03.06.2023 Genetics

Siege of the genes

A study seeks to identify how genetic mutations linked to autism interfere in neurological development

Créditos: Punto Comunicação

According to scientific knowledge accumulated over decades, Autism Spectrum Disorder (ASD) presents an extremely complex and heterogeneous genetic architecture. More recent models indicate that the sum of rare and common genetic variants contribute to shaping patient phenotypes, with significant variation. For this reason, scientists from around the world are attempting to identify genes and neurobiological pathways that can help explain autism.

“In the case of oligogenic inheritance of ASD, what we see is the interaction between two or more mutated genes that, individually, are insufficient to cause the clinical phenotype. These genes interact additively or synergistically to result in the disorder,” states biologist Andrea Laurato Sertié, a researcher at Hospital Israelita Albert Einstein (HIAE).

The study published in Translational Psychiatry magazine, was conducted by a group of Brazilian and Canadian researchers and was led by the Brazilian scientist. The study proceeds to explain precisely how genetic mutations linked to autism interfere in neurological development. It is yet another step towards uncovering the disease’s intricate architecture.

“First, by analyzing a single patient’s DNA, we identified genes that act in calcium channels and the Reelin pathway, a protein that controls synapses functioning,” says Sertié. By expanding the search for these genes to other individuals with autism and a control group, the puzzle pieces began to fall into place.

Two sample sets of genetic material were analyzed. One Brazilian set of 861 samples, 291 with ASD, and another from a Canadian database with 11,181 samples, 5,102 with ASD. In the latter, the same mutations were present in seven samples, while two were identified in the Brazilian genomes—mutations that were not even present in the parents’ genetic material.

They are not always the same genes, explains Sertié, but the neurobiological pathways they command are always the same. It is the rare and potentially pathogenic genetic variants in the Reelin pathway and calcium channels that appear to act additively to increase the risk of ASD, claim the researchers.


“The study’s main finding is that it demonstrated the importance of genes that command two seemingly different metabolic pathways acting in a unique manner,” says Maria Rita Passos-Bueno, a researcher at the Human Genome and Stem Cell Research Center, which is part of the University of São Paulo’s Institute of Biosciences (IB-USP). “Understanding how these pathways converge is a major challenge in the field of autism genetics.”

The patient whose genetic material was first analyzed separately has Asperger’s Syndrome, says Passos-Bueno, who coauthored the international article. “It is a mild form, and he currently has a very successful professional career. It is important to understand the genetics of this group of individuals, who usually have milder cases,” explains the researcher.

All of the work performed jointly by Brazilians and Canadians is carried out in vitro. As an experimental model, the researchers use neural progenitor cells derived from pluripotent stem cells taken from both the patient and the individuals in the control group to trace the impacts of genetic mutations on neurobiological pathways.

To this day, there are few studies that delve into the existing genetic interactions between different rare and potentially deleterious variants found in patients. Researchers also do not know how many variants are needed to trigger ASD. The recent study, emphasizes Sertié, suggests that calcium channels and the Reelin pathway may be behind ASD, but there are still many steps to be taken before this is fully assured.

“The idea now is to reconstruct the entire process, correcting the mutations in 3D systems. Or even inducing them in individuals in the control group,” explains the HIAE researcher. According to her, another future step should be attempting to reconstruct the ASD phenotype through medication. “It is also important to know when the mutations occurred.”


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