Key points are not available for this paper at this time.
Complex alleles of the CFTR gene complicate the diagnosis of cystic fibrosis (CF), the classification of its pathogenic variants, affect the clinical picture of the disease and can affect the efficiency of targeted drugs. The total frequency of complex allele L467F;F508del in the Russian population of patients with CF is 0. 74%, and in patients with the F508del/F508del genotype, its frequency reaches 8%. This article presents multi-faceted study of the complex allele L467F;F508del in a cohort of patients with genotypes L467F;F508del/class I (c. 3532₃535dup, c. 1766+2T>C, W1310X, 712-1G>T), and data for a unique patient with the genotype L467F;F508del/L467F;F508del. Using the intestinal current measurement method, it was demonstrated the absence of CFTR function for L467F;F508del/class I and L467F;F508del/L467F;F508del genotypes. In intestinal organoids, it was shown that L467F;F508del in combination with class I variants and in the homozygotes abolishes the efficacy of both two-component (ivacaftor+lumacaftor; ivacaftor+tezacaftor) and three-component (ivacaftor+tezacaftor+elexacaftor) targeted drugs. When prescribing ivacaftor+tezacaftor+elexacaftor to three patients, they did not have a clinical effect after 6–12 months.
Ефремова et al. (Fri,) studied this question.