by Olivia Dimmer, Northwestern University

Cell-type-specific expression of GSK3B in the developing human brain. Credit: Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02806-z

Newly discovered genetic variants have been linked to autism and developmental delays, according to an international study published in Molecular Psychiatry.

The newly-described gene will add to previously known genetic variants associated with autism and may aid in genetic diagnoses for more families, said Sarah Jurgensmeyer, MS, a lecturer in the Northwestern University Department of Pediatrics Division of Genetics, Genomics, and Metabolism, who was a co-author of the study.

"More and more frequently as gene discovery happens, we are finding genetic variants in what we call candidate genes," said Jurgensmeyer, a genetic counselor in the Division of Cardiology at the Ann & Robert H. Lurie Children's Hospital of Chicago. "While a candidate gene is not typically enough for a diagnosis—the research and evidence might not be quite there yet—there are ways that we as a genetics community have found to connect with other people who are interested in the same candidate gene."

Hoping to find more answers for one of her clients with a genetic variant in the GSK3B gene, Jurgensmeyer connected with other investigators on GeneMatcher, a platform dedicated to connecting scientists and clinicians in hopes of better understanding rare or undescribed genetic variants.

From there, investigators in the study analyzed the genotype and phenotype of 15 people with variants in GSK3B. Study participants with genetic variants in GSK3B all presented with similar symptoms, including developmental delay, autism, sleeping disturbances and other behavioral challenges.

Enrichment analyses of intronic DNVs adjacent to canonical splicing sites (CSS) in ASD cohorts compared to unaffected siblings. Credit: Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02806-z

Next, using single-cell transcriptomic data, investigators found that GSK3B is enriched in excitatory neurons in the developing brain. By inhibiting GSK3B in mice, investigators observed that expected development was disrupted and led to a neurodevelopmental disorder with similar features to autism.

The findings will add to existing knowledge of genes associated with autism and provide more information to families with genetic variants in GSK3B, Jurgensmeyer said.

"We have come so far in terms of our understanding of the genetics of some neurodevelopmental diagnoses," Jurgensmeyer said. "The next time someone is found to have a variant in this gene in the future, there will be more data out there that will hopefully reduce some uncertainty about what those results mean for that patient and their family."

The findings may also help guide the long-term management of symptoms in people born with these GSK3B variants, Jurgensmeyer added.

"This is a small step in a much bigger conversation," Jurgensmeyer said. "I'm always happy anytime that we can help provide more answers to the families we get to work with every day."

More information: Senwei Tan et al, Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay, Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02806-z

Journal information: Molecular Psychiatry 

Provided by Northwestern University