GENOTYPE PHENOTYPE ASSOCIATION IN CYSTIC-FIBROSIS - ANALYSES OF THE DELTA-F508, R553X, AND 3905INST MUTATIONS

A striking clinical phenomenon of cystic fibrosis is the heterogeneous disease expression. It must therefore be assumed that the nature of the mutations associated with cystic fibrosis might partly determine the phenotypic manifestations. The relation between the cystic fibrosis mutations DELTA-F508, R553X, and 3905insT and clinical parameters such as sweat test electrolytes, age at chronic Pseudomonas aeruginosa colonization, Chrispin-Norman x-ray scores, and relative underweight have been investigated in 45 patients homozygous for DELTA-F508 (DELTA-F2), in 12 compound heterozygotes for DELTA-F508/R553X (DELTA-F1/RX1), in three R553X homozygotes (RX2), and in 13 patients compound heterozygous for DELTA-F508/3905insT (DELTA-F16). We have found significant differences between the genetically defined subgroups concerning the mean age at onset and the cumulative incidence of chronic P. aeruginosa colonization and Chrispin-Norman x-ray scores. The significant results as well as some trends regarding the relative underweight demonstrate a milder clinical course in R553X heterozygotes and more severe disease in the DELTA-F16 group compared to DELTA-F508 homozygotes. The three patients homozygous for R553X presented with a two-stage course showing mild progression before P. aeruginosa infection and as severe a course as the DELTA-F16 patients after P. aeruginosa colonization at the age of 12 y. The findings presented here indicate that specific mutations can influence the severity and progression of the disease, implicating the importance of mutation and haplotype analyses. However, wide variations within the genetically homogeneous subgroups illustrate that other determinants of the clinical status do exist.