Cure4CF Update
Rare Genetic Mutations in Cystic Fibrosis – Why They Matter More Than You Think
Professor Jodie Simpson, Head of Research, Cure4CF
Cystic fibrosis (CF) is what’s called an autosomal recessive condition. That means a person needs to inherit two faulty copies of the CF gene (one from each parent) to develop CF.
If you only inherit one faulty copy, you’re a carrier. Carriers don’t have CF, but new research suggests having one faulty copy may still have some health impacts (that’s a story for another day!).
Here’s the surprising part: scientists have identified over 2,000 different mutations of the CF gene, and not all behave the same way. Some are very common, while others are so rare that only a handful of people worldwide carry them. Find out more here.
Not all mutations are created equal
The most common CF mutation is called F508del. About 90% of people with CF in Australia carry it.
Treatments like Orkambi and Trikafta (CFTR modulator therapies) were designed with F508del in mind. Early modulator treatments like Orkambi were first approved for people with two copies of F508del (called “homozygous”). As research has progressed and new combinations have been tested, approval was expanded to include people with just one copy (heterozygous) of the F508del mutation. Of course, these medicines are not yet available in some countries, and many people continue to go without these therapies
But what happens if you don’t have a F508del mutation?
What if your mutations are so rare that they weren’t included in clinical trials?
For a long time, this meant you couldn’t access modulator therapies. Thankfully, new rules and research now allow more people with rare mutations to try modulators—if lab testing shows they’re likely to respond.
However, not all mutations respond. For example, those with two “Class I” mutations still don’t benefit from current modulator therapy.
Living with a rare mutation
For people with rare mutations, it can feel like being left behind. While others gain access to life-changing treatments, they’re still waiting.
Because patient numbers are so small, traditional clinical trials aren’t always possible. Research must get creative.
How science is adapting
One breakthrough is the use of organoids—tiny, lab-grown versions of a patient’s own tissues. Scientists can test different modulators on these organoids to see if chloride transport improves (that’s the core defect in CF).
If the drug works in the dish, it’s a good sign it may help the person too. This personalised approach has already brought new hope to people once thought “untreatable.”
Why rare mutations matter to everyone
It might seem like rare mutations only affect a small group, but progress here often drives scientific innovation for all.
Take gene therapy. People with rare, non-responsive mutations may be the very first to benefit. If it works, it could pave the way for cures that help everyone with CF—and even other genetic conditions.
Think about how quickly the COVID-19 vaccine was developed once the technology and resources were in place. Advances for rare CF mutations could spark the same kind of leap forward.
The human side
Behind every “rare mutation” is a real person, a family, a community. While we celebrate the success of modulators like Trikafta, we must also keep sight of those still waiting.
CF is often invisible, but people with rare mutations shouldn’t feel invisible in the journey toward better treatments. This is about fairness, equity, and hope.
Looking ahead
The story of rare CF mutations is really the story of precision medicine—tailoring treatment to the individual. The future won’t be one-size-fits-all. It will be about what works for your specific mutation, whether that’s a modulator, organoid-guided therapy, or gene therapy.
So next time you hear about “rare mutations,” remember they’re not just scientific curiosities. They’re part of the bigger CF story—and progress only counts when it includes everyone.
What you can do:
- Support funding for CF research
- Advocate for equal access to therapies
- Help spread awareness about rare mutations
Every voice brings us closer to making sure no one is left behind.