This multicenter translational research study integrates diagnostic analyses and ex-vivo functional testing to support future clinical trials evaluating the safety and efficacy of CFTR modulator treatments in individuals with cystic fibrosis (CF) carrying rare or orphan mutations that may benefit from these therapies. Patient-derived nasal epithelial cells will be collected through standardized nasal brushing procedures, expanded, and cultured under air-liquid interface conditions to generate differentiated epithelia. Short-circuit current measurements will be used to assess baseline CFTR dysfunction and evaluate functional recovery following treatment with available CFTR modulators. These results will be complemented by DNA sequencing to identify complex alleles, quantitative and qualitative CFTR mRNA analyses to investigate gene expression and splicing defects, and assessments of epithelial transcriptomics, surface liquid viscosity, and mucociliary transport to identify additional mechanisms contributing to CF-like lung disease. The study will not include patient follow-up. The duration of participation will be limited to the time required to perform and analyze the nasal brushing procedure. Baseline CFTR activity will be compared with previously published data from individuals without cystic fibrosis.
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Inclusion Criteria: * Adult or pediatric patients diagnosed with cystic fibrosis (CF) who have, on the first allele, a missense mutation or a small deletion (not resulting in a frameshift) that has not been functionally characterized or for which responsiveness to currently available therapies is limited or unknown, AND a second allele carrying another uncharacterized mutation, a stop-gain mutation, a class II mutation, or a large deletion of the CFTR gene; OR * Pediatric patients with Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID), meeting the following definition: "an asymptomatic newborn with a positive CF newborn screening (NBS) result and a sweat chloride concentration \<30 mmol/L and two CFTR variants, at least one of which has unclear phenotypic consequences; or an intermediate sweat chloride concentration (30-59 mmol/L) and one or no CF-causing variants"; OR * Adult or pediatric patients with CFTR-related disorders (CFTR-RD) meeting the following criteria: a CFTR-RD-associated phenotype, evidence of CFTR dysfunction, and exclusion of a diagnosis of cystic fibrosis; OR * Adult patients aged ≥18 years carrying a single CF-causing variant and diagnosed with idiopathic bronchiectasis. * Written informed consent/assent for study participation and personal data processing must be obtained before the initiation of data collection and any study-related procedures. Exclusion Criteria: * Failure to meet the eligibility criteria for study enrollment. * Failure to provide signed informed consent/assent for study participation or for the processing of personal data.