One in 3,000 people at risk of punctured lung from faulty gene – almost 100 times higher than previous estimate

(Press-News.org) As many as one in 3,000 people could be carrying a faulty gene that significantly increases their risk of a punctured lung, according to new estimates from Cambridge researchers. Previous estimates had put this risk closer to one in 200,000 people.

The gene in question, FLCN, is linked to a condition known as Birt-Hogg-Dubé syndrome, symptoms of which include benign skin tumours, lung cysts, and an increased risk of kidney cancer.

In a study published today in the journal Thorax, a team from the University of Cambridge examined data from UK Biobank, the 100,000 Genomes Project, and East London Genes & Health – three large genomic datasets encompassing more than 550,000 people.

They discovered that between one in 2,710 and one in 4,190 individuals carries the particular variant of FLCN that underlies Birt-Hogg-Dubé syndrome. But curiously, whereas patients with a diagnosis of Birt-Hogg-Dubé syndrome have a lifetime risk of punctured lung of 37%, in the wider cohort of carriers of the genetic mutation this was lower at 28%. Even more striking, while patients with Birt-Hogg-Dubé syndrome have a 32% of developing kidney cancer, in the wider cohort this was only 1%.

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.

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 optimise the care and treatment of patients with rare, inherited forms of familial pneumothorax, and to support research into this condition. 

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 tumour it should still be early enough to cure it.”

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.”

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.”

The research was funded by the Myrovlytis Trust, with additional support from the National Institute for Health and Care Research Cambridge Biomedical Research Centre.

Reference

Yngvadottir, B et al. Inherited predisposition to pneumothorax: Estimating the frequency of Birt-Hogg-Dubé syndrome from genomics and population cohorts. Thorax; 8 April 2025; DOI: 10.1136/thorax-2024-221738

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