Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis

Background: Defective airway host-defense (e.g., altered mucus properties, ciliary defects) contributes to the pathogenesis of bronchiectasis. This study aims to determine whether genetic mutations associated with defective airway host-defense are implicated in the pathogenesis of bronchiectasis.

Methods: Based on the systematic screening of 32 frequently reported bronchiectasis-associated genes, we performed next-generation sequencing (NGS) on peripheral blood samples from 192 bronchiectasis patients and 100 healthy subjects. The variant distribution frequency and pathogenicity of mutations were analyzed.

Results: We identified 162 rare variants in 192 bronchiectasis patients, and 85 rare variants among 100 healthy subjects. Among bronchiectasis patients, 25 (15.4%), 117 (72.2%) and 18 (11.1%) rare variants were associated with cystic fibrosis transmembrane receptor (CFTR), epithelial sodium channel, and primary ciliary dyskinesia genes, respectively. Biallelic CFTR variants were detected in four bronchiectasis patients but none of the healthy subjects. Carriers of homozygous p.M470 plus at least one CFTR rare variant were detected in 6.3% of bronchiectasis patients (n=12) and in 1.0% of healthy subjects (n=1, P=0.039). Twenty-six patients (16 with idiopathic and 6 with post-infectious bronchiectasis) harbored biallelic variants. Bronchiectasis patients with biallelic DNAH5 variants, or biallelic CFTR variants plus an epithelial sodium channel variant, tended to have greater disease severity.

Conclusions: Genetic mutations leading to impaired host-defense might have implicated in the pathogenesis of bronchiectasis. Genetic screening may be a useful tool for unraveling the underlying causes of bronchiectasis, and offers molecular information which is complementary to conventional etiologic assessment for bronchiectasis.