A gene once believed to be extremely rare may actually be surprisingly common—and capable of quietly raising the risk of serious health issues.
New research from Cambridge scientists shows that as many as one in 3,000 people carry a faulty version of the FLCN gene, which is linked to a condition called Birt-Hogg-Dubé syndrome. This disorder can lead to collapsed lungs, lung cysts, skin growths, and kidney cancer. But here’s the twist: while people formally diagnosed with the syndrome face significant risks, those who carry the mutation without a diagnosis appear to be far less affected.
The FLCN Gene and Birt-Hogg-Dubé Syndrome
As many as one in 3,000 people may carry a faulty gene that raises their risk of a punctured lung, according to new research from the University of Cambridge. That’s nearly 100 times more common than previous estimates, which put the number closer to one in 200,000.
The gene, known as FLCN, is associated with a rare condition called Birt-Hogg-Dubé syndrome. This syndrome can cause benign skin tumors, lung cysts, and an increased risk of kidney cancer.
Massive Genomic Datasets Reveal New Prevalence
In a study published today (April 8) in the journal Thorax, researchers analyzed data from over 550,000 people using three major genomic databases: UK Biobank, the 100,000 Genomes Project, and East London Genes & Health.
They found that between 1 in 2,710 and 1 in 4,190 individuals carry the FLCN gene variant linked to Birt-Hogg-Dubé syndrome. Surprisingly, not all gene carriers faced the same level of risk. Among people formally diagnosed with the syndrome, the lifetime risk of a punctured lung was 37%. But in the broader group of carriers, the risk dropped to 28%. The contrast was even greater for kidney cancer: 32% of diagnosed patients developed it, compared to just 1% of carriers in the wider cohort.
Not All Pneumothoraxes Are Genetic
Punctured lung – known as pneumothorax – is caused by an air leak in the lung, resulting in painful lung deflation and shortness of breath. Not every case of punctured lung is caused by a fault in the FLCN gene, however. Around one in 200 tall, thin young men in their teens or early twenties will experience a punctured lung, and for many of them the condition will resolve itself, or doctors will remove air or fluid from their lungs while treating the individual as an outpatient; many will not even know they have the condition.
If an individual experiences a punctured lung and doesn’t fit the common characteristics – for example, if they are in their forties – doctors will look for tell-tale cysts in the lower lungs, visible on an MRI scan. If these are present, then the individual is likely to have Birt-Hogg-Dubé syndrome.
A Nationwide Push to Understand Rare Lung Conditions
Professor Marciniak is a researcher at the University of Cambridge and an honorary consultant at Cambridge University Hospitals NHS Foundation Trust and Royal Papworth Hospital NHS Foundation Trust. He co-leads the UK’s first Familial Pneumothorax Rare Disease Collaborative Network, together with Professor Kevin Blyth at Queen Elizabeth University Hospital and University of Glasgow. The aim of the Network is to optimize the care and treatment of patients with rare, inherited forms of familial pneumothorax, and to support research into this condition.
Catching Cancer Early Through Genetic Clues
Professor Marciniak said: “If an individual has Birt-Hogg-Dubé syndrome, then it’s very important that we’re able to diagnose it, because they and their family members may also be at risk of kidney cancer.
“The good news is that the punctured lung usually happens 10 to 20 years before the individual shows symptoms of kidney cancer, so we can keep an eye on them, screen them every year, and if we see the tumor it should still be early enough to cure it.”
A Mystery in the Genetics
Professor Marciniak says he was surprised to discover that the risk of kidney cancer was so much lower in carriers of the faulty FLCN gene who have not been diagnosed with Birt-Hogg-Dubé syndrome.
“Even though we’ve always thought of Birt-Hogg-Dubé syndrome as being caused by a single faulty gene, there’s clearly something else going on,” Professor Marciniak said. “The Birt-Hogg-Dubé patients that we’ve been caring for and studying for the past couple of decades are not representative of when this gene is broken in the wider population. There must be something else about their genetic background that’s interacting with the gene to cause the additional symptoms.”
Rethinking Screening for Carriers
The finding raises the question of whether, if an individual is found to have a fault FLCN gene, they should be offered screening for kidney cancer. However, Professor Marciniak does not believe this will be necessary.
“With increasing use of genetic testing, we will undoubtedly find more people with these mutations,” he said, “but unless we see the other tell-tale signs of Birt-Hogg-Dubé syndrome, our study shows there’s no reason to believe they’ll have the same elevated cancer risk.”
Reference: “Inherited predisposition to pneumothorax: estimating the frequency of Birt-Hogg-Dubé syndrome from genomics and population cohorts” by Bryndis Yngvadottir, Lucy Richman, Avgi Andreou, Jessica Woodley, Anita Luharia, Derek Lim, Genes & Health Research Team, Eamonn R Maher and Stefan J Marciniak, 10 April 2025, Thorax.
DOI: 10.1136/thorax-2024-221738
The research was funded by the Myrovlytis Trust, with additional support from the National Institute for Health and Care Research Cambridge Biomedical Research Centre.
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