From Fold to Phenotype: AI-Enabled Structural Biology and Drosophila Functional Genetics to Solve Rare Brain Disorders

Project Overview

Some children are born with changes in a gene called IRF2BPL. These changes can cause a rare neurological condition called NEDAMSS. Children with NEDAMSS may develop normally at first, but later lose skills such as speech, movement, or walking. They may also develop seizures, abnormal movements, or symptoms related to autism. However, not all children with IRF2BPL changes are affected in the same way. Some have milder symptoms, and others have genetic changes that doctors cannot yet clearly classify as harmful or harmless. This uncertainty makes it difficult for families to get answers.
This project will help solve that problem by studying how different IRF2BPL gene changes affect the function of the protein. First, the research team will use advanced computer-based tools, including protein prediction methods, to estimate which genetic changes are most likely to cause disease and how they may disrupt the protein. Because IRF2BPL has regions that are difficult to study using standard prediction tools, the team will adapt these methods specifically for this gene.
Second, the team will test selected genetic changes in fruit flies. Fruit flies are a powerful model for studying human disease genes because many basic biological processes are shared between flies and humans. The researchers will use several fly-based tests to determine whether specific IRF2BPL changes reduce gene function, interfere with the normal copy of the gene, or affect important biological pathways such as Wnt signaling.
The long-term goal is to give clinicians and families clearer information about what specific IRF2BPL variants mean. This work may improve diagnosis, guide expectations about disease severity, and create models that can be used in the future to test possible treatments.

Partners and Donors

Brain Canada, Weizmann Canada, and the Weizmann Institute of Science