Two complex alleles of the CFTR gene in one patient – clinical picture and assessment of the functional activity of epithelial membrane channels

Introduction. The diagnosis and treatment of cystic fibrosis (CF) is complicated by the possible presence of complex alleles. An allele is considered complex if it carries at least two genetic variants of the CFTR gene; in this case, each pathogenic variant can affect individual stages of CFTR protein biogenesis. The frequency and role of complex alleles are currently underestimated.

Objective. To describe a clinical case of cystic fibrosis in a patient carrying two complex alleles: c.[1521_1523delCTT;1399C>T];[c.1397 C>G;3209G>A], p.[Phe508del;Leu467Phe];[Ser466*;Arg1070Gln], the “traditional” name being [L467F;F508del]/[S466X;R1070Q]. 

Methods. We analyzed the patient’s medical history data, including outpatient records and hospital inpatient records from 2018 to 2023. We also analyzed CFTR gene sequencing data, ICM data from rectal biopsies, and data from forskolin-induced swelling of intestinal organoids obtained from rectal biopsies.

Results. The disease course in a 5-year-old child with the presence of two complex alleles [L467F;F508del]/[S466X;R1070Q] in the genotype is described. A severe course of the disease is demonstrated, early colonization with Pseudomonas aeruginosa, development of signs of chronic hypoxia, respiratory failure, course of polypous chronic rhinosinusitis, severe body weight deficit, poor compensation of intestinal syndrome. The results of functional tests performed using ICM data showed the absence of the CFTR chloride channel function, the forskolin-indused swelling on intestinal organoids revealed the absence of swelling when stimulated with forskolin and CFTR modulators. The combination of elexacaftor/tezacaftor/ivacaftor has an insignificant effect on the restoration of CFTR functional activity.

Conclusions. This is the first description of the clinical course of CF in a patient with two complex alleles, [L467F;F508del] and [S466X;R1070Q]. Using diagnostic methods such as the ICM and the forskolin-induced intestinal organelle swelling test, we demonstrated the absence of CFTR chloride channel function and a weak response to elexacaftor/tezacaftor/ivacaftor.

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