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Family-Based Homozygosity Mapping Study Uncovers Possible Autism Culprits

NEW YORK (GenomeWeb News) – A new homozygosity mapping study is at once underscoring the genetic diversity behind autism and highlighting a common neural pathway that may be altered in some who have the condition.
In an effort to find new autism genes, an international team of investigators examined nearly 90 Middle Eastern families that contained parents who were cousins and, as such, had a shared ancestor. The research, published online today in Science, implicates at least six new genes in autism. And while these genes have a variety of functions, they seem to share one important characteristic: they are each thought to contribute to the developing brain’s ability to form new connections.
“The emerging picture of the genetics of autism is quite surprising. There appear to be many separate mutations involved, with each family having a different genetic cause,” National Institute of Mental Health Director Thomas Insel, who was not involved in the study, said in a statement. “The one unifying observation from this new report is that all of the relevant mutations could disrupt the formation of vital neural connections during a critical period when experience is shaping the developing brain.”
Autism is a neurodevelopmental condition affecting as many as one in every 150 children in the US. It is characterized by social impairment, communication problems, and repetitive behavior, though it may also include other symptoms — including mental retardation and seizures. Both heritable and environmental factors have been implicated in autism and autism spectrum disorders. But even though all those with autism and ASD share a core set of symptoms the underlying genetics are varied and poorly understood.
“At the moment, we understand the genetic causes of 15 to 20 percent of autism,” senior author Christopher Walsh, chief of genetics at the Children’s Hospital Boston, said in a statement. “The remaining 80 percent remain unexplained.”
Elucidating the remaining genetic factors of autism continues to challenge researchers, with growing evidence to suggest that autism encompasses several syndromes ranging from relatively mild to severe. “The extreme genetic heterogeneity of autism, and the high de novo mutation rate, have hindered linkage studies of inherited autism susceptibility loci,” the authors wrote.
As part of the Homozygosity Mapping Collaborative for Autism, researchers from the Boston Children’s Hospital, the Boston-based group Autism Consortium, and their collaborators recruited 104 families from the Arabic Middle East, Turkey, and Pakistan that had at least one child affected by autism or ASD. Of these, 88 included cousins who were married.
The team then used a technique called homozygosity mapping, looking at the genetic patterns within these consanguineous families. Because autosomal recessive mutations are more common in children of cousins, the technique allows researchers to pick out these mutations much more easily than they can in the general population.
As predicted, their results were consistent with enriched autosomal recessive mutations in consanguineous families. In roughly six percent of the consanguineous families tested, the researchers detected large, rare, inherited homozygous deletions in or near at least six different genes: RNF8, SCN7A, CNTN3, NHE9, PCDH10, and c3orf58, which the team dubbed “deleted in autism-1” or DIA1.
Three of these genes — DIA1, NHE9, and PCDH10 — were previously shown to be regulated by neuronal activity and all six are normally expressed at high levels in the brain.
That made the researchers suspect that the genes detected in this study may be part of a network involved in activity-dependent regulation of synapse development — the formation of novel connections between neurons in children’s brains in response to new experiences. That, in turn, could affect a child’s ability to learn and form memories.
“Taken together, our findings suggest that experience-dependent learning could be relevant to autism, and that autism might result from the deregulation of any one of a number of genes that are part of the same signaling pathway,” co-author Michael Greenberg, director of the Children’s Hospital Boston Neurobiology Program, said in a statement.
And because several mutations detected were in regulatory rather than coding regions of genes, the team speculated that altered gene regulation may contribute to at least some forms of autism.
“This means that we would not need to replace the gene, if we could only figure out how to reactivate it, perhaps with medications,” lead author Eric Morrow, a researcher affiliated with the Massachusetts General Hospital and several other Boston-based research institutions, said in a statement.

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