Genetic results stack up in some individuals with autism | Spectrum
Multiple hits: Combinations of genetic variants can affect autism traits by altering the expression of other genes.
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Rare genetic variants that alter the expression of genes in the brain contribute to autism in people who also have a rare autism-related mutation, according to a new study. The results help explain how some “second hits” promote autism in people with known mutations, the researchers say.
The study analyzed families with DNA deletions in the chromosomal region 16p12.1. About 30 percent of people with this deletion are autistic; Ninety percent inherit the mutation from a parent who often exhibits mild or no neuropsychiatric characteristics.
Children with autism and the 16p deletion who carry other genetic variants – often inherited from the parent without the deletion – tend to have deeper characteristics than those without second genetic “hits,” as the researchers showed in 2018.
Unpublished work by the same group supports these “second hit” results: In an analysis of 113 families with the deletion, carrier parents tended to have different and often milder neuropsychiatric characteristics than their carrier children. The researchers presented the work at the American Society of Human Genetics meeting last month.
The new work shows that the second hits in the children influence the autism characteristics mainly by changing the expression of other genes.
“We already suspect that these mechanisms are at play, but what this study shows well is that it is the combination of these traits,” says Dan Arking, a professor of genetic medicine at Johns Hopkins University in Baltimore, Maryland, not at the Work involved. “It’s nice to be able to show.”
Taken together, the results could also help clinicians better advise families about their children’s likely developmental paths, says lead researcher Santhosh Girirajan, associate professor of genomics at Pennsylvania State University. Children with the deletion and a family history of psychiatric illness are more likely to have deeper features.
“A lot can happen, but in general, family history plays a big role,” says Girirajan.
Girirajan and his colleagues sequenced the entire genome of 32 people from five families. Each family includes some members who carry the deletion: 10 children – 8 of them autistic – 6 non-autistic parents and 3 non-autistic grandparents. They also collected blood cells to establish cell lines to measure gene expression, as well as information about participants’ health and developmental traits.
More than 1,500 genes were expressed differently between carriers and non-carriers, the team found. And many of the genes are strongly linked to autism, including FOXP1, ANK3, and EP300.
The carrier children, however, shared an equal number of expression changes with their non-carrier parents – who likely passed the additional genetic “hits” on – and their carrier parents, a result Girirajan describes as “interesting”.
The results were published in Genome Medicine in October.
DNA sequencing revealed 25 groups of additional rare variants in the cohort, at least one of which was found in approximately 10 percent of the genes with expression changes.
Many of the variants involve genes belonging to a brain-specific gene-interaction network, suggesting that they might affect gene expression levels in the developing brains of carrier children, the researchers say.
In several cases, the combination of gene expression differences from the 16p12.1 deletion and an additional hit was greater than the overall effect of either mutation alone, the team found, suggesting an interaction between the two.
“The synergistic effect is 1 plus 2 is 5,” says Girirajan.
It’s useful that the team tried to go beyond associations to identify mechanisms by which additional genetic hits work, says Arking. Future work with more siblings who are not carriers would make the results more robust, as would the analysis of gene expression in neurons generated from the participants’ stem cells rather than the blood cell lines used in this study.
But the work helps show how the same erasure can produce results so different in people, says Nicola Grissom, an uninitiated professor of psychology at the University of Minnesota at Minneapolis.
“It’s really important to be aware that it’s not deterministic, but to try to understand what this variant gene is actually doing and how it could do it,” she says.
And it shows the importance of better understanding the genetic background, not just in humans but also in mouse models of mutations associated with autism, she says.
“That is a really important question that has basically not been researched enough,” says Grissom.