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Autism Sequencing Study Uncovers New Disease-Associated Genes, Functional Clues

NEW YORK – A team led by researchers at Icahn School of Medicine at Mount Sinai has tracked down more than 100 genes with apparent roles in autism spectrum disorder (ASD), including 30 genes not implicated in the condition in the past.

As they reported in Cell on Thursday, the researchers compared exome sequences of almost 12,000 individuals with ASD and more than 23,500 unaffected individuals, identifying 102 genes that appeared more prone to de novo mutations or rare variants in the ASD cases. That set not only included genes linked to ASD in prior studies but also genes implicated in developmental delay or severe neurodevelopmental conditions, making it possible to more fully tease apart the shared and distinct genetic contributors between the conditions.

When the team used single-cell sequence data for the brain cortex to study in which cell types the ASD-related genes have higher-than-usual expression, for example, it saw some genes with enhanced expression in excitatory neurons from newborn or more mature brains and others that appeared more prominent in inhibitory newborn or maturing neurons, hinting that both nerve cell types could contribute to the neurodevelopmental condition.

"Through our genetic analyses, we discovered that it's not just one major class of cells implicated in autism, but rather that many disruptions in brain development and in neuronal function can lead to autism," co-senior and corresponding author Joseph Buxbaum, director of Mount Sinai's Seaver Autism Center for Research and Treatment, said in a statement.

For their analysis, the researchers assessed exome sequence data for 11,986 ASD cases and 23,598 controls enrolled at dozens of sites that are part of the Autism Sequencing Consortium. The group included sequences from almost 6,200 individuals for the first time for the study.

Using a computational strategy that combined rare variant and de novo variant data, the team uncovered both new and known risk genes for ASD. It went on to characterize the alterations in the frequently mutated genes more fully, before analyzing the genes within phenotypic, functional, and cell type enrichment frameworks.

"It's critically important that families of children with and without autism participate in genetic studies because genetic discoveries are the primary means to understanding the molecular, cellular, and systems-level underpinnings of autism," Buxbaum suggested, noting that "new drugs will be developed based on our newfound understanding of the molecular bases of autism."

Among other findings, the investigators noted that de novo protein-truncating changes falling in evolutionarily constrained genes were roughly twice as common in female ASD cases, despite the increased prevalence of the condition in males, consistent with a previously proposed "female protective effect model" — the notion that a larger genetic burden may be needed to produce ASD symptoms in females compared to males.

On the phenotypic front, the team distinguished between 53 ASD-related genes that tend to have disruptive de novo variants in cases classified as having higher intelligence quotient scores and 49 genes that appeared more apt to be altered in ASD-affected individuals with lower average IQ scores. The latter set overlapped with genes previously identified in neurodevelopmental delay studies.

"[A]SD-associated genes are distributed across a spectrum of phenotypes and selective pressure," the authors noted. "At one extreme, gene haploinsufficiency leads to global developmental delay with impaired cognitive, social, and gross motor skills, leading to strong negative selection … At the other extreme, gene haploinsufficiency leads to ASD, and there is more modest involvement of other developmental phenotypes and selective pressure."

With the help of RNA sequence data spanning dozens of tissues tested for the Genotype-Tissue Expression project, meanwhile, the researchers found that 58 of the ASD-related genes were marked by prenatal expression in the developing brain cortex — particularly those with potential ties to gene regulation. On the other hand, two dozen of the genes have been functionally linked to neuronal communication and typically have more prominent brain cortical expression during postnatal stages of development.

"The differing expression patterns of [gene expression regulation] and [neuronal communication] genes could reflect two distinct periods of ASD susceptibility during development or a single susceptibility period when both functional gene sets are highly expressed in mid to late fetal development," the authors suggested.

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