The CFTR 3849+10kbC->T and 2789+5G->A alleles are a ssociated with a mild CF phenotype

Most cystic fibrosis (CF) transmembrane receptor mutations are rare. The French CF Registry offers an opportunity to study the genotype-phenotype relationship of these rare allelles. Since 1992, 39 CF patients carrying one copy of the 3849+10kbC->T mutation and 88 the 2789+5G->A allele have been seen at least once in a CF care centre. Among them, 16 carrying the 3849+10kbC->T/DeltaF508 genotype and 34 with the 2789+5G->A/DeltaF508 genotype were seen in 2000. Their age at diagnosis, sweat chloride concentration, anthropometric and lung function results, and clinical aspects were compared with those homozygous for the DeltaF508 mutation matched for sex, age and CF care centre. Major differences, most of them statistically significant, in the age at diagnosis, prevalence of pancreatic insufficiency, and other clinical signs, anthropometric and lung function measures were observed between both compound heterozygote groups and their matched DeltaF508/DeltaF508 groups. The mean sweat chloride concentration was also lower (close to normal values) among 3849+10kbC->T/AF508 patients, but not among 2789+5G->A/AF508 patients. In conclusion, both mutations studied here are associated with a milder course of cystic fibrosis disease. The 3849+10kbC->T and 2789+5G->A alleles are splice site mutations, leading to abnormal mRNA; however, a small amount of normally spliced transcripts can also be detected. The presence of these small amounts of normal cystic fibrosis transmembrane receptor protein in these cystic fibrosis patients is likely to be responsible for the milder severity of disease and a better life expectancy.