The role of CFTR/ENaC genotype in cystic fibrosis-like phenotypes

Background In patients with cystic fibrosis (CF)-like phenotypes, establishing the CFTR genotype and confirming the diagnosis is challenging. Mutation in both ENaC and CFTR genes can lead to deficient ENaC/CFTR channel interaction and CF lung disease or bronchiectasis. Aim of this study was to investigate the relationship between CFTR/ENaC genotype and channels functionality in patients with questionable CF. Methods Fifty patients (26 F, 24 M, 7-36 years) with CF-like symptoms and inconclusive diagnosis were investigated by sweat test (ST), nasal potential difference (NPD) measurement and extensive analysis of CFTR (sequencing + MLPA) and ENaC (sequencing) genes. Results According to genotypes, ST and NPD results (testing ENaC and CFTR function), patients were classified as: CF unlikely without ENaC-hyperactivity (n=24), CF unlikely with ENaC-hyperactivity (n=7), ENaC-related disorder independent of CFTR mutations/dysfunction (n=6), CFTR-related disorder (n=5), PS-CF (n=4) and PI-CF (n=4). Conclusions This study provides evidence that ENaC plays an important role in the pathophysiology of CF-like phenotypes. Patients with ENaC–related disorder or transheterozygosity for ENaC/CFTR mutations seem to be underestimated cases with CF or CF-like phenotypes, implying the need of a differentiated CF diagnostic guidelines update. Supported by Polish National Science Centre, an ERS Longterm Fellowship and Wescor.