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

Abstract

Birt-Hogg-Dubé syndrome (BHDS) is the most common monogenic cause of pneumothorax. Most affected families have pathogenic variants in the <i>FLCN</i> 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 <i>FLCN</i> variants is 1 in 2710 to 4190. While the lifetime risk of pneumothorax in <i>FLCN</i> 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 <i>FLCN</i> mutations.