Comprehensive genetic and clinical profiling of people with cystic fibrosis ineligible for CFTR modulator therapy: Insights from a diverse patient cohort

<bold>Background:</bold> Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in <italic>CFTR</italic>. Over 2000 mutations have been identified, and new drugs called CFTR modulators have been developed to target specific defects in the protein. However, these drugs are only suitable for patients with certain variations in <italic>CFTR</italic>, and eligibility rates vary depending on race and geographical region¹. This study aimed to reveal the detailed genetic and clinical characteristics of people with CF (pwCF) in our center in Turkey, a developing country, who are not eligible for modulator drugs. <bold>Methods:</bold> A total of 445 pwCF followed up at Marmara University were reviewed retrospectively. Mutations of the patients ineligible to all the modulator drugs were classified based on American College of Medical Genetics guidelines, <italic>CFTR</italic> classification, the change in the encoded protein, and the mutation type. <bold>Results:</bold> The study revealed that 139 (%31.2) patients weren’t eligible for the modulator drugs. There were 60 different mutations in the 276 alleles. The majority of patients had missense or nonsense mutations, and that the most common variation was c.1545_1546del, which can be said unique to this geography. <bold>Conclusion:</bold> The study highlights the importance of detecting the mutations of ineligible patients in detail to guide future approaches for more targeted and effective interventions in CF care. Testing the effectiveness of CFTR modulators for rare or newly occurring mutations is crucial to ensure equal access for pwCF to these therapies from diferen racial backgrounds and ethnic minorities. ¹Çobanoğlu, N. et al. Pediatric Pulmonology 2020;55:2302-2306