of families with only one child on the spectrum. These de novo mutations are not inherited from parents' DNA, arising instead in their egg or sperm or very early in embryonic development. Researchers compared the DNA of children with ASD to that of their unaffected sibling(s) and identified a diverse array of rare genetic abnormalities that may contribute to autism. Recent advances in technology have allowed researchers to identify genetic mutations on a finer scale than was previously possible. Some of thede novo mutations, known as copy number variations (CNVs) because they contain deleted or duplicated sections of DNA, were located in regions known to be associated with ASD, while others implicate new regions. Many of the mutations are thought to affect genes or gene networks involved in brain development. The study confirmed that these non-inherited CNVs are more common in children with ASD compared to their non-affected siblings; however, each unique variant is exceedingly rare, some found in only one family. In addition, researchers found evidence that inherited "ultrarare" genetic duplications may also contribute to autism. Based on the results of the study, the authors note that females have a greater resistance to autism from genetic causes, raising questions about the fate of female carriers. The study findings emphasize the diversity of rare genetic variations that contribute to ASD and suggest the possibility that a treatment for one form of autism may not have value for the majority of cases. The DNA samples analyzed in the study were part of the Simons Simplex Collection, a repository of over 1,000 families in the U.S. and Canada with only one child on the spectrum.

--IACC 2011 Summary of Advances in ASD Research

Protein Interactome Reveals Converging Molecular Pathways

Source: 
Science Translational Medicine
Date Published: 
June 8, 2011
Year Published: 
2011

A recent study sheds light on how a variety of different mutations in genes that seemingly have little in common can each result in the symptoms of autism. To answer this question, researchers developed a molecular map of protein networks or "interactome" to identify how proteins associated with ASD interact with hundreds of other proteins. Researchers used genes known to be associated with syndromic autism as a starting point for building the interactome. Syndromic autism occurs as part of a broader genetic disorder such as fragile X, Angelman syndrome, and Rett syndrome -- understanding protein interactions with syndromic autism may give insight into idiopathic autism, or autism with no known cause. Using 26 genes associated with syndromic autism, researchers hypothesized that the seemingly dissimilar genes might interact with shared partners in common molecular pathways, leading to the symptoms of autism. Indeed, researchers identified a complex network of 539 proteins that interacted with the autism-related proteins, successfully demonstrating that all of the proteins linked to autism are connected by interactions with common partners. The interactome confirmed previously suspected gene relationships and several new pairings, such as the connection between SHANK3 and TSC1, which share 21 common protein partners. Researchers then performed a microarray analysis on 288 individuals with idiopathic autism in a search for genes within the interactome. They identified three novel copy number variations -- chromosomal deletions and duplications -- on genes found in the network, demonstrating that the interactome may help to identify new genes related to ASD and understand complicated genetic variation.

--IACC 2011 Summary of Advances in ASD Research

Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathways

Source: 
Nature
Date Published: 
May 25, 2011
Year Published: 
2011

A study found surprising consistency in molecular changes seen in the brains of people with autism across the spectrum, suggesting a common biological basis that may span multiple subtypes. Researchers analyzed postmortem brain tissue and found atypical patterns of gene expression common to many of the individuals with ASD. These findings may provide clues about how autism changes the brain at the molecular level, and lead to new avenues for developing treatments. In the study researchers focused on gene expression -- the way information from the gene is used in the synthesis of functional gene products, often proteins. These proteins then perform specific tasks in the cell. In brains affected by autism, genes involved in neuron function and communication were expressed at much lower levels than in typically developing individuals, and the expression of genes involved in certain immune functions was abnormally high. The authors note that many of these genes are active during fetal development, supporting the theory that abnormal brain development may start very early in the womb. The findings also provide evidence that molecular changes in neuron function and communication are probably a cause of autism, rather than a result of the disorder. To identify common patterns of gene expression among people with autism, the researchers compared the frontal and temporal lobes of the brain – the frontal lobe is responsible for higher-level thinking including judgment and social response, while the temporal lobe plays a key role in hearing and language and is also involved in sensory integration. They found that more than 500 genes were expressed at different levels in the frontal and temporal lobes of typically developing individuals, as would be expected in separate brain regions with differing functions. However, there was almost no difference in the levels of gene expression between the two regions in the brains of those with ASD. This blurring suggests a failure to differentiate regions in early brain development.

