Researchers have been saying for many years that autism spectrum disorder (ASD) is a highly complex group of related conditions. A new study adds an important dimension to our understanding of just how complex it is.

A team that included three current and past NARSAD grant recipients, all of them at the Hospital for Sick Children and the University of Toronto, Canada, reports in the February issue of Nature Medicine the results of a detailed study of 85 families with two children diagnosed with ASD. Each of these is called a quartet family, in reference to two unaffected parents and two affected children. The genomes of each family member, parents and children alike, were sequenced in their entirety using a technique called WGS (whole-genome sequencing).

WGS differs from a method used to discover many of the 100 known genetic variations that are linked with a higher susceptibility to ASD. Almost all of these variants were discovered using a method that sequenced less than 2 percent of a patient’s genome––the portion called the exome. The exome is exclusively devoted to instructing cells how to manufacture the body’s many different proteins. The rationale for sequencing only the exome is compelling: since proteins form all of our bodily and cellular structures and perform nearly all of the “work” in cells, it makes sense to see if genes linked to ASD are encoding proteins that might be dysfunctional.

But this ignores the other 98 percent of the human genome, which contains a great deal of information that regulates the activity of genes. Variations in this larger region are almost certain to play a role in ASD and other complex genetic disorders. Although WGS is the best method of looking for DNA variations linked with illness, it’s rarely used because it takes longer and costs much more money, per person. But Ryan Yuen, Ph.D. and his colleagues did perform this more laborious and costly full-genome search in 85 quartet families, which included 170 children with ASD.

The results were somewhat surprising. Knowing that ASD has a comparatively strong inherited component, they hoped that in families with more than one affected offspring, those children would tend to have the same or similar genetic variations (compared with their parents and other healthy people). However, Dr. Yuen and his team found that siblings often had “discordant” (different) variations. Such siblings tended to differ more in their symptoms than did siblings who inherited greater numbers of the same genome variations.

There are two takeaway messages: One is that genetic variations in ASD, even within the same nuclear family, tend to differ among affected siblings. The other is that it took WGS to see this important yet subtle phenomenon. As gene sequencing costs continue to decline, WGS will undoubtedly become the gold standard for studies trying to explain the stunning complexity of conditions like ASD.

Read the abstract.