A new study led by UCLA scientists shows that in families with multiple children on the autism spectrum, the pattern of genetic factors is different from that seen in families with just one affected child.
The study 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 included the discovery of more than a dozen promising new candidates for genes linked to the risk of autism spectrum disorders, highlighting 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 Aug. 25 issue of 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: 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, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics at the David Geffen School of Medicine at UCLA. “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.
The relative exclusion of multiplex families, which account for about 11 percent of families with children who have an autism spectrum disorder, 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 — in the form of an unlucky non-inherited mutation that accounts 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 variation in many genes, so that the presence or absence of a large, inherited copy-number variation influences only 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, a postdoctoral researcher in the Geschwind Laboratory.
The research was part of a collaborative effort including researchers from Yale University, University of California, San Francisco, Washington University at St. Louis, and other institutions.
Funding was provided by the National Institute for Mental Health (R01 MH081754, R01 MH100027, R01 MH074090, R01 MH06454701S1). The Autism Genetic Resource Exchange was initially supported by the Cure Autism Now foundation, which later merged with another organization, Autism Speaks.