Largest study of its kind sheds new light on the complex genetics of autism.

Genetic variation accounts for a major proportion of the liability to autism spectrum disorder (ASD). Now, a study from led by researchers at UCLA shows that in families with multiple children on the autism spectrum, the pattern of genetic factors is different from families with just one affected child. The team state that their findings provide a better picture of how genetic variation contributes to autism disorders, and could point to a new target for future therapies. The opensource study is published in the American Journal of Human Genetics.

Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. The current study identifies more than a dozen promising new candidates for genes linked to the risk of autism spectrum disorders, highlighting the complexity of genetic factors in the disorders.

The current study analyzes 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. Results show that among children with an autism spectrum disorder who have siblings with autism disorders, inherited copy-number variations had a stronger influence than non-inherited CNVs. Data findings show that when an affected child has an inherited genetic variation that is known to be an autism spectrum disorder risk factor, it is seldom the case that all his affected siblings have that same variation.

Results show that of the potential new autism spectrum disorder risk genes identified, one of them, NR4A2, is linked to some rare cases of autism disorder with delays in language ability. The lab state that the language connection fits with a their earlier study which found NR4A2 is expressed in the human brain in areas involved in language development. They go on to add that, to their knowledge, this is the largest study of its kind in families with multiple autism spectrum disorder children.

The team surmise that their findings show families with two or more ASD children and simplex families show distinct patterns of genetic risk; the rate of large, rare de novo CNVs is lower in multiplex families, and there is an increased burden of large, rare inherited CNVs. For the future, the researchers emphasize that the complex genetic underpinnings of autism spectrum disorder in multiplex families needs to be better characterized with larger studies.

Source: University of California, San Francisco