P384 Evaluation of rare cystic fibrosis transmembrane conductance regulator gene variants according to seven functional classes from Turkish National Cystic Fibrosis Patient Registry

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Objectives Over 2,100 variants in the cystic fibrosis transmembrane conductance regulator( CFTR) gene have been documented.To address the need for effective therapies targeting CFTR defect in people with cystic fibrosis (pwCF) who are not eligible for existing treatments, CFTR mutations are categorized into seven functional groups according to Amaral et al. Methods In this study, based on the 2023 data from the Turkish National Cystic Fibrosis Patient Registry, CFTR variants were categorized into three groups Class I,Class VII,and Class II-VI according to literature.Variants identified in the population but with unknown effects were assessed using in silico tools,including MutationTaster,Sorting Intolerant from Tolerant,MutPred LOF,Functional Analysis Through Hidden Markov Models,Polymorphism Phenotyping v2,and GOR IV.The decision of eligibility for the CFTR modulators(CFTRm) was determined according to the‘Vertex treatment‐Finder'on the Vertex® website in January 2025. Results There were 2.258 registered patients from 34 centers,2.196 (97.2%) had genetic evaluation.Two alleles were identified in 1.916 (84.8%), which included 279 different CFTR alleles.Of these,61 pathogenic variants with a frequency higher than 0.2%(79.8% of all alleles)have been prioritized so far.In silico tools were applied to 23 variants with unknown effects,and at the end all variants were determined to be pathological. Among these variants,15(10.8% of all alleles)were classified as Class I and 6 (9.4%)as Class VII mutations.Remaining 40 variants(37.4%) were classified as Class II-VI.Between those Class II-VI,11 variants(10.3%)were found to be ineligible for CFTRm. Conclusion Patient-centered approach in cystic fibrosis care is crucial, particularly identifying the need for effective treatments in populations with a high prevalence of rare mutations. Functional studies have not yet been conducted in Türkiye but the results of this ongoing study will help address the unmet treatmetment needs.

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