Cystic fibrosis in Pakistan : population harbouring rare variants non-responsive to CFTR modulators and the dilemma of poor health facilities
Safdar, Anum Ghani, Muhammad Usman Bano, Iqbal Mehmood, Tahir Rafique, Hassan Sabar, Muhammad Farooq Akbar, Ali Shaikh, Rehan Sadiq
Safdar, Anum
Ghani, Muhammad Usman
Bano, Iqbal
Mehmood, Tahir
Rafique, Hassan
Sabar, Muhammad Farooq
Akbar, Ali
Shaikh, Rehan Sadiq
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Affiliation
University of the Punjab; University of Child Health Science Lahore; Centre for Applied Molecular Biology; Sandwell and West Birmingham NHS Trust
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Publication date
2025-01-24
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Abstract
Background: Pathogenic mutations in the CFTR gene disrupt the normal function of the chloride ion channel CFTR protein, resulting in Cystic Fibrosis (C.F.). Pakistan's situation regarding C.F. mutation is largely unknown, complicating the disease management and treatment. This study is designed to identify the disease-causing CFTR mutations in the Pakistani C.F. cohort and perform an in silico analysis of rare/novel variants. Methodology: Ninety-five C.F. patients were recruited from pediatric healthcare facilities in different regions of Pakistan. Initially, we investigated ∆F508 mutation in all patients, followed by whole exome sequencing (W.E.S.) of nineteen patients and in silico analysis of identified rare/novel mutations. Results and discussion: Initial screening revealed that ∆F508 mutation was absent in 73.74% of cases. W.E.S. identified three novel variants (c.3036del/Q1012Hfs*11, c.488 A > T/p.K163M, c.2384del/S795Yfs*8), one rare variant (c.489 + 2T > C) previously reported in two Pakistani residing in U.K. and one (c.164 + 1G > T/p.?) extremely rare in other populations. Additionally, c.1705T > G/p.Y569D, c.653T > A/p.L218X, c.2125 C > T/p.R709X, and c.3484 C > T/p.R1162X were also identified. Most variants in our cohort are either frameshift or nonsense, while only two are missense variants. Alarmingly, most of these variants, except ∆F508, are non-responsive to modulator drugs, while the responsiveness of c.488 A > T/p.K163M is yet to be determined. High consanguinity (73.40%) and homozygous status of all mutations, except c.3036del/Q1012Hfs*11, are indicative of a high ratio of C.F. carriers in Pakistan. Conclusion: These findings represent the diverse pattern of CFTR mutations within the Pakistani population, highlighting the imperative need to improve earlier C.F. diagnostic and management facilities and to conduct research on treatment strategies other than modulator therapies.
Citation
Safdar A, Ghani MU, Bano I, Mehmood T, Rafique H, Sabar MF, Akbar A, Shaikh RS. Cystic fibrosis in Pakistan: population harbouring rare variants non-responsive to CFTR modulators and the dilemma of poor health facilities. Mol Biol Rep. 2025 Jan 24;52(1):155. doi: 10.1007/s11033-025-10258-z
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Article