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Research shows an estimated 1 in 3,000 individuals may carry a genetic variant tied to pneumothorax and RCC—approximately 100 times more than previously estimated.

An estimated 1 in 3,000 individuals may harbor a pathogenic FLCN genetic variant associated with pneumothorax and renal cancer (RCC)—nearly 100 times more than earlier estimates—according to findings published in Thorax.¹

“Although BHDS [Birt-Hogg-Dubé syndrome] has been estimated to affect only 1 in 200,000 people, our analysis of genomic data … suggests that pathogenic FLCN variants are far more common (1 in 2710 to 4190),” Stefan Marciniak, PhD, co-lead of the UK’s Familial Pneumothorax Rare Disease Collaborative Network, and colleagues wrote.¹

The Link Between FLCN, BHDS, Pneumothorax, & RCC

The FLCN gene plays a critical role in maintaining cellular homeostasis and suppressing cancer. Germline mutations in this gene are associated with the autosomal dominant disorder BHDS, recognized as the most common monogenic cause of pneumothorax. BHDS is characterized by the presence of pneumothorax, lung cysts, RCC, renal cysts, and fibrofolliculomas; and patients diagnosed with BHDS face a 37% lifetime risk for pneumothorax and a 32% risk for developing RCC.¹

Methodology & Key Results

To assess the prevalence and penetrance of BHDS, Marciniak and his team analyzed the exomes and genomes of 556,898 individuals from the 100,000 Genomes Project (100kGP), East London Genes & Health (ELGH), and the UK Biobank (UKB). Variants in the FLCN gene region were extracted from sequencing data, annotated, and filtered to prioritize loss of function (LoF) before being reviewed for pathogenicity and class-categorized. Prevalence was calculated separately for each cohort, and age-related risks for carriers of the FLCN mutation were compared between the UKB cohort and a UK clinical series of patients with BHDS.

The analysis identified 155 unrelated individuals harboring 45 distinct pathogenic LoF FLCN variants (Table). After adjusting for potential causes of ascertainment bias, prevalence was calculated by cohort as follows:

• 100kGP: 1 in 2,710 (95% CI, 1,650-4,480)
• UKB: 1 in 4,190 (95% CI, 3,360-5,230)
• ELGH: 1 in 1,490 (95% CI, 680-3,240)

Subsequently, the frequency of pneumothorax and RCC among individuals with a pathogenic LoF FLCN genetic variant in the 100kGP and UKB cohorts was evaluated:

• Pneumothorax
  • 100kGP: 3.1% (1 of 32) had a history of pneumothorax (at age <28 years)
  • UKB: 25.6% (30 of 117) had pneumothorax (median age, 47 years; range, 23-83 years)
• RCC
  • 100kGP: 15.6% (5 of 32; median age, 61 years; range, 25-77 years)
  • UKB: 5.1% (6 of 117; median age, 72 years; range, 46-80 years)

Further calculations compared age-related risks of pneumothorax and RCC in the UKB cohort with those in a UK clinical series of patients with BHDS.

Surprising Findings & Clinical Implications

Notably, although patients diagnosed with BHDS carry a 37% lifetime risk of pneumothorax, the broader UKB cohort of carriers of the FLCN mutation exhibited a lower risk at 28%. Similarly, although BHDS is associated with a 32% risk of developing RCC, the risk in the UKB cohort was observed to be only 1%.²  In a University of Cambridge press release, Marciniak remarked on this discrepancy, noting: “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 study authors emphasized the importance of considering clinical context when managing patients with an FLCN genetic variant, concluding: “The finding that FLCN mutation carriers are much more common than previously supposed should encourage the application of genetic testing for BHDS in individuals with familial or recurrent pneumothorax or familial or multiple RCC, even if a family history or other features of BHDS are absent.”