Clinical Characteristics and Genetic Analysis of a Chinese Family with Birt–Hogg–Dubé Syndrome Harboring a Novel FLCN Gene Mutation

Background Birt–Hogg–Dubé syndrome (BHDS) is a rare hereditary disorder characterized by skin lesions, pulmonary cysts, spontaneous pneumothorax, and renal neoplasia. Mutations in the FLCN gene are known causes, yet novel variants continue to be identified, expanding 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 using multiple bioinformatic prediction tools in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. To evaluate 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 presented with bilateral pulmonary cysts, a small left-sided pneumothorax, a left renal tumor, and suspected cutaneous lesions. Family screening revealed that several children had pulmonary cysts, some accompanied by pneumothorax, and two had previously undergone lobectomy. Whole-exome sequencing identified a novel heterozygous nonsense mutation in exon 11 of FLCN, c.1222C > T (p.Gln408Ter), which has not been previously reported. This mutation was also detected in one of the proband’s sons, while the proband’s husband and an asymptomatic daughter were wild type at this locus. Functional prediction indicates a loss of normal folliculin activity. Based on ACMG guidelines, the variant is classified as pathogenic. Conclusions The novel FLCN nonsense variant c .1222C > T (p.Gln408Ter) is the likely genetic basis of BHDS in this family. These findings expand the mutational spectrum of FLCN , inform genotype–phenotype relationships, and support improved diagnosis and genetic counseling of BHDS.