The founder missense mutation of WFDC2 in Koreans leads to severe respiratory distress accompanied by bronchiectasis and rhinosinusitis

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ABSTRACT Background Chronic airway diseases like cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) pose substantial clinical challenges. This study explores the p.C97W variant in WFDC2 , proposed as a new genetic origin of respiratory distress, especially among Koreans. Methods Whole-exome/genome sequencing (WES/WGS) were performed on 64 patients from 62 families presenting with severe bronchiectasis and chronic rhinosinusitis. In vitro analyses and protein modeling were utilized to evaluate the functional implications of the WFDC2 variant. Results Pathogenic variants were found in 11.3% of families, including a novel homozygous WFDC2 missense variant (c.291C>G, p.Cys97Trp) in five unrelated families, confirmed by Sanger sequencing. The variant, rare globally but more frequent in Koreans, caused persistent wet cough, chronic rhinosinusitis, and bronchiectasis in affected patients. Lung tissue pathology showed chronic inflammation and interstitial fibrosis. The p.C97W variant impaired WFDC2 protein folding, secretion, and function. Conclusions The p.C97W variant in WFDC2 is a critical genetic factor in severe chronic airway disease that shares clinical features with CF and PCD. Given its implications for diagnosis and treatment, genetic testing for WFDC2 mutations in individuals with CF or PCD-like symptoms is recommended.

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