Genetics first

People with autism can differ markedly from one another. This prompts the question, to what extent can these differences be explained by their genes?

Another way of asking this question is as follows: If one were to study a large number of people with the same genetic event, would they share particular traits, brain characteristics and perhaps have a similar response to behavioral or pharmacological treatments?

The Simons Variation in Individuals Project Simons VIP aims to find out.

Funded by the Simons Foundation Autism Research Initiative (SFARI), the project was launched in September 2010 to study a large number of individuals who carry a deletion or duplication of a region on the 16^th chromosome, 16p11.2. This genetic event has turned out to be one of the more recurrent causes of autism — accounting for about one percent of cases. Interestingly, the genetic event is also associated with schizophrenia and other neuropsychiatric disorders.

In contrast to the existing genetic collections for the study of autism, in which recruitment of participants is based on having a clinical diagnosis of autism, the Simons VIP takes a ‘genetics first’ approach. Individuals (and their family members) are recruited to the project if they have a deletion or duplication of 16p11.2, regardless of their clinical diagnosis or age. To find families with a 16p11.2 deletion or duplication, we created a web portal, Simons VIP Connect, and established close relationships with clinical genetic testing laboratories.

This approach has worked remarkably well: Within one year, Simons VIP has recruited more than 100 individuals with a 16p11.2 deletion or duplication to participate in research (registered families are indicated by state, above), making it a remarkably successful effort for a rare genetic disorder. We are certainly gratified with the extent to which families are motivated to participate in the research.

Not only do we expect the Simons VIP to generate rapid results that could benefit individuals with a 16p11.2 deletion or duplication, but we also think that the approach will be broadly applicable to other conditions, especially neuropsychiatric disorders, and hope to inspire the research community to embark on similar collaborations.

For more details on the project, check out our recent publication in Neuron, which explains why we chose to focus on 16p11.2, lessons learned in the recruitment and retention of participants, the types of information we’re gathering and other issues.

The project has also reached an important milestone: The phenotype information and biospecimens (whole blood DNA and fibroblasts) for the first set of individuals — approximately 50 deletion and 50 duplication carriers — were just released (log-in required). By immediately making this valuable information available to the community, we hope researchers will be able to order samples or comb through phenotype data to test their hypotheses. Future data releases will occur quarterly and will eventually include the full dataset, including brain imaging data.

In the coming months we expect researchers using the biospecimens to make rapid progress on questions that could have major implications for our thinking about treatments for the syndrome. For example, which genes in the 16p11.2 region are particularly important for the phenotype? Exome and/or whole-genome sequencing combined with gene expression studies should be quite informative. And transforming the fibroblasts into stem cells could provide an efficient way to screen a large number of drugs that could be subsequently tested for efficacy in this genetically more homogeneous cohort.

Furthermore, we expect that there will be great synergy between the human research from the Simons VIP and other projects supported by SFARI and other funders. For example, a mouse model in which the homologous genes in the 16p11.2 region have been deleted or duplicated is now available for study. The mice are inbred in such a way that they are virtually genetically identical — so, unlike in humans with a 16p11.2 deletion or duplication, where genetic background varies greatly, the mouse allows one to ask specifically how phenotype varies with the same genetic event.