About this condition
Cystic Fibrosis
Cystic fibrosis (CF) is an autosomal recessive multisystem disorder affecting the lungs, pancreas, liver, reproductive tract, and sweat glands. Prevalence is approximately 1 in 2,500–3,500 in Caucasian populations; carrier frequency is approximately 1 in 25 Caucasians. Disease is caused by biallelic pathogenic variants in CFTR, which encodes cystic fibrosis transmembrane conductance regulator, a chloride channel critical for proper fluid and electrolyte balance in epithelial tissues. More than 2,000 CFTR variants have been identified. F508del (deletion of phenylalanine 508) is by far the most common, accounting for approximately 70% of CF alleles worldwide and present in approximately 90% of CF patients (either heterozygous or homozygous). Clinically, CF presents with progressive lung disease (recurrent infections, bronchiectasis), pancreatic insufficiency (malabsorption, diabetes), and salt loss. Median life expectancy has extended from infancy in the 1980s to approximately 50 years today, primarily due to aggressive pulmonary management and increasingly due to CFTR modulator therapies, which have transformed CF from a fatal childhood disease into a manageable chronic condition.
CFTR encodes a 1,480-amino acid cAMP-regulated chloride channel localized to apical membranes of epithelial cells. Variants are classified by mechanism: Class I (nonsense, frameshift, canonical splice site) produce no protein; Class II (processing defects including F508del) cause misfolding and ER degradation; Class III (defective channel gating) impair opening; Class IV (reduced conductance) allow partial chloride flow; Class V (reduced amount) produce low levels of functional protein. F508del is a Class II variant causing misfolding and premature degradation. The CFTR protein is absolutely critical for chloride secretion; loss of function leads to dehydrated, viscous secretions in airways and ducts, causing obstruction, infection, and inflammation. Three CFTR modulator drugs are now approved and have transformed outcomes: ivacaftor activates gating mutations; lumacaftor/ivacaftor corrects F508del misfolding; elexacaftor/tezacaftor/ivacaftor extends to approximately 90% of CF patients.
CFTR genotyping is critical for CF diagnosis and increasingly for therapy selection. Ivacaftor (Kalydeco) activates specific gating mutations (G551D, G1244E, and others) and benefits approximately 4–6% of CF patients. Lumacaftor/ivacaftor (Orkambi) targets F508del homozygous patients—approximately 15% of CF—producing approximately 6-point FEV1 improvement. Elexacaftor/tezacaftor/ivacaftor (Trikafta), approved for CF patients with at least one F508del copy, extends eligibility to approximately 90% of CF patients; Trikafta produces approximately 10-point FEV1 improvement and has dramatically changed the CF landscape—mortality appears to be declining since approval. CFTR genotype directly determines which modulator(s) a patient can access, making genetic testing essential for therapy guidance and enabling individualized treatment selection.
- Gene locus
- CFTR (7q31.2)
