Two novel genetic variants in WFDC2 gene from patients with bronchiectasis

Background Bronchiectasis is a chronic respiratory condition characterized by irreversible dilation and damage of the bronchial walls, leading to impaired mucociliary clearance and recurrent infections. Its etiology is diverse; however, genetic factors are critical in its congenital and severe forms. Therefore, we aimed to identify two novel variants of the WFDC2 gene, known as antiprotease, from patients with bronchiectasis and/or related phenotypes using trio-based whole-genome sequencing analysis. Methods Patients with bronchiectasis were recruited as trio or quad, and their genomic DNA was isolated. The whole genome sequence was produced and analyzed to find causative genetic variants through an internal pipeline using GATK-DARGEN-Hail. Variant interpretation and pathogenicity assessment using various in-silico tools were performed to identify causative variants. Clinical characteristics were collected from patients with identified variants. Results In the discovery study involving four patients from three families, two novel variants in the WFDC2 gene were identified and suggested as causative pathogenic variants for bronchiectasis. The first variant (c.291C > G, p.Cys97Trp) is a homozygous variant that was not found in the population genome data. However, the second variant (c.278G > C, p.Cys93Ser) was identified in another patient as a heterozygous variant, forming a compound heterozygous state with the first variant. Notably, both variants, located at cysteine residues that are conserved across many species, are crucial in forming disulfide bonds essential for protein structure and function. In-silico analyses classified both variants as pathogenic, and they were identified as likely pathogenic according to American College of Medical Genetics and Genomic guidelines. Furthermore, in an expansion study, the homozygous variant was also found in two unrelated patients. Conclusion We identified two novel bi-allelic variants located at cysteine residues in the WFDC2 gene from patients with bronchiectasis who had previously not received a genetic diagnosis. Therefore, considering prior research on the pivotal role of the WFDC2 protein in the respiratory system, these two novel variants may serve as potential diagnostic markers and therapeutic targets for bronchiectasis.