Which SCN (epithelial sodium channel) gene mutations are associated with bronchiectasis?

SCN Mutations Associated with Bronchiectasis

Epithelial sodium channel (ENaC) gene mutations, particularly in SCNN1A, SCNN1B, and SCNN1G, have been identified in patients with bronchiectasis and may contribute to disease pathogenesis through impaired airway surface hydration, especially when combined with CFTR variants.

Specific ENaC Gene Mutations Identified

SCNN1B (ENaC β-subunit) Mutations

• p.Ser82Cys was found in 3 unrelated bronchiectasis patients, notably all were also heterozygous for CFTR mutations or variants (F508del, IVS8-5T), suggesting a trans-heterozygote mechanism 1
• p.Pro369Thr was identified in patients with idiopathic bronchiectasis 1
• p.Asn288Ser was detected in bronchiectasis patients without identifiable CFTR mutations 1

SCNN1G (ENaC γ-subunit) Mutations

• p.Gly183Ser was found in single patients with bronchiectasis 1
• p.Glu197Lys was identified in 2 patients with bronchiectasis 1

SCNN1A (ENaC α-subunit) Mutations

• p.V114I and p.F61L may explain CF-like disease through a Mendelian mechanism 2
• p.W493R shows a significantly higher incidence in bronchiectasis patients (OR 2.7) and results in four-fold increased ENaC channel activity when expressed in oocytes, representing a gain-of-function mutation 2
• c.-55+5G>C variant shows markedly increased frequency in patients versus controls (OR 13.5) 2

Pathophysiologic Mechanism

ENaC mutations cause bronchiectasis through excessive sodium absorption leading to airway surface dehydration:

• ENaC normally regulates epithelial surface liquid volume necessary for mucociliary clearance in respiratory epithelia 3
• Gain-of-function mutations (like p.W493R) cause excessive Na+ absorption, depleting airway surface fluid 2
• This creates a CF-like phenotype with impaired mucus clearance, chronic infection, and progressive airway damage 1, 2
• The mechanism mirrors cystic fibrosis pathophysiology, where CFTR dysfunction also leads to airway dehydration 4

Clinical Significance and Polygenic Interactions

The most clinically important finding is that ENaC mutations often act through a polygenic mechanism rather than simple Mendelian inheritance:

• Approximately 30% of bronchiectasis patients carry rare ENaC polymorphisms versus only 9% of controls (>3-fold increase) 2
• Trans-heterozygosity for ENaC and CFTR mutations appears particularly pathogenic - about 1 in 975 individuals carry both a hyperactive ENaC mutation and a CFTR variant resulting in 0-10% functional CFTR 2
• Among 192 bronchiectasis patients screened, 72.2% of rare variants involved epithelial sodium channel genes 5
• Five of 8 patients with ENaC mutations had functional abnormalities suggesting impaired sodium transport (abnormal sweat chloride or nasal potential difference) 1

Diagnostic Implications

When evaluating bronchiectasis etiology, consider ENaC genetic testing particularly in these scenarios:

• Idiopathic bronchiectasis with functional evidence of abnormal sodium transport (elevated sweat chloride >30 mmol/L or abnormal nasal potential difference) 1
• Patients heterozygous for a single CFTR mutation who have CF-like lung disease but don't meet full CF diagnostic criteria 1, 2
• Next-generation sequencing panels screening SCNN1A, SCNN1B, and SCNN1G genes alongside CFTR can identify 16% of patients with biallelic variants 5
• Patients with biallelic ENaC variants or combined ENaC/CFTR variants tend to have greater disease severity 5

Common Pitfalls

• Don't dismiss single heterozygous ENaC variants - they may be pathogenic when combined with CFTR variants through a digenic inheritance pattern 1, 2
• Standard CF genetic testing may miss these patients - they require specific ENaC gene sequencing, not just CFTR panel testing 1
• Functional testing matters - genetic variants should be correlated with sweat chloride and nasal potential difference measurements to assess clinical significance 1