ArticleOrphanet journal of rare diseases2026
Characterization of two ultra-rare CFTR variants, P.Leu999del and P.Glu1104Lys, with unknown theratyping profiles.
Article in Orphanet journal of rare diseases, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundIndividuals carrying ultra-rare CFTR variants remain untreated with CFTR modulator therapies due to a lack of functional and clinical data supporting variant-specific responsiveness. This study aimed to functionally characterize two ultra-rare CFTR variants, p.Glu1104Lys (E1104K) and p.Leu999del (L999del), each found in trans with the minimal function variant G542X, and to evaluate their responsiveness to the triple-combination regimens elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and vanzacaftor/tezacaftor/ivacaftor (VAN/TEZ/IVA).
resultsPatient-derived intestinal organoids (PDIOs) of two people with cystic fibrosis (G542X/E1104K and G542X/L999del) were cultured from rectal biopsies and subjected to forskolin-induced swelling (FIS) assays. CFTR function was quantified by calculating the area under the curve after 60 minutes. Human nasal epithelial cells (HNECs) were obtained by nasal brushing, expanded under air-liquid interface conditions, and evaluated in Ussing chambers. CFTRinh-172-sensitive stimulated currents (ΔCFTRinh-172 I
conclusionsE1104K and L999del exhibit measurable residual CFTR function and in vitro responsiveness to two CFTRm triple-combination regimens. These findings support theranostic approaches to guide therapy in individuals with ultra-rare CFTR genotypes, while clinical use remains dependent on regulatory approval and individualized patient assessment.
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