A new study shows that the pattern of genetic factors associated with autism among siblings is a different pattern than that seen in families with just one affected child.
University of California, Los Angeles scientists focused on genetic changes known as copy-number variations (CNVs), which are losses or gains of normal DNA.
Previous research has linked non-inherited CNVs, which originate as defects in the sperm or egg cell from which the affected child is conceived, to autism spectrum disorder in children whose siblings are not affected.
The research findings discovered more than a dozen new genes linked to the risk of autism spectrum disorders. This knowledge highlights the complexity of genetic factors in the disorders.
The findings provide a better picture of how genetic variation contributes to autism disorders, and could perhaps point to a possible new target for future therapies.
The study appears in the American Journal of Human Genetics.
The researchers found that, among children with an autism spectrum disorder who have siblings with autism disorders, inherited copy-number variations had a stronger influence than non-inherited CNVs. This was expected, but had previously not been demonstrated.
Although the researchers expected inherited factors to appear to play a greater role in families in which more than one child has an autism spectrum disorder, they were surprised by another observation in these families. Specifically, when an affected child has an inherited genetic variation that is known to be an autism spectrum disorder risk factor, it is seldom the case that all his affected siblings have that same variation.
“It’s actually the exception rather than the rule,” said principal investigator Dr. Daniel Geschwind, a distinguished professor of human genetics at the David Geffen School of Medicine at University of California, Los Angeles.
“So for example, there are families in which only two of three kids have the rare CNV inherited from the parent, yet they all have been diagnosed with an autism disorder. One might have expected all three to inherit this major risk factor.”
The study arose from a long-running project by Geschwind and collaborators to gather DNA and clinical data on families with more than one child with autism spectrum disorder.
These are known as “multiplex families.” Most autism genetics studies have focused on families with just one affected child, known as “simplex families,” because researchers predicted that certain types of disease-related DNA changes were in principle easier to detect in such families.
Mutliplex families are not common accounting for about 11 percent of families with children who have an autism spectrum disorder. Because of this, the lack of investigation may have distorted the picture of how DNA changes contribute to autism disorders.
Most obviously, cases of autism spectrum disorder diagnosed in siblings, which appear to run in the family, would be expected to result more from heritable genetic variations than non-inherited CNVs. Heritability is the extent to which genetic differences contribute to observed physical differences.
One possible explanation for the finding that autistic siblings in a family usually do not all have the same disease-linked genetic variation, Geschwind said, is that lightning has indeed struck twice. That is, an unlucky non-inherited mutation may account for an autism spectrum disorder in a child who lacks inherited risk factors found in siblings.
Another possibility is that the autism spectrum disorder arises in the siblings mostly from other, harder-to-find factors. For example, common or rare inherited variations may occur in many genes which could then influence the severity of the disorder.
The analysis is based on the final collection of data on 1,532 ASD families, which is known as the Autism Genetic Resource Exchange. About 80 percent of the families in the database are multiplex.
“This is the largest study of its kind in families with multiple autism spectrum disorder children, and it shows that looking at such families can provide significant new insights,” said Geschwind, who is also a professor of neurology and psychiatry.
Of the potential new autism spectrum disorder risk genes discovered by the researchers, one of them, NR4A2, is linked to some rare cases of autism disorder with delays in language ability.
The language connection, Geschwind said, fits with a previous finding from his laboratory that NR4A2 is expressed in the human brain in areas involved in language development, specifically the temporal lobe.
Geschwind emphasized that the complex genetic underpinnings of autism spectrum disorder in multiplex families need to be better characterized with larger studies of these families. “There are a lot of multiplex families out there waiting to be studied, but unfortunately it seems there is no effort now to study these families on a larger scale,” Geschwind said.
The lead author of the study, who performed most of the analyses, was Virpi Leppa, Ph.D., a postdoctoral researcher in the Geschwind Laboratory from Helsinki, Finland.