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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 teams 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 –CCorring to Findings Published in Thorax.1
“Although BHDS (Birt-Hogg-Dubé Syndrome) has be esteimed to affect Only 1 in 200,000 PeopleOur Analysis of Genomic Data… Suggests That Pathogenic FLCN Variants Are Far More Common (1 in 2710 to 4190), ” Stefan Marciniak, PhDco-head of the uk’s FAMILIAL PNEUMOTHORAX RARE DISEASE COLBRABATIVE NETWORKand colleagues wrote.1
The Link Between FLCNBHDS, Pneumothorax, & RCC
The FLCN Plays genes the critical roller in maintaining cellullar homeostasis and suppressing cancer. Germline mutations in this gene are associated with the autosomal dominant disorder BHDS, recognized as the most common monogenic caus of pneumothorax. BHDS IS CHARACTERIZED BY THE PRESS OF PNEUMOTHORAX, LUNG CYSTS, RCC, RENAL CYSTS, AND FIBROFOLLICULOMAS; AND PATENTS DIAGNOSED with BHDS FACE TO 37% LIFETIME RISK FOR PNEUMOTHORAX AND A 32% RISK FOR DEVELOPING RCC.1
Methodology & Key Results
To assess the prevalence and penetration of bhds, Marciniak and His Team Analyzed the Exacts and Genomes of 556,898 Individuals from the 100,000 Genomes Project (100kgp), East London Genes & Health (Elgh), and the UK BOBANK (UKB). Variants in the FLCN Gene Region Were Extracted from Sequrancing Data, Annotated, and Filtered to Prioritize Loss of Function (Lof) Before Being Review for Pathogenicity and Class-Categorized. Prevalence was Calculated Separaly for Each Cohort, and Age-Relaced Risks for Carriers of the FLCN Mutation Were Compreded 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)
- CCR
- 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-REFLATED RISKS OF PNEUMOTHORAX AND RCC IN THE UKB COHORT WITH TOSE IN A UK Clinical Series of Patients with BHDS.
Surprising Findings & Clinical Implications
Notably, Although Patients Diagnosed with BHDS Carry at 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 ReleaseMarciniak Remarked on this Discredency, 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 Is Broken in the Wider Population. There 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 Pats 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 Recurent Pneumothorax or Familial Or Multiple RCC, Even IF A Family History or other Features of BHDS Are Absent. ”
