Inherited predisposition to pneumothorax: estimating the frequency of Birt-Hogg-Dubé syndrome from genomics and population cohorts
Disease areas:
cancer and other tissue growths
lungs
Last updated:
Author(s):
Bryndis Yngvadottir, Lucy Richman, Avgi Andreou, Jessica Woodley, Anita Luharia, Derek Lim, Shaheen Akhtar, Mohammad Anwar, Elena Arciero, Omar Asgar, Samina Ashraf, Saeed Bidi, Gerome Breen, James Broster, Raymond Chung, David Collier, Charles J Curtis, Shabana Chaudhary, Megan Clinch, Grainne Colligan, Panos Deloukas, Ceri Durham, Faiza Durrani, Fabiola Eto, Sarah Finer, Joseph Gafton, Ana Angel, Chris Griffiths, Joanne Harvey, Teng Heng, Sam Hodgson, Qin Qin Huang, Matt Hurles, Karen A Hunt, Shapna Hussain, Kamrul Islam, Vivek Iyer, Benjamin M Jacobs, Ahsan Khan, Claudia Langenberg, Cath Lavery, Sang Hyuck Lee, Daniel MacArthur, Sidra Malik, Daniel Malawsky, Hilary Martin, Dan Mason, Rohini Mathur, Mohammed Bodrul Mazid, John McDermott, Caroline Morton, Bill Newman, Elizabeth Owor, Asma Qureshi, Shwetha Ramachandrappa, Mehru Raza, Jessry Russell, Nishat Safa, Miriam Samuel, Michael Simpson, John Solly, Marie Spreckley, Daniel Stow, Michael Taylor, Richard C Trembath, Karen Tricker, David A van Heel, Klaudia Walter, Caroline Winckley, Suzanne Wood, John Wright, Ishevanhu Zengeya, Julia Zöllner, Eamonn R Maher, Stefan J Marciniak
Birt-Hogg-Dubé syndrome (BHDS) is the most common monogenic cause of pneumothorax. Most affected families have pathogenic variants in the FLCN 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 FLCN variants is 1 in 2710 to 4190. While the lifetime risk of pneumothorax in FLCN 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 FLCN mutations.
