FLCN – Familial Spontaneous Pneumothorax

Familial spontaneous pneumothorax (FSP) is an autosomal dominant lung disorder characterized by recurrent pneumothoraces and bullous changes in the lung parenchyma. Germline heterozygous variants in the folliculin gene (FLCN) underlie both Birt-Hogg-Dubé syndrome and isolated familial PSP, implicating FLCN as a critical regulator of pulmonary extracellular matrix and pleural integrity in familial spontaneous pneumothorax.

Clinical Validity

The FLCN–familial spontaneous pneumothorax association is classified as Strong based on identification of pathogenic FLCN variants in ≥4 unrelated pedigrees (PMID:15657874;PMID:28839995;PMID:31625278;PMID:31567476), consistent autosomal dominant segregation and concordant functional data.

Genetic Evidence

FSP due to FLCN follows an autosomal dominant inheritance pattern with high penetrance of lung cyst formation and pneumothorax. In a multigenerational Turkish kindred, a truncating mutation c.1273C>T (p.Gln425Ter) (PMID:31625278) co-segregated with PSP in five affected relatives. Across >20 families and >80 affected individuals, variant classes include frameshift, nonsense, splice-site, small indels and intragenic deletions.

Functional / Experimental Evidence

Minigene splicing assays confirmed that noncanonical intronic variants (e.g., c.1300+5G>A) disrupt FLCN RNA processing, leading to exon skipping and protein truncation (PMID:36410626). In promoter deletion studies, FLCN haploinsufficiency in lung cyst tissue demonstrated reduced transcript and protein levels, supporting a loss-of-function mechanism (PMID:26398834).

Conflicting Evidence

No studies to date have refuted the FLCN–FSP link, and no alternative genes have been consistently implicated in familial PSP outside of FLCN in comprehensive screening studies.

Integration & Clinical Utility

Cumulative genetic and functional data provide strong support for routine FLCN testing in patients with familial PSP, guiding surveillance for renal neoplasia. Identification of truncating FLCN variants enables definitive diagnosis, risk stratification, and tailored clinical management.

Key Take-home: Heterozygous loss-of-function FLCN variants cause autosomal dominant familial spontaneous pneumothorax with strong genetic and functional evidence, justifying genetic testing in affected families.

References

• American journal of human genetics • 2005 • A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax PMID:15657874
• Journal of thoracic disease • 2017 • Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax PMID:28839995
• Molecular genetics & genomic medicine • 2019 • A novel FLCN mutation in family members diagnosed with primary spontaneous pneumothorax PMID:31625278
• The Journal of molecular diagnostics : JMD • 2023 • Minigene Assay as an Effective Molecular Diagnostic Strategy in Determining the Pathogenicity of Noncanonical Splice-Site Variants in FLCN PMID:36410626

Evidence Based Scoring (AI generated)