AbstractBackgroundClinical phenotype varies among cystic fibrosis (CF) patients with identical CF transmembrane conductance regulator (CFTR)genotype, suggesting that genetic modifiers exist. Transgenic mice that overexpress SCNN1β present CF-like lung disease symptoms. Mutations or variants in SCNN1β may therefore potentially modulate the clinical phenotype in CF patients.MethodsWe analysed by DHPLC SCNN1β and SCNN1γ genes in 56 patients with classical CF. Patients were classified into two groups according to their CFTR genotype and their severity: 38 patients with severe genotype and an unexpectedly mild lung phenotype, and 18 patients with mild genotype and a severe lung phenotype.ResultsWe found 3 patients out of 56 carrying at least one missense mutation. Two were novel (p.Thr313Met in SCNN1β, p.Leu481Gln in SCNN1γ) and two were previously described (p.Gly589Ser in SCNN1β and p.Val546Ileu in SCNNγ). p.Thr313Met has been identified in a CF patient with mild genotype and severe lung phenotype suggesting that it could act in increasing ENaC activity. The three other variants have been identified in CF patients with severe genotype and mild lung phenotype suggesting that they might decrease ENaC activity. However, the function of ENaC in the nasal epithelia of these patients, evaluated by nasal potential difference measurements, did not support the fact that these variants were functional, at least in nasal epithelium.ConclusionOur results suggest that genetic variants in ENaCβ and γ genes do not modulate disease severity in the majority of CF patients.