title: The novel complex allele [A238V;F508del] of the CFTR gene: clinical phenotype and possible implications for cystic fibrosis etiological therapies.
abstract: 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.
authors.affiliation: Cystic Fibrosis Regional Puglia Center, Department of Pediatric Surgery and Sciences - Operational Unit B. Trambusti, University Hospital Policlinico, Bari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Diana
authors.affiliation: Cystic Fibrosis Regional Puglia Center, Department of Pediatric Surgery and Sciences - Operational Unit B. Trambusti, University Hospital Policlinico, Bari, Italy.
authors.forename: Angela Maria
authors.initials: AM
authors.lastname: Polizzi
authors.affiliation: Cystic Fibrosis Regional Puglia Center, Department of Pediatric Surgery and Sciences - Operational Unit B. Trambusti, University Hospital Policlinico, Bari, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Santostasi
authors.affiliation: Cystic Fibrosis Support Center, Pediatrics Section, Hospital of Cerignola, Cerignola, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ratclif
authors.affiliation: Cystic Fibrosis Regional Puglia Center, Department of Pediatric Surgery and Sciences - Operational Unit B. Trambusti, University Hospital Policlinico, Bari, Italy.
authors.forename: Maria Giuseppina
authors.initials: MG
authors.lastname: Pantaleo
authors.affiliation: Cystic Fibrosis Regional Puglia Center, Department of Pediatric Surgery and Sciences - Operational Unit B. Trambusti, University Hospital Policlinico, Bari, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Leonetti
authors.affiliation: Cystic Fibrosis Regional Puglia Center, Department of Pediatric Surgery and Sciences - Operational Unit B. Trambusti, University Hospital Policlinico, Bari, Italy.
authors.forename: Danila Rosa
authors.initials: DR
authors.lastname: Iusco
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Crescenzio
authors.initials: C
authors.lastname: Gallo
authors.affiliation: Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Massimo
authors.identifier: http://orcid.org/0000-0003-3465-6641
authors.initials: M
authors.lastname: Conese
authors.affiliation: Cystic Fibrosis Regional Puglia Center, Department of Pediatric Surgery and Sciences - Operational Unit B. Trambusti, University Hospital Policlinico, Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Manca
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D001424:Bacterial Infections / Q000175:diagnosis / Q000209:etiology; D015415:Biomarkers; D002097:C-Reactive Protein / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002712:Chlorides / Q000378:metabolism; D003062:Codon; D003550:Cystic Fibrosis / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010641:Phenotype; D011379:Prognosis; D012129:Respiratory Function Tests; D017384:Sequence Deletion
chemical_list: D015415:Biomarkers; D002712:Chlorides; D003062:Codon; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002097:C-Reactive Protein