Truncate mutation sites related to diversity, severity of autism symptoms

One of the most recognizable characteristics of autism is an incredible diversity of associated behavioral symptoms. Clinicians view autism as a wide range of related disorders, and the origin of the disease’s heterogeneity has puzzled scientists, physicians, and affected families for decades.

In a recent study, researchers at the College of Physicians and Surgeons at Columbia University Vagelos took an important step towards understanding the biological mechanisms underlying the cognitive and behavioral diversity of autism cases triggered by truncated mutations of novo. These mutations occur in the germ cells of the parents and usually severely disrupt the functions of the target genes. De novo truncated mutations are responsible for nearly 5% of autism cases and up to 20% of clinically seen cases.

Autism spectrum disorders that are triggered by a single disturbed gene represent a relatively simple genetic type of the disease. The puzzling observation that scientists have grappled with for many years is that even when truncated mutations occur in the same gene, they often lead to a wide range of symptoms and behavior patterns in different children.

The new study found that the severity of autism symptoms often depends on the specific functional unit of a gene that is the target of a mutation.

“It turns out that we weren’t looking closely enough at how and where an autism gene is mutated,” says study leader Dennis Vitkup, PhD, associate professor of systems biology and biomedical informatics at the ‘Columbia University Vagelos College of Physicians.

Human genes, similar to genes in other eukaryotic species, are made up of separate coding units, called exons, which frequently come together in different combinations across tissues and stages of development. “Upon closer examination, we found that different children with truncated mutations in the same exon have surprisingly similar symptoms and behavioral disabilities,” says Vitkup.

The study was published online in the journal Molecular psychiatry.

Same exon, similar symptoms

In the study, Vitkup and colleagues Andrew H. Chiang, Jonathan Chang, and Jiayao Wang analyzed genetic and clinical data from more than 2,500 people with autism, focusing on cases resulting from truncated mutations.

When the researchers compared random pairs of children with autism, they found that their non-verbal, verbal and general IQ scores differed on average by more than 30 points. Children with truncated mutations in the same gene showed similar differences.

However, when the researchers compared children with autism affected by mutations in the same exon of the same gene, their IQ differed by less than ten points, which is comparable to the IQ measurement errors. Researchers observed very similar patterns for several other scores characterizing children’s communication, social, and motor skills.

“This tells us that with the truncated mutations associated with autism, it is the exon, not the entire gene, that often represents a functional unit of impact,” says Vitkup.

More serious symptoms associated with frequently used exons

Researchers have shown that the behavioral and cognitive severity of autism is proportional to the likelihood with which targeted exons are used in gene transcripts, with more severe effects associated with mutations in more frequently used exons. When mutations occur in the same exon, the resulting changes in expression level are particularly similar, leading to similar clinical consequences.

Surprisingly, the study also showed that gene expression changes caused by truncated mutations can be quite mild. “Our analysis demonstrates that cases of autism can be triggered by relatively small changes in the overall dosage of genes, often as small as 15%,” says study lead author Andrew Chiang, a graduate student of the Department. biomedical informatics.

Implications for precision medicine

The study may have significant implications for precision medicine. Diagnostic and prognostic testing can now pay particular attention to specific exons affected by truncated mutations.

The study also suggests a therapeutic approach to mitigate the consequences of truncated mutations in autism. “It would be very difficult to develop drugs for thousands of different mutations in several hundred target genes for autism,” says Vitkup, “but our study shows that behavioral abnormalities often arise from relatively small decreases in the dosage of the target gene. . These genetic attacks can be, at least partially, compensated by increasing the expression of an unaffected gene copy using new molecular tools such as CRISPR. “