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A new study published in the  brings researchers one step closer to answering the question: Why do children with mutations in the same gene often experience very different symptoms?

A University of Ä¢¹½´«Ã½ research team worked with clinicians and scientists across the globe to discover that mutations in CELF2, a gene linked to a rare group of neurodevelopmental disorders, are not all the same. Instead, different types of mutations affect the protein in different ways, helping explain why some patients develop seizures while others do not. 

The team included , PhD; , MD; PhD candidate Michelle Hua, BSc’21; and Isabel Clark, MSc’24.

Since the team’s first CELF2 discovery five years ago, there have been only 30 patients with neurodevelopmental disorders linked to the CELF2 gene known globally. However, there are likely more undiagnosed cases. The study findings could help medical professionals provide an accurate diagnosis for those living with these rare conditions, which is a critical first step to guide personalized, effective treatments.

Five years ago, your team first linked the CELF2 gene to neurodevelopmental disorders. What question were you trying to answer with this study?

Dr. Guang Yang: When we first identified CELF2 as a disease gene, we knew it was associated with developmental disorders, but we didn't know exactly how it was causing disease or why patients could look so different clinically.

With many rare diseases, families see symptoms like developmental delays, speech impairments or seizures, but they don't know what's actually causing them. That makes diagnosis difficult and makes it even harder to think about treatment.

Our goal with this study was to understand the biological cause of those symptoms. If we understand what's happening inside the cell, we can start thinking about how to diagnose patients more accurately.

For someone who's never heard of CELF2, what does it actually do?

Yang: CELF2 is what's known as an RNA-binding protein. You can think of it as a coordinator or gatekeeper inside the cell.

Genes contain instructions for making proteins, but those instructions have to be carefully regulated. CELF2 helps control how those genetic instructions are processed and ultimately influences which proteins are made and when. Without that co-ordination, brain cells can't function normally.

Your paper describes CELF2 as "shuttling" between different parts of the cell. What does that mean?

Yang: Think of it as your workday at the office and being at home at the end of the day. At work you have one set of responsibilities and being at home you have another. Healthy living depends on being able to move between both places.

CELF2 works the same way. It normally moves back and forth between the nucleus, the inner compartment of the cell, and the cytoplasm, the outer compartment. It performs different jobs in each location.

If you stayed at work all the time, no one would be home to take care of your family. If you never left home, your work wouldn't get done. CELF2 needs that same balance inside the cell.

Michelle Hua: CELF2 normally moves between the nucleus, which contains the cell’s genetic material, and the surrounding part of the cell called the cytoplasm. It has different roles depending on where it is located. Some disease-causing mutations prevent CELF2 from moving properly and cause it to remain in the cytoplasm. In neurons grown from patient cells, this was linked to unusually high levels of activity. This type of overactivity may help explain why some patients experience seizures.

One of the biggest findings is that not all CELF2 mutations behave the same way. Why is that so important?

Yang: When we started the project to study CELF2 mutations, we thought they all lead to one disease condition. What we've discovered now suggests that there are actually at least two subgroups.

That matters because accurate diagnosis is the foundation of treatment. If different mutations cause disease through different mechanisms, they may require different therapeutic approaches. For rare diseases especially, that's incredibly important.

Dr. Micheil Innes: This study confirms that knowing which gene is impacted is not enough information for rare disease patients and their families anymore. More precision is required; knowledge on the type of variant guides prognosis and treatment.

Your study also identified a drug pathway that reversed abnormal neuronal activity in patient-derived cells. How significant is that finding?

Hua: It's an exciting finding because it gives us a possible direction for future treatments.

We identified a signalling pathway that hadn't previously been linked to these localization changes. When we targeted that pathway in patient-derived neurons, we were able to reverse the abnormal neuronal hyperactivity that we associate with seizures. This is an important step toward future therapies, but there is still much work to do before these discoveries can be translated into patient care.

Families living with rare diseases often spend years searching for answers. How could these findings help them?

Innes: There are over 7,000 rare genetic diseases known. Patients and families undergo what we recognize now as a long diagnostic odyssey where first a rare genetic condition needs to be suspected then further referral and genetic testing. Once the rare variants are identified, we need to be sure that what we are seeing on the genetic testing fits with the patient’s symptoms, so this study goes a long way to clarifying what to expect with CELF2.

This research involved collaborators around the world. Why was international collaboration so important?

Innes: Over the last 10 years, we’ve realized the importance of global matchmaking to connect clinicians, researchers and patients working on rare diseases. Since our first CELF2 discovery five years ago, there are still less than 30 known patients worldwide. We're sure there are many more who can't access the testing, or their doctors aren’t sure about the relevance of the variants found. We couldn’t have made these discoveries without our international connections.

Looking ahead, what excites you most about this research?

Hua: I think this opens the door to much more research into rare neurodevelopmental disorders and potentially other diseases involving RNA-binding proteins. Most importantly, it moves us one step closer to finding therapies for these patients.

Isabel Clark: Patients with these ultra-rare conditions are finally being recognized. Many now have a diagnosis and a community they can connect with.

Yang: As a basic scientist, it's exciting to discover a new biological mechanism. But what's even more rewarding is knowing that those discoveries may eventually help patients and families.

Innes: Our initial observations in 2021 began with a single patient referred to the Alberta Children’s Hospital. To be able to provide precise diagnoses and prognoses, and soon we hope therapies to patients worldwide is an inspiring reminder that research is care. 

This study fills an important knowledge gap, but it's also just the beginning.