--IACC 2011 Summary of Advances in ASD Research

Brain Enlargement in Autism due to Brain Changes Occurring Before Age 2

Source: 
Science Daily
Date Published: 
May 3, 2011
Abstract: 

In 2005, researchers from the University of North Carolina at Chapel Hill found that 2-year-old children with autism have brains up to 10 percent larger than children of the same age without autism. A follow-up study by UNC researchers has found that the children who had enlarged brains at age 2 continued to have enlarged brains at ages 4 and 5, but the amount of the enlargement was to the same degree found at age 2. This increased brain growth did not continue beyond 2 years of age and the changes detected at age 2 were due to overgrowth prior to that time point. In addition, the study found that the cortical enlargement was associated with increased folding on the surface of the brain (or increased surface area) and not an increase in the thickness of outer layer of the brain (or gray matter).

Multiple Recurrent De Novo CNVs, including Duplications of the 7q11.23 Williams Syndrome Region, are Strongly Associated with Autism

Source: 
Pediatrics
Date Published: 
May 2011
Year Published: 
2011

A recent collaborative study identified six genetic mutations that are strongly associated with autism spectrum disorder, including an area of DNA that likely holds clues to understanding the nature of human social behavior. The researchers estimate that these mutations represent only a few of the hundreds of spontaneously arising variants that are likely to increase autism risk. Using gene chip or microarray technology, the researchers analyzed the genomes of over 1,100 families with a single child on the autism spectrum, and compared the results of affected and unaffected siblings. The DNA samples analyzed in the study were part of the Simons Simplex Collection. The scan revealed a variety of copy number variants (CNVs) -- genetic mutations that can range from micro-deletions and duplications to large sequences of missing or additional DNA. Notably, one of the non-inherited or de novo CNVs was located on a genetic region linked to Williams-Beuren syndrome, a rare disorder that causes people to be extremely social, overly trusting, and highly empathetic.While loss of DNA from the area results in Williams-Beuren syndrome, gain of extra DNA in this area is associated with autism, which is marked by difficulty with social interaction and lack of empathy. This region's connection with both disorders suggests its importance in understanding the nature of the social brain. The study also supports earlier findings of higher rates of de novo CNVs in people with autism compared to their unaffected siblings. Uncovering the genetic basis of autism is critical to understanding the neurobiology underlying the disorder and may aid in developing targeted treatment approaches for different subtypes.

--IACC 2011 Summary of Advances in ASD Research

Researchers Reveal 18 Novel Subtype-Dependent Genetic Variants for Autism Spectrum Disorders and Identify Potential Genetic Markers for Diagnostic Screening

Source: 
Science Daily
Date Published: 
April 28, 2011
Abstract: 

By dividing individuals with autism spectrum disorders (ASD) into four subtypes according to similarity of symptoms and reanalyzing existing genome-wide genetic data on these individuals vs. controls, researchers at the George Washington University School of Medicine and Health Sciences have identified 18 novel and highly significant genetic markers for ASD. In addition, ten of the variants were associated with more than one ASD subtype, providing partial replication of these genetic markers. This study thus identifies candidate genes for ASD and potential subtype-dependent genetic markers for diagnostic screening.

Autism Spectrum Disorder Linked to Genetic Synaptic Behaviors

Source: 
Medical News Today
Date Published: 
April 21, 2011
Abstract: 

It seems that the place where your brain transfers electricity between synapses and how your genes determine how these processes function, are tied to autism in one way or another. There can be genetically driven disturbances in this process that lead to varying levels of autism according to a new study of DNA from approximately 1,000 autistic children and their kin.

Atlas Gives Scientists New View of the Brain

Source: 
The Wall Street Journal
Date Published: 
April 13, 2011
Abstract: 

Scientists funded by Microsoft Corp. co-founder Paul Allen unveiled a $55 million computerized atlas of the human brain Tuesday, offering the first interactive research guide to the anatomy and genes that animate the mind.

A project of the Seattle-based Allen Institute for Brain Science, the online atlas offers researchers a powerful new tool to understand where and how genes are at work in the brain. That could help them find new clues to conditions rooted in the brain, such as Alzheimer's disease, autism and mental-health disorders like depression.