HomeScienceGeneticsGenetic markers for autism, hidden in plain sight

Genetic markers for autism, hidden in plain sight

Overview: It is estimated that 80% of autism is hereditary, but causative genes are difficult to identify. Researchers have identified the ACMSD gene as associated with nonverbal forms of ASD.

Source: DOE/Oak Ridge National Laboratory

An Oak Ridge National Laboratory-led research team discovered genetic mutations underlying autism using a new approach that could lead to better diagnostics and drug therapies.

Scientists estimate that 80% of autism is hereditary, but they have yet to identify the causative genes.

“We realized the value of untapped hereditary information from other people’s research,” says ORNL’s Michael Garvin. Garvin and colleagues focused on genomic mutations called structural variants and made a direct link to autism traits.

The key has been observing that many structural variants have been ruled out because they often show non-traditional inheritance patterns.

Scientists estimate that 80% of autism is hereditary, but they have yet to identify the causative genes. The image is in the public domain

By focusing on these variants, ORNL scientists found a mutation in the ACMSD gene associated with nonverbal forms of autism.

They then used artificial intelligence and high-performance computing to find additional variants associated with three autism subtypes.

“We’ve established a workflow for using this oft-ignored data that can be applied not only to autism, but to other conditions as well,” said ORNL’s David Kainer.

About this autism and genetics research news

Author: Kim Askey
Source: DOE/Oak Ridge National Laboratory
Contact: Kim Askey – DE/Oak Ridge National Laboratory
Image: The image is in the public domain

Original research: Open access.
Structural variants identified using non-Mendelian inheritance patterns advance mechanistic understanding of autism spectrum disorderby Michael Garvin et al. HGG Progress


Abstract

Structural variants identified using non-Mendelian inheritance patterns advance mechanistic understanding of autism spectrum disorder

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The heritability of autism spectrum disorder (ASD), based on 680,000 families and five countries, is estimated to be close to 80%, but the heritability reported from SNP-based studies is consistently lower and few significant loci have been identified with genome-wide association studies.

This gap in genomic information may lie in rare variants, interaction between variants (epistasis), or cryptic structural variation (SV) and may provide mechanisms underlying ASD.

Here we use a method to identify potential SVs based on non-Mendelian inheritance patterns in pedigrees using parent-child genotypes from ASD families and demonstrate that they are enriched in ASD risk genes.

Most reside in the noncoding genetic space and are overrepresented in expression quantitative trait loci, suggesting that they affect gene regulation, which we confirm with their overlap of differentially expressed genes in postmortem brain tissue of ASD individuals.

Next, we identify an SV in the GRIK2 gene that alters RNA splicing and a regulatory region of the gene ACMSD gene in the kynurenine pathway as significantly associated with a nonverbal ASD phenotype, supporting our hypothesis that these currently excluded loci may provide a clearer mechanistic understanding of ASD.

Finally, we use an explainable artificial intelligence approach to define subgroups demonstrating their use in the context of precision medicine.

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