Genetic link to pneumothorax: Estimating BHD rates using UK Biobank

New research funded by the Myrovlytis Trust into the number of people with the genetic variation associated with BHD syndrome shows that many more people than originally thought have a risk of developing a punctured lung or features of BHD syndrome.

In this special blog for National DNA Day 2025, we break down the new research and explain what it means for the BHD patient community.

What is BHD syndrome?

Birt-Hogg-Dubé syndrome (BHD) is a rare genetic condition which can affect the skin, lungs and kidneys. Features of BHD include:

• Skin bumps (known as fibrofolliculomas)
• Lung cysts
• Punctured lung (known as a pneumothorax)
• Kidney cysts and an increased risk of developing kidney cancer. Up to 1 in 3 patients can develop kidney cancer.

What is this study about?

BHD is genetic and is linked to a genetic variation in the folliculin gene (FLCN gene). Folliculin is involved in stopping tumour growth in the body. In BHD, tumour growth is not effectively controlled which leads to cysts and tumours growing on the skin, in lungs, and kidneys. Punctured lungs are often a feature of people who have BHD. Punctured lungs are medically known as a pneumothorax.

What is a pneumothorax?

“A pneumothorax (punctured lung) happens when there’s air in the space between your chest wall and your lung (pleural space). Air in the pleural space can build up and press against your lung, causing it to partially or fully collapse.” – Cleveland Clinic, 2025

This study aimed to calculate the estimated amount of people with the FLCN genetic variant associated with BHD in the general population of the UK. This was done using genetic information from ‘biobanks’. These biobanks hold genetic information from UK residents.  

Why was this study done?

To understand this condition better, it is important to know how many people may live with BHD. For people with BHD, an accurate diagnosis means they can access potentially lifesaving kidney cancer screening.

Currently the rate of people with BHD is quoted as affecting 600 families worldwide. This figure is considered far too low, and researchers wanted to gain a better estimate of BHD populations.

What did the researchers do?

The researchers looked at the DNA profiles of over 550,000 people from the UK.

The biobanks used were the:

• 100,000 Genomes Project
• UK Biobank
• East London Genes and Health biobank.

They looked at how many people in these biobanks had a variation in the FLCN gene associated with BHD syndrome.

What do genes do?

Genes provide information for making proteins in the body which are needed for biological functions. When there is a variation in a gene, this information is disrupted. This reduces or eliminates gene function and can result in health conditions. The effect of a genetic variation can be very mild or severe disability.

The researchers looked at the following information from the biobanks:

• They identified loss of function variations in the genetic information (DNA), such as in the FLCN gene. A loss of function variation is a change in the gene which affects how well the gene works. In BHD, the FLCN gene is affected by a loss of function variation.
• They checked whether each genetic variation they found was likely to cause disease. This was done based on UK clinical guidelines. 

• They also calculated how common these genetic variations were in each biobank population. 

• Finally, they compared age-related risk of health issues between people in the general population with FLCN mutations and patients diagnosed with BHD in clinical settings. Age-related risk refers to the increased chance of having certain health issues that are tied to ageing.
• The BHD patient group included 128 carriers of the FLCN genetic variation from 43 families. 

What did the researchers find?

• A total of 155 individuals across the three biobanks studied had 45 different disease-causing FLCN variations.
• The estimated number of people with the FLCN genetic variations linked to BHD syndrome is between 1 in 2710 and 1 in 4190. This is a lot higher than previously thought.
• The researchers looked at lifetime risk of punctured lung in people with the FLCN variation. Over their lifetime, the risk of punctured lung was different in the people in the UK general population and the BHD patient group.
• The risk of developing a punctured lung during their lifetime was 28.4% in the UK general population group and 37.3% in the BHD syndrome patient group. This means that people with BHD syndrome are slightly more likely to develop a punctured lung than the general UK population.
• The risk of developing kidney cancer was lower in the UK general population group than the BHD patient group.
• In the UK general population group, the risk of developing kidney cancer was only 1%. The BHD patient group had 32.1% risk of developing kidney cancer. This means that BHD patients are much more likely to develop kidney cancer than the general population.
• The risks calculated were statistically significant. This means that they are a reliable source of information about the risks of developing kidney cancer in both the UK general population and in the BHD syndrome patient group.

Why is there a difference between the number of those with the genetic FLCN variant and number of those diagnosed with BHD?

This difference could mean that there is something else which affects the FLCN gene in order for BHD to develop and be medically diagnosed. This could be something in the environment, or another gene which influences how the FLCN gene expresses itself. More research would need to be done to understand this connection.

Why is there such a difference in the risk of developing kidney cancer?

In the UK general population there are no routine kidney scans given, unless a problem arises. Kidney cancer is often symptomless and detected with a scan. In diagnosed BHD patients, yearly to two-yearly kidney scans are recommended to check for kidney cancer. These results could partially be explained by the lack of monitoring in UK general population. More of the UK general population could have hereditary kidney cancers, but this isn’t being detected by doctors.

Were there any limitations in this study?

Limitations are things that limit how reliable a research study is. There are nearly always limitations in research studies, and it is important to note them. In this study there are several limitations to consider.

1. Researchers excluded related people in the study populations
2. They focused only on ‘strong loss of function’ variations in the FLCN gene. A ‘strong loss of function’ means the gene is likely to be part of the cause of the health conditions the person experiences. This means that those people in the UK population group were excluded from the study if they had only small variation in how the FLCN gene expressed itself.
3. In this study there was no information on the how many people had the BHD-related skin bumps (known as fibrofolliculomas) or lung cysts. This means the rate of these BHD-related symptoms in the study populations are unknown.

What do these findings mean for me and my family?

Since FLCN mutations are more common than previously thought, genetic testing for BHD should be considered for people with more than one punctured lung and if this runs their family history. This should also be considered in multiple or familial kidney cancers. This should be done even if people do not show other typical signs of BHD. More long-term studies are needed to better guide how to care for people with these genetic variations when they are found outside of a clinical diagnosis of BHD.

How can this research help the BHD patient community?

This research raises awareness of the amount of people that may develop BHD as a lot more than originally thought. It can also help researchers understand more about the FLCN gene and what happens when there is a variation in this gene.

It will help medical professionals to learn that BHD is more common and to think about testing for BHD when a patient presents with repeated or familial punctured lung. It could also improve treatment and research into managing BHD.

The ERN-GENTURIS European clinical guidelines for when to suspect BHD and send for testing can help when BHD is suspected in a patient. You can read more about these clinical guidelines here (link to our blog and the patient friendly version of the guidelines).

You can read the original research paper this blog is about here https://thorax.bmj.com/content/early/2025/04/10/thorax-2024-221738.long  

References

Yngvadottir B, Richman L, Andreou A, Woodley J, Luharia A, Lim D; Genes & Health Research Team; Maher ER, Marciniak SJ. Inherited predisposition to pneumothorax: estimating the frequency of Birt-Hogg-Dubé syndrome from genomics and population cohorts. Thorax. 2025 Apr 10:thorax-2024-221738. doi: 10.1136/thorax-2024-221738. Epub ahead of print. PMID: 40210444.

Team B, 20 PM. Loss of function mutation: Consequences for genes and health [Internet]. 2025 [cited 2025 Apr 24]. Available from: https://biologyinsights.com/loss-of-function-mutation-consequences-for-genes-and-health/  

 Pneumothorax (collapsed lung) [Internet]. 2025 [cited 2025 Apr 24]. Available from: https://my.clevelandclinic.org/health/diseases/15304-collapsed-lung-pneumothorax