Genotype and phenotype in cystic fibrosis

Respiration. 2000;67(2):117-33. doi: 10.1159/000029497.


Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene which encodes a protein expressed in the apical membrane of exocrine epithelial cells. CFTR functions principally as a cAMP-induced chloride channel and appears capable of regulating other ion channels. Besides the most common mutation, DeltaF508, accounting for about 70% of CF chromosomes worldwide, more than 850 mutant alleles have been reported to the CF Genetic Analysis Consortium. These mutations affect CFTR through a variety of molecular mechanisms which can produce little or no functional CFTR at the apical membrane. This genotypic variation provides a rationale for phenotypic effects of the specific mutations. The extent to which various CFTR alleles contribute to clinical variation in CF is evaluated by genotype-phenotype studies. These demonstrated that the degree of correlation between CFTR genotype and CF phenotype varies between its clinical components and is highest for the pancreatic status and lowest for pulmonary disease. The poor correlation between CFTR genotype and severity of lung disease strongly suggests an influence of environmental and secondary genetic factors (CF modifiers). Several candidate genes related to innate and adaptive immune response have been implicated as pulmonary CF modifiers. In addition, the presence of a genetic CF modifier for meconium ileus has been demonstrated on human chromosome 19q13.2. The phenotypic spectrum associated with mutations in the CFTR gene extends beyond the classically defined CF. Besides patients with atypical CF, there are large numbers of so-called monosymptomatic diseases such as various forms of obstructive azoospermia, idiopathic pancreatitis or disseminated bronchiectasis associated with CFTR mutations uncharacteristic for CF. The composition, frequency and type of CFTR mutations/variants parallel the spectrum of CFTR-associated phenotypes, from classic CF to mild monosymptomatic presentations. Expansion of the spectrum of disease associated with the CFTR mutant genes creates a need for revision of the diagnostic criteria for CF and a dilemma for setting nosologic boundaries between CF and other diseases with CFTR etiology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Bronchiectasis / diagnosis
  • Bronchiectasis / genetics
  • Cystic Fibrosis / diagnosis
  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / biosynthesis
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Diagnosis, Differential
  • Digestive System / pathology
  • Genotype
  • Humans
  • Male
  • Mutation
  • Oligospermia / diagnosis
  • Oligospermia / genetics
  • Organ Specificity / genetics
  • Phenotype
  • Protein Processing, Post-Translational / genetics
  • Respiratory System / pathology
  • Sweat Gland Diseases / diagnosis
  • Sweat Gland Diseases / genetics


  • CFTR protein, human
  • cystic fibrosis transmembrane conductance regulator delta F508
  • Cystic Fibrosis Transmembrane Conductance Regulator