First published report of the FLCN c.1222 C > T (p.Gln408Ter) variant in a Chinese family with Birt-Hogg-Dubé syndrome and literature review

BACKGROUND: Birt–Hogg–Dubé syndrome (BHDS) is a rare inherited disorder defined by skin lesions, pulmonary cysts, spontaneous pneumothorax, and renal neoplasia. Mutations in the FLCN gene are known causes, and identifying specific variants in different populations is essential for elucidating genotype-phenotype correlations. METHODS: We investigated a Chinese family with suspected BHDS. The proband was admitted to the Affiliated Cangnan Hospital of Wenzhou Medical University in October 2023. Comprehensive clinical evaluations and imaging studies were performed. Peripheral blood samples were collected from the proband and available family members after obtaining informed consent. Whole-exome sequencing (WES) was conducted to identify potential variants in the FLCN gene. Candidate variants were subsequently validated by Sanger sequencing and analyzed for co-segregation within the family. Pathogenicity was assessed in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. To illustrate the structural impact of the variant, a three-dimensional model of the folliculin protein was generated using SWISS-MODEL and visualized with PyMOL. RESULTS: The proband exhibited bilateral pulmonary cysts, a small left-sided pneumothorax, a left renal mass, and possible cutaneous manifestations. Family evaluation identified pulmonary cysts in multiple children, with pneumothorax in some and a history of lobectomy in two. Genetic testing revealed a heterozygous FLCN nonsense variant, NM_144997.7:c.1222 C > T (p.Gln408Ter), in the proband and one son, while her husband and asymptomatic daughter were noncarriers. This variant meets ACMG criteria for pathogenicity. Structural modeling demonstrated that the premature stop codon truncates folliculin at residue 408, eliminating most of the C-terminal domain and severely compromising protein integrity. Although this variant is listed in ClinVar (RCV001953597) as pathogenic, detailed phenotypic documentation has been limited, and it has not been previously described in Chinese BHDS patients. CONCLUSIONS: We describe, to our knowledge, the first report of the FLCN NM_144997.7:c.1222 C > T (p.Gln408Ter) variant in a Chinese BHDS family and characterize its associated clinical phenotype. These findings extend the known FLCN variant spectrum, enhance population-specific genotype–phenotype understanding, and offer meaningful evidence for clinical diagnosis and genetic counseling.