Inherited predisposition to pneumothorax: estimating the frequency of Birt-Hogg-Dubé syndrome from genomics and population cohorts

Bryndis Yngvadottir; Lucy Richman; Avgi Andreou; Jessica Woodley; Anita Luharia; Derek Lim; Genes & Health Research Team; Eamonn R Maher; Stefan J Marciniak

doi:10.1136/thorax-2024-221738

Inherited predisposition to pneumothorax: estimating the frequency of Birt-Hogg-Dubé syndrome from genomics and population cohorts

Bryndis Yngvadottir, Lucy Richman, Avgi Andreou, Jessica Woodley, Anita Luharia, Derek Lim, Genes & Health Research Team, Eamonn R Maher, Stefan J Marciniak

Research output: Contribution to journal › Article › peer-review

Abstract

Birt-Hogg-Dubé syndrome (BHDS) is the most common monogenic cause of pneumothorax. Most affected families have pathogenic variants in the gene. Using large genomic registries (UK Biobank (UKB), 100,000 Genomes Project and East London Genes & Health) including >550 000 individuals, we demonstrate that the frequency of clinically validated loss-of-function variants is 1 in 2710 to 4190. While the lifetime risk of pneumothorax in mutation carriers in the UKB and a BHDS clinical cohort was substantial (28.4% and 37.3%, respectively, to age 65 years), the lifetime risk of renal cancer was significantly lower in UKB than in BHDS patients (1% vs 32.1%). These findings highlight the importance of clinical context in managing individuals with mutations.

Original language	English
Article number	e221738
Number of pages	3
Journal	Thorax
Early online date	10 Apr 2025
DOIs	https://doi.org/10.1136/thorax-2024-221738
Publication status	E-pub ahead of print - 10 Apr 2025

Bibliographical note

Copyright © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. https://creativecommons.org/licenses/by-nc/4.0/

Data Access Statement

100kGP: Research on the de-identified patient data used in this publication can be carried out in the Genomics England Research Environment subject to a collaborative agreement that adheres to patient led governance. All interested readers will be able to access the data in the same manner that the authors accessed the data. For more information about accessing the data, interested readers may contact [email protected] or access the relevant information on the Genomics England website: https://www.genomicsengland.co.uk/research. UKB: Data from UK Biobank is available on application from https://www.ukbiobank.ac.uk/ All researchers who wish to access the research resource must register with UK Biobank by completing the registration form in the Access Management System (AMS). https://www.ukbiobank.ac.uk/ enable-your-research/register ELGH: The VCF data (accession number EGAD00001005469) is available from the EBI-EGA genotype phenotype archive (www.ebi.ac.uk/ega). Users need to complete the standard Wellcome Sanger Institute Data Access Agreement.

Keywords

Pleural Disease

Access to Document

10.1136/thorax-2024-221738Licence: CC BY-NC 4.0

Inherited predisposition to pneumothorax
Copyright © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. https://creativecommons.org/licenses/by-nc/4.0/
Final published version, 469 KBLicence: CC BY-NC 4.0

Cite this

Yngvadottir, B., Richman, L., Andreou, A., Woodley, J., Luharia, A., Lim, D., Research Team, G. . H., Maher, E. R., & Marciniak, S. J. (2025). Inherited predisposition to pneumothorax: estimating the frequency of Birt-Hogg-Dubé syndrome from genomics and population cohorts. Thorax, Article e221738. Advance online publication. https://doi.org/10.1136/thorax-2024-221738

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abstract = "Birt-Hogg-Dub{\'e} syndrome (BHDS) is the most common monogenic cause of pneumothorax. Most affected families have pathogenic variants in the gene. Using large genomic registries (UK Biobank (UKB), 100,000 Genomes Project and East London Genes & Health) including >550 000 individuals, we demonstrate that the frequency of clinically validated loss-of-function variants is 1 in 2710 to 4190. While the lifetime risk of pneumothorax in mutation carriers in the UKB and a BHDS clinical cohort was substantial (28.4% and 37.3%, respectively, to age 65 years), the lifetime risk of renal cancer was significantly lower in UKB than in BHDS patients (1% vs 32.1%). These findings highlight the importance of clinical context in managing individuals with mutations.",

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AU - Andreou, Avgi

AU - Woodley, Jessica

AU - Luharia, Anita

AU - Lim, Derek

AU - Research Team, Genes & Health

AU - Maher, Eamonn R

AU - Marciniak, Stefan J

N1 - Copyright © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. https://creativecommons.org/licenses/by-nc/4.0/

PY - 2025/4/10

Y1 - 2025/4/10

N2 - Birt-Hogg-Dubé syndrome (BHDS) is the most common monogenic cause of pneumothorax. Most affected families have pathogenic variants in the gene. Using large genomic registries (UK Biobank (UKB), 100,000 Genomes Project and East London Genes & Health) including >550 000 individuals, we demonstrate that the frequency of clinically validated loss-of-function variants is 1 in 2710 to 4190. While the lifetime risk of pneumothorax in mutation carriers in the UKB and a BHDS clinical cohort was substantial (28.4% and 37.3%, respectively, to age 65 years), the lifetime risk of renal cancer was significantly lower in UKB than in BHDS patients (1% vs 32.1%). These findings highlight the importance of clinical context in managing individuals with mutations.

AB - Birt-Hogg-Dubé syndrome (BHDS) is the most common monogenic cause of pneumothorax. Most affected families have pathogenic variants in the gene. Using large genomic registries (UK Biobank (UKB), 100,000 Genomes Project and East London Genes & Health) including >550 000 individuals, we demonstrate that the frequency of clinically validated loss-of-function variants is 1 in 2710 to 4190. While the lifetime risk of pneumothorax in mutation carriers in the UKB and a BHDS clinical cohort was substantial (28.4% and 37.3%, respectively, to age 65 years), the lifetime risk of renal cancer was significantly lower in UKB than in BHDS patients (1% vs 32.1%). These findings highlight the importance of clinical context in managing individuals with mutations.

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Inherited predisposition to pneumothorax: estimating the frequency of Birt-Hogg-Dubé syndrome from genomics and population cohorts

Abstract

Bibliographical note

Data Access Statement

Keywords

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