EPS01.3 Genotype–phenotype correlation in Russian cystic fibrosis patients with S466X–R1070Q complex allele

Abstract

In the databases of CFTR mutations (CFTR1 and CFTR2) mutations S466X and R1070Q are described as separate ones: mutation S466X (p.Ser466X, c.1397C>G) – CF causing mutation (refers to mutations of class I); mutation R1070Q (p.Arg1070Gln, c.3208C>A) is considered as a mutation with variable clinical CF manifestations (mutation of class IV). Objectives To study genotype–phenotype correlations in Russian CF patients with S466X–R1070Q complex allele. Methods Sequencing of the coding region of CFTR gene and adjacent regions in 69 CF patients (with at least one unidentified mutation after standard analysis on 28 mutations) and clinical observation. Results In five unrelated patients we detected S466X–R1070Q complex allele. In all cases mutation S466X (p.Ser466X) was a substitution c.1397C>G. In three cases, DNA was available from the parents and the analysis confirmed that mutation S466X and R1070Q are in cis . Since S466X mutation leads to disruption of the CFTR protein synthesis, we can assume that the consequences of allele S466X–R1070Q are determined by mutation S466X. In all the patients a second mutant allele was identified. One patient without pancreatic insufficiency had class V mutation – 3849+10kbC>T (c.3717 + 12191C>T). Four were pancreatic insufficient: two had class I mutations [2143delT (p.Leu671X, c.2012delT) and R785X (p.Arg785X; c.2353C>T)] and the other two had class II mutation: F508del (p.Phe508del, c.1521_1523delCTT) and N1303K (p.Asp1303Lys, c.3909C>G). Conclusion Complex allele S466X–R1070Q violates protein synthesis and can be referred to severe mutations. It is associated with pancreatic-insufficient CF when paired with a known severe CF mutation.