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Autism-Linked Mutations Replicate at Higher Levels, Implicate Certain Pathways

NEW YORK (GenomeWeb) – Researchers have traced mutations uncovered in scores of people with autism spectrum disorder to similar genes and pathways.

Autism spectrum disorder affects about 1 percent of the population and while numerous variants have been associated with the condition, they have been difficult to link to disease mechanisms.

Using a hierarchical approach to analyze autism-related mutations from two large whole-exome sequencing studies, researchers led by the University of North Carolina-Charlotte's Cory Brouwer found that while those mutations did not replicate at the single-nucleotide level, some did at the gene and pathway levels. As they reported today in Science Advances, these alterations coalesced to pathways involved in synaptic function, morphology, and plasticity.

"Our results suggest that isolated, rare mutation events are actually connected and recurrent at higher (gene and pathway) levels," Brouwer and colleagues wrote in their paper.

He and his colleagues examined de novo autism-related mutations, genes, and pathways uncovered by the Simons Simplex Collection and the Autism Sequencing Consortium in their whole-exome sequencing studies. The groups reported a respective 3,392 and 4,792 autism-related variants.

However, autism-related mutations uncovered in the different cohorts didn't replicate at the variant level. More and more of them did, though, when the researchers examined the genes and pathways affected by them. Similarly, autism-related mutations from the same cohort didn't replicate at the variant level, though some did at the gene and pathway levels. Among siblings, the researchers noted the mutations did not replicate or converge.

According to the researchers, there could be three explanations for increase in replication at the gene and pathway levels: a smaller background space, high local mutation rates, or true and recurrent disease mechanisms. They noted that lack of recurrence among siblings suggests the mutations are disease-related.

Based on their findings, Brouwer and colleagues posited that a gene-plus-pathway dual-hit model could describe autism genetic associations. This model, they noted, depends on the effect of the disrupted genes and whether that effect also influences related pathways. They added that their proposal is, in essence, a Noisy-AND model in which the gene risk variant is both gene disrupting and pathway hitting. It's noisy, they said, because knowledge about gene-disrupting and pathway assignment is incomplete.

Indeed, the researchers found that probands not only harbored more variants in general, but more gene-disrupting ones and ones that affected selected pathways. Probands, they reported, have 55 percent more likely gene-disrupting and 11 percent more missense mutations than their siblings do.

These variants tended to repeatedly affect a number of canonical signaling pathways, the researchers reported. At the variant level, 43 likely gene disrupting and 75 missense mutations mapped to these pathways, while at the gene level, 92 did.

These pathways included the Wnt signaling, GABAergic signaling, and glutamatergic synapse pathways, among others. In particular, they noted that the canonical branch of the Wnt signaling pathway is involved, while the whole of the GABAergic signaling pathway is involved.

The researchers noted that the pathways implicated are interrelated, though separate into two modules. One module, through its inclusion of Wnt signaling, cell adhesion, junction, and cytoskeletal-associated pathways, highlights the role of synapse morphology in autism. Meanwhile, the other module underscores the role of synapse function with its inclusion of glutamatergic synapse, GABAergic synapse, and related processes. This, they said, suggests synaptic transmission and function and neuronal wiring and morphology have key roles in autism.

"ASD is not only a multigenic, but also a multipathway disease, and it is ultimately a synapse disease," the researchers wrote. The affected pathways, they added, could be a collection of genetic risk factors for autism.