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Why are autistic females rare and severe? An approach to autism gene identification.

State/Province Full: 
United States

In autism, males and females are not affected with autism at the same frequency. Males are more often affected comprising about 80% of autism cases and females the remaining 20%. Why this occurs has not fully been studied in the autism field but its implications are powerful. We assume that autism is caused by both genetic and environmental factors; in other words, a ‘multifactorial’ or ‘complex’ disease. Under this model, females have a higher biological threshold for affection with autism and for this reason either contain more mutations or more severe mutations in order to become affected. We are utilizing this unique feature of autism to identify autism genes in families where there are 2 or more affected individuals and all of them are female. Our families are quite rare and should allow us to identify autism genes by examining the protein-coding portions of their genome (called the ‘exome’). The research team has already identified a gene called delta-2-catenin (CTNND2) through this approach by looking at the exomes of 10 unrelated, females with autism. With collaborators, they found additional mutations in this gene in other autism patients. They also examined this gene in another 363 females with autism, to look for additional mutations for comparison with similar male autism and non-autism data. Testing the effects of mutations in this gene involves a model organism, the zebrafish, and so far the research has demonstrated the effects of this gene on early development. Additional work will be done using neuronal cells in culture. The researchers have also focused on two genes, known to be involved in autism, in these families. Mutations in one of these genes, MECP2, cause Rett Syndrome and mutations in the other gene, FMR1, cause Fragile X Syndrome. Both syndromes display autism as part of the disorder and the roles of these genes have not been tested in our families. In 96 affected females, variants in MECP2 were identified and are in the process of sequencing the FMR1 gene. The study will include testing of changes in these genes for functional deficits as well. Lastly, the researchers are screening the genome for additional regions implicated in females with autism by genetic methods that, in preliminary studies of 32 sib-pairs, have identified two regions, one on chromosome 19 and the other on the X chromosome around the FMR1 gene