TY - JOUR T1 - Genotype–phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles JF - Journal of Medical Genetics JO - J Med Genet SP - 224 LP - 235 DO - 10.1136/jmedgenet-2016-103985 VL - 54 IS - 4 AU - Vito Terlizzi AU - Giuseppe Castaldo AU - Donatello Salvatore AU - Marco Lucarelli AU - Valeria Raia AU - Adriano Angioni AU - Vincenzo Carnovale AU - Natalia Cirilli AU - Rosaria Casciaro AU - Carla Colombo AU - Antonella Miriam Di Lullo AU - Ausilia Elce AU - Paola Iacotucci AU - Marika Comegna AU - Manuela Scorza AU - Vincenzina Lucidi AU - Anna Perfetti AU - Roberta Cimino AU - Serena Quattrucci AU - Manuela Seia AU - Valentina Maria Sofia AU - Federica Zarrilli AU - Felice Amato Y1 - 2017/04/01 UR - http://jmg.bmj.com/content/54/4/224.abstract N2 - Background The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies.Objectives To describe the genotype–phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator (CFTR) complex alleles.Methods We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p.[Arg74Trp;Val201Met;Asp1270Asn], n=8; p.[Ile148Thr;Ile1023_Val1024del], n=5; p.[Arg117Leu;Leu997Phe], n=6; c.[1210-34TG[12];1210-12T[5];2930C>T], n=3; p.[Arg74Trp;Asp1270Asn], n=4; p.Asp1270Asn, n=2; p.Ile148Thr, n=6; p.Leu997Phe, n=36. In 39 patients, we analysed the CFTR gating activity on NEC in comparison with patients with CF (n=8) and carriers (n=4). Finally, we analysed in vitro the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele.Results The p.[Ile148Thr;Ile1023_Val1024del] caused severe CF in five compound heterozygous with a class I–II mutation. Their CFTR activity on NEC was comparable with patients with two class I–II mutations (mean 7.3% vs 6.9%). The p.[Arg74Trp;Asp1270Asn] and the p.Asp1270Asn have scarce functional effects, while p.[Arg74Trp;Val201Met;Asp1270Asn] caused mild CF in four of five subjects carrying a class I–II mutation in trans, or CFTR-related disorders (CFTR-RD) in three having in trans a class IV–V mutation. The p.[Arg74Trp;Val201Met;Asp1270Asn] causes significantly (p<0.001) higher CFTR activity compared with compound heterozygous for class I–II mutations. Furthermore, five of six compounds heterozygous with the p.[Arg117Leu;Leu997Phe] had mild CF, whereas the p.Leu997Phe, in trans with a class I–II CFTR mutation, caused CFTR-RD or a healthy status (CFTR activity: 21.3–36.9%). Finally, compounds heterozygous for the c.[1210-34TG[12];1210-12T[5];2930C>T] and a class I–II mutation had mild CF or CFTR-RD (gating activity: 18.5–19.0%).Conclusions The effect of complex alleles partially depends on the mutation in trans. Although larger studies are necessary, the CFTR activity on NEC is a rapid contributory tool to classify patients with CFTR dysfunction. ER -