Disrupted Genetic Systems Discovered in Autistic Brain

Autism, the severe state resulting from multiple neurodevelopmental disorders named autism spectrum disorders (ASDs), is known to have a strong genetic basis. However, efforts to identify the responsible genes have so far had mixed results due to the influence of many different genes as well as that different genes are involved in different autistic individuals. Scientists at the Hebrew University of Jerusalem (HUJ; Jerusalem, Israel) chose to examine groups of genes to identify and better understand multiple pathways involved in ASDs.

The study, published in the journal PLoS Genetics in March 2012, showed that the different genes involved in autism tend to be involved in specific brain processes. This can explain similarities in the behavioral symptoms of different autistics as well as the large spectrum of behaviors observed in different autistic individuals.

The main goal of the project, conducted by Dr. Sagiv Shifman and his doctoral student Eyal Ben-David at the HUJ Department of Genetics, was to test the contribution of rare genetic mutations as well as genetic variations common in the population, and to see whether these different types of genetic risk factors are related. To that end, the scientists used the Allen Brain Atlas RNA microarray dataset to construct a robust network of the human brain transcriptome based on the expression pattern of genes across different brain areas. This allowed them to discover groups of genes with shared function in the brain. Next, based on genetic data from thousands of families with autistic children, the researchers studied the contribution of different groups of genes to autism.

To their surprise, they found -- when looking at mutations found in autism as well as thousands of common gene variants that are more frequently seen in autistics -- that these mutations and variations are located in specific functional groups, that the genetic risk factors were enriched in specific groups of connected genes. When looking at families with one autistic individual (sporadic cases), and in families where there is more than one affected individual (multiplex cases), the same variants were seen acting in both cases. These groups of genes are highly active in the first year of life, and the strongest enriched of risk factors corresponded to a group of genes involved in processes of learning, memory, and sensory perception.

Shifman and Ben-David believe their work could help pave the way for development of genetic scans for early diagnosis of autism, and, by concentrating on specific gene groups, for the design of effective therapeutic drugs that could alleviate symptoms in autistics with different genetic backgrounds.

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Hebrew University of Jerusalem