Work

A comprehensive study of a rare pathogenic CFTR gene variant G1047S in two siblings

Year: 2025

Type: article

Abstract: Most of the known pathogenic variants of the CFTR gene are rare. Studying these variants allows us to gain new knowledge about the pathogenesis of cystic fibrosis, assess the variability of its manifestations among patients, and optimize therapeutic approaches. The aim was to comprehensively study a rare variant of the CFTR gene G1047S (c.3139G>A, p.(Gly1047Ser)) in two siblings, including a description of the clinical picture, functional assessment of the CFTR channel ex vivo by determining the intestinal current measurement (ICM) and the forskolin-induced swelling (FIS) assay of the effect of CFTR modulators in vitro in the intestinal organoids. Methods. The case history was presented. The ICM was used to study membrane channels of the intestinal epithelium. The FIS assay in the intestinal organoids of the patients was used to assess the sensitivity of the G1047S variant to ivacaftor, lumacaftor, tezacaftor, and elexacaftor. Results. The missense variant G1047S is pathogenic but “mild” since the residual CFTR function is observed. The results of functional tests are consistent with the clinical picture: the siblings have pancreatic sufficiency, no nutritional deficiency, and a “mild” course of the disease. The ivacaftor + tezacaftor + elexacaftor therapy can be recommended for patients with the G1047S variant since the intestinal organoid model shows restoration of CFTR functional activity. Conclusion. The G1047S variant is “mild”, but with lower sensitivity to known combination targeted drugs compared to F508del/F508del.

Source: PULMONOLOGIYA

DOI: 10.18093/0869-0189-2025-35-2-230-240