Research Centre for Medical Genetics, Moskvorechye Str. 1, 115522 Moscow, Russia.
Int J Mol Sci. 2024 Sep 27;25(19):10424. doi: 10.3390/ijms251910424.
Complex alleles of the 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.3532_3535dup, 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.
基因的复杂等位基因使囊性纤维化 (CF) 的诊断复杂化，其致病变体的分类，影响疾病的临床表现，并可能影响靶向药物的效率。在俄罗斯 CF 患者人群中，复杂等位基因 [L467F;F508del] 的总频率为 0.74%，而在 F508del/F508del 基因型的患者中，其频率达到 8%。本文对 [L467F;F508del] 复杂等位基因在一组基因型为 [L467F;F508del]/I 类（c.3532_3535dup、c.1766+2T>C、W1310X、712-1G>T）的患者中的多方面研究，并提供了一名具有独特基因型 [L467F;F508del]/[L467F;F508del] 的患者的数据。通过肠电流测量法，证明了 [L467F;F508del]/I 类和 [L467F;F508del]/[L467F;F508del] 基因型缺乏 CFTR 功能。在肠类器官中，结果表明 [L467F;F508del] 与 I 类变体组合以及在纯合子中，两种二组分（ivacaftor+lumacaftor；ivacaftor+tezacaftor）和三种组分（ivacaftor+tezacaftor+elexacaftor）靶向药物的疗效都被消除。当给三名患者开处方 ivacaftor+tezacaftor+elexacaftor 时，他们在 6-12 个月后没有临床效果。
