Genotype/phenotype correlation

The CFTR2 project has produced a remarkable amount of data from a number of CF patients never collected before. The website provides information on phenotypes related to many mutations, which will certainly be useful from an epidemiological perspective, but have to be regarded with circumspection when single individuals are considered.

Interpretation of individual genotype/phenotype correlation is hindered by undetected CFTR factors like extra changes of sequence, intragenic modifiers, and complex alleles. Also non CFTR factors such as modifier genes and environmental circum- stances (including the beneficial and harmful effects of treatment) contribute to variability in phenotype in patients carrying the same genotype.2 Moreover, the relative impact of CFTR genotype on clinical phenotype is organ specific. The correlation between CFTR genotype and pancreatic status is strong, but not absolute, as some mutations may be associated with either pancreatic sufficiency or insufficiency, or the pancreatic phenotype may progress from sufficiency to insufficiency.

The lung has the greatest variability of disease severity of all organs involved in CF. Patients homozygous for F508del exhibit an extremely wide range of severity of pulmonary disease.2 Similar considerations apply also to the other CF-causing mutations, making it impossible to predict progression of lung disease and therefore survival in individual patients based only on CFTR genotype.

In consideration of these limitations, CFTR2 phenotype data connected to specific mutations should not be used to predict the clinical course of individual patients.