Four new genes linked to autism via first-time genome-wide analysis of Canadian cohort

July 12, 2013

NeuroDevNet researchers played pivotal roles in a groundbreaking study examining genetic sequencing in 32 Canadian families affected by ASD. The study, the first to rely on a genome-wide approach, yielded links to the disorder between four genes not previously associated with autism.

Dr. Stephen Scherer, co-lead of NeuroDevNet's Autism Research Group, and more than three dozen international colleagues joined in the study, published electronically on July 12 in the American Journal of Human Genetics.

"For the first time, we can really look at inherited variants," said Dr. Scherer. High-quality data, obtained through Dr. Peter Szatmari's work on the Autism Speaks funded Consortium Study, and study design and analysis backed by NeuroDevNet, encouraged the group to venture a genome-wide search looking specifically at genetic alterations passed on from mothers to sons.

The $1 million pilot study examining the whole genomes of 32 Canadian families is part of an international effort that will eventually analyze the whole genomes of 10,000 families affected by ASD, including 1,000 in Canada.

Genetic variants in the four genes newly linked to ASD were found in half of the 32 initial families. The proportion of families identified with known mutations was much larger than any previously reported. Deleterious variants also found in the families  included nine known, and eight candidate ASD risk genes, variously implicated in other conditions, including Fragile X syndrome, social-cognitive deficits, and epilepsy. 

"The power was often having multiple affected people in a family, in multiple generations, as well as unaffected kids, to look at segregation," added Dr. Scherer.  "Doing this increased our diagnostic yield immensely."

Among the objectives of the study is increasing the potential for early detection and eventual therapeutics targeting core symptoms of ASD. Initial diagnosis in Canada, based on behavioural red flags, typically takes place at age 41/2. That timeline may be shortened based on the new findings, as in at least one instance, investigators determined a sibling not previously thought to have autism, carried a relevant gene and was in fact affected by the disorder.

Earlier diagnosis and intervention are known to improve outcomes for children on the spectrum and their families. Families found to have specific gene variants linked to ASD may also be fast tracked for intervention studies targeting the symptoms and behaviours tied to those variants.

The availability of detailed phenotypic (behavioural) data from NeuroDevNet's Autism Research Group co-lead Dr. Lonnie Zwaigenbaum was critical to the study, according to Dr. Scherer, and highlights the unique contributions and capacities of the network. 

"We are very pleased with the paper," added Dr. Scherer. "It has primed many other things coming soon, and many ideas to follow." 

To read more about the study, visit the Sickkids Newsroom article.

Jiang et al., Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing, The American Journal of Human Genetics (2013) ,