The novel complex allele [A238V;F508del] of the CFTR gene: clinical phenotype and possible implications for cystic fibrosis etiological therapies

Few mutations in cis have been annotated for f508del homozygous patients. southern italy patients who at a first analysis appeared homozygous for the f508del mutation (n=63) or compound heterozygous for the f508del and another mutation in the cystic fibrosis transmembrane conductance regulator gene (n=155) were searched for the a238v mutation in exon 6. the allelic frequency of the complex allele [a238v;f508del] was 0.04. when the whole data set was used (comprised also of 56 f508del/f508del and 34 f508del/other mutation controls), no differences reached the statistical significance in the clinical parameters, except chloride concentrations which were lower in [a238v;f508del]/other mutation compared with f508del/other mutation (p=0.03). the two study groups presented less complications than the control groups. within the minimal data set (34 f508del/f508del, 27 f508del/other mutation, 4 [a238v;f508del]/f508del cases and 5 [a238v;f508del]/other mutation cases); that is, presenting all the variables in each patient, forced expiratory volume in 1 s and forced vital capacity presented a trend to lower levels in the study groups in comparison with the f508del/f508del group, and c-reactive protein approximated statistically significant higher levels in the [a238v;f508del]/other mutation as compared with f508del/f508del patients (p=0.09). the analysis of statistical dependence among the variables showed a significant anticorrelation between chloride and body mass index in the [a238v;f508del]/other mutation group. in conclusion, the complex allele [a238v;f508del] seems to be associated with less general complications than in the control groups, on the other hand possibly giving a worse pulmonary phenotype and higher systemic/local inflammatory response. these findings have implications for the correct recruitment and clinical response of f508del patients in the clinical trials testing the new etiological drugs for cystic fibrosis.