Autism is a highly variable condition that affects 1% of the population. The collective term, Autism Spectrum Disorders (ASD), encompasses individuals with core features – impairments in social-communication functioning, repetitive behaviours and restricted interests – that are disabling to a degree from mild to severe. ASD affects >100,000 Canadians with >$1 billion/year spent on support services.The past 10 years of ASD research have completely redefined our understanding of this once enigmatic disorder, and over 100 ASD susceptibility genes and copy number variations (CNVs) of variable (and largely undetermined) clinical effect are known, and hundreds of others estimated to exist. Many of these discoveries were by our group (e.g. Nature Genetics 2007; Nature 2010; Nature Genetics 2014). Our latest whole genome sequencing (WGS) results identify clinically relevant variants in ~40% of subjects that explain the manifestation of ASD, or a related medical complication (AJHG 2013, Nature Medicine 2015).My group, with 12 Program Experts, will conduct three congruent programs of research having the overarching theme of identifying and characterizing novel ASD risk variants, and determining how to best relay WGS information effectively to clinicians and families. We believe that personalized medicine will come into its own for ASD, as we recognize the individual constellations of risk factors, varied prognoses, and potential treatment opportunities to be applied differentially to each person affected.First, we will apply the revolutionary WGS technology on 10,000 individuals to determine the complete DNA mutation architecture for ASD. Under my leadership, with Autism Speaks and Google, we already launched an initiative named MSSNG (finding the missing information in autism). My existing grants have supported WGS of 3,000 genomes and Autism Speaks will complete another 7,000. Here, we will develop novel computational methods to exploit this unprecedented WGS resource, and unearth those genome-wide variants missed in other approaches, but which are capable of causing ASD. We estimate that ~100 new ASD susceptibility genes or regulatory variants will be identified, creating a resource for validated diagnostics and targets in drug trials.Second, we will develop new capabilities to perform functional studies to decode the WGS data. We will use technologies such as microarray-based DNA methylation profiling, induced pluripotent stem cell, and RNA guided mutation engineering coupled to gene expression analysis to elucidate the effects of epigenetic, intronic and intergenic mutations in ASD pathogenesis.Third, our team will develop genome-based health services for ASD. The autism spectrum is heterogeneous, and the core behavioural features can be accompanied by other medical challenges. With detailed comparisons of WGS with rich longitudinal phenotype data gathered by our Canadian clinical networks, we will develop a program to enable earlier accurate diagnosis, which is critical for optimal treatment response. A major deliverable will be to implement WGS for diagnostic testing in Canadian hospitals and to generate evidence-based guidelines on the use of genetic testing for ASD.We will also expand our already dynamic training program to ensure our basic and clinical students and fellows are fully prepared to harness genome science data, and transfer the knowledge stemming from it, to the health care system to maximally benefit families with ASD.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
