Safdar Anum, Ghani Muhammad Usman, Bano Iqbal, Mehmood Tahir, Rafique Hassan, Sabar Muhammad Farooq, Akbar Ali, Shaikh Rehan Sadiq
Precision Genomics Research Lab, Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan.
Children Hospital, University of Child Health Science Lahore, Lahore, Pakistan.
Mol Biol Rep. 2025 Jan 24;52(1):155. doi: 10.1007/s11033-025-10258-z.
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.
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.
Initial screening revealed that ∆F508 mutation was absent in 73.74% of cases. W.E.S. identified three novel variants (c.3036del/Q1012Hfs11, c.488 A > T/p.K163M, c.2384del/S795Yfs8), 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.
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.
CFTR基因中的致病突变会破坏氯离子通道CFTR蛋白的正常功能，导致囊性纤维化（C.F.）。巴基斯坦关于C.F.突变的情况在很大程度上尚不清楚，这使得疾病的管理和治疗变得复杂。本研究旨在确定巴基斯坦C.F.队列中导致疾病的CFTR突变，并对罕见/新变体进行计算机模拟分析。
从巴基斯坦不同地区的儿科医疗机构招募了95名C.F.患者。最初，我们对所有患者进行了∆F508突变检测，随后对19名患者进行了全外显子组测序（W.E.S.），并对鉴定出的罕见/新突变进行了计算机模拟分析。
初步筛查显示，73.74%的病例不存在∆F508突变。W.E.S.鉴定出三个新变体（c.3036del/Q1012Hfs11、c.488 A>T/p.K163M、c.2384del/S795Yfs8）、一个先前在居住在英国的两名巴基斯坦人中报道过的罕见变体（c.489+2T>C）以及一个在其他人群中极其罕见的变体（c.164+1G>T/p.?）。此外，还鉴定出了c.1705T>G/p.Y569D、c.653T>A/p.L218X、c.2125 C>T/p.R709X和c.3484 C>T/p.R1162X。我们队列中的大多数变体要么是移码突变，要么是无义突变，只有两个是错义突变。令人担忧的是，除了∆F508之外，这些变体中的大多数对调节剂药物无反应，而c.488 A>T/p.K163M的反应性尚待确定。高近亲结婚率（73.40%）以及除c.3036del/Q1012Hfs*11之外所有突变的纯合状态表明巴基斯坦C.F.携带者的比例很高。
这些发现代表了巴基斯坦人群中CFTR突变的多样模式，突出了迫切需要改善早期C.F.诊断和管理设施，并开展除调节剂疗法之外的治疗策略研究。
