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Autism Study Points to Frequent Risk Variant Differences in Affected Siblings

NEW YORK (GenomeWeb) – A new Nature Medicine study is highlighting the genetic heterogeneity of autism spectrum disorder, even between ASD-affected children from the same family.

An international team led by investigators at the Hospital for Sick Children in Toronto and the University of Toronto scrutinized genome sequence data for more than seven-dozen families comprised of two ASD-affected children and their parents — a search that unearthed known ASD-related glitches in just over 42 percent of families.

When they considered rare or de novo variant patterns within each family, the researchers found the same ASD-associated variants in just over one-third of the sibling pairs. On the other hand, nearly 70 percent of children with ASD carried risk variants that were different than those found in their affected siblings.

"We believe that each child with autism is like a snowflake — unique from the other," the study's senior author Stephen Scherer, director of the Hospital for Sick Children's Centre for Applied Genomics and the University of Toronto's McLaughlin Centre, said in a statement.

"This means we should not be looking just for suspected autism-risk genes, as is typically done in diagnostic genetic testing," Scherer argued. "A full assessment of each individual's genome is needed to determine how to best use knowledge of genetic factors in personalized autism treatment."

Although past studies have incriminated high penetrance de novo mutations as the ASD culprits in families with just one affected child, the researchers explained, it was suspected that siblings with ASD might share inherited risk factors for the condition.

To investigate that possibility further, Scherer and colleagues considered 85 quartets — each comprised of two siblings with ASD and two unaffected parents — as part of an Autism Speaks effort called MSSNG. The families included 139 male and 31 female children with the condition.

The team did whole-genome sequencing on the 340 members of the quartets with Complete Genomics to produce genomes sequenced to average depths of 20-fold coverage across roughly 96 percent of the protein-coding exome sequences.

When they began sorting through the spontaneous single nucleotide changes, small insertions and deletions, copy number variations, and so on, the researchers saw similar rates of such de novo alterations as described in past studies of ASD families with a single affected child.

All told, they found de novo or rare mutations associated with ASD in 36 of the families. Siblings shared the same rare ASD-related genetic glitch in 11 of those families, while the remaining cases seemed to stem from discordant mutations between affected siblings.

De novo mutations suspected of contributing to ASD were shared between nearly 19 percent of the siblings, with over half of those apparently stemming from the father's side.

Moreover, the analysis unearthed CNVs not found using an array-based approach, the study's authors explained, suggesting that widespread sequencing could help in untangling the genetic architecture of ASD in more detail than has been available previously.

Members of the team plan to assess at least 10,000 genomes from individuals with ASD as part of the ongoing MSSNG project.

Sequence data for around 1,000 of the de-identified ASD genomes are being released in tandem with the Nature Medicine study and will be openly available to other members of the research community through an Autism Speaks MSSNG Google Cloud platform. 

The move "marks the first time whole-genome sequences for autism will be available for research on the MSSNG open-science database," Scherer noted, calling it "an exemplar for a future when open-access genomics will lead to personalized treatments for many developmental and medical disorders."