Abstract Rationale Birt-Hogg-Dubé syndrome (BHDS) is caused by FLCN gene mutations and is characterized by fibrofolliculomas, renal tumors, and pulmonary cysts. BHDS research primarily focuses on Caucasians: 80% develop fibrofolliculomas, while Chinese patients predominantly show pulmonary manifestations with less cutaneous/renal involvement. Caucasian BHDS shows FLCN hotspot in Exon11-C8; Japanese study (n = 312) identified other two hotspots in Exon13 and Exon12. The cell landscape of BHD lung and the pathogenesis of lung cycts still remains unknow. This study aims to investigate the clinical features, genetic mutation profiles of BHDS in Chinese populations and clinical revelence of FLCN mutations by comparing Caucasian mutation spectrum with that of Chinese. And we firstly applied Single-cell RNA sequencing (scRNA-seq) in BHD lung tissue, providing a cell portrait, trying to contribute to the illumination of pathogenesis of BHD lung cysts. Methods From 2019 to 2025, 103 patients from 85 unrelated Chinese families with BHDS have been diagnosed in our department by FLCN sequencing, clinical characteristics and radiological presentations. Among 4 of them, scRNA-seq was conducted to their lung cysts tissue obtaind by VATS. Result There were 103 (85 Females, 18 Males) patients diagnosed, the average age was 44.56 years (range: 14-72 y). 40.0% (34/85) probands had a family history of pulmonary bullae or pneumothorax. 70.2% (59/84) probands have experienced dyspnea, and 71.1% (59/83) had spontaneous pneumothorax history. Only 5 patients had skin lesions and only 4 had malignant renal tumor occurred. 72.0% ( 36/50) probands were found to have alveoli in pathological diagnosis. In 91/103 patients, FLCN mutations were identified as likely or confirmed pathogenicity. We identified some unique Chinese mutation hotspots in FLCN that differ from Japanese-reported variants, as well as 20 novel FLCN mutations. Comparative scRNA-seq of BHD and other Rare Cystic Lung Diseases (RCLD) lung tissues revealed a novel, BHD-specific Epi-EMT-like cell population. These aberrant epithelial cells (represented by KRT8) co-expressed mesenchymal markers represented by COL1A1, and exhibited upregulation of the Epithelial-Mesenchymal Transition (EMT), HYPOXIA, and ANGIOGENESIS signaling pathways. Conclusions Our data revealed that Chinese BHD patients showed less frequent cutaneous/renal manifestations but more pulmonary lesions compared with Caucasian cohorts, which may relate to genotypic differences. The scRNA-seq discovery provides a novel cellular mechanism for BHD pathogenesis: we propose that the activation of this EMT program, in the context of BHD, primarily drives cyst formation by compromising epithelial integrity—a finding that corroborates previous reports of epithelial adhesion defects in BHD—rather than inducing canonical fibrosis. This abstract is funded by: the Natural Science Foundation of Guangdong Province (2023A1515010308), the Project of 2022 Student Innovation Ability Enhancement Program of Guangzhou Medical University (02-408-2203-2106), Guangdong Province 2022 Graduate Education Innovation Plan project(2022ANLK049).
Jie et al. (Fri,) studied this question.
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