Abstract：
BACKGROUND: Cystic fibrosis (CF) is a rare and debilitating autosomal recessive disorder. It hampers the normal function of various organs and causes severe damage to the lungs, and digestive system leading to recurring pneumonia. Cf also affects reproductive health eventually may cause infertility. The disease manifests due to genetic aberrations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This study aimed to screen for CFTR gene variants in Pakistani CF patients representing variable phenotypes.
METHODS: Clinical exome and Sanger sequencing were performed after clinical characterization of 25 suspected cases of CF (CF1-CF25). ACMG guidelines were followed to interpret the clinical significance of the identified variants.
RESULTS: Clinical investigations revealed common phenotypes such as pancreatic insufficiency, chest infections, chronic liver and lung diseases. Some patients also displayed symptoms like gastroesophageal reflux disease (GERD), neonatal cholestasis, acrodermatitis, diabetes mellitus, and abnormal malabsorptive stools. Genetic analysis of the 25 CF patients identified deleterious variants in the CFTR gene. Notably, 12% of patients showed compound heterozygous variants, while 88% had homozygous variants. The most prevalent variant was p. (Met1Thr or Met1?) at 24%, previously not reported in the Pakistani population. The second most common variant was p. (Phe508del) at 16%. Other variants, including p. (Leu218*), p. (Tyr569Asp), p. (Glu585Ter), and p. (Arg1162*) were also identified in the present study. Genetic analysis of one of the present patients showed a pathogenic variant in G6PD in addition to CFTR.
CONCLUSIONS: The study reports novel and reported variants in the CFTR gene in CF patients in Pakistani population having distinct phenotypes. It also emphasizes screening suspected Pakistani CF patients for the p. (Met1Thr) variant because of its increased observance and prevalence in the study. Moreover, the findings also signify searching for additional pathogenic variants in the genome of CF patients, which may modify the phenotypes. The findings contribute valuable information for the diagnosis, genetic counseling, and potential therapeutic strategies for CF patients in Pakistan.
METHODS: Clinical exome and Sanger sequencing were performed after clinical characterization of 25 suspected cases of CF (CF1-CF25). ACMG guidelines were followed to interpret the clinical significance of the identified variants.
RESULTS: Clinical investigations revealed common phenotypes such as pancreatic insufficiency, chest infections, chronic liver and lung diseases. Some patients also displayed symptoms like gastroesophageal reflux disease (GERD), neonatal cholestasis, acrodermatitis, diabetes mellitus, and abnormal malabsorptive stools. Genetic analysis of the 25 CF patients identified deleterious variants in the CFTR gene. Notably, 12% of patients showed compound heterozygous variants, while 88% had homozygous variants. The most prevalent variant was p. (Met1Thr or Met1?) at 24%, previously not reported in the Pakistani population. The second most common variant was p. (Phe508del) at 16%. Other variants, including p. (Leu218*), p. (Tyr569Asp), p. (Glu585Ter), and p. (Arg1162*) were also identified in the present study. Genetic analysis of one of the present patients showed a pathogenic variant in G6PD in addition to CFTR.
CONCLUSIONS: The study reports novel and reported variants in the CFTR gene in CF patients in Pakistani population having distinct phenotypes. It also emphasizes screening suspected Pakistani CF patients for the p. (Met1Thr) variant because of its increased observance and prevalence in the study. Moreover, the findings also signify searching for additional pathogenic variants in the genome of CF patients, which may modify the phenotypes. The findings contribute valuable information for the diagnosis, genetic counseling, and potential therapeutic strategies for CF patients in Pakistan.
摘要：
背景：囊性纤维化（CF）是一种罕见且使人衰弱的常染色体隐性遗传疾病。它妨碍各种器官的正常功能，并对肺部造成严重损害，和消化系统导致反复发作的肺炎.Cf还影响生殖健康，最终可能导致不孕。该疾病的表现是由于囊性纤维化跨膜传导调节因子（CFTR）基因的遗传畸变。本研究旨在筛选代表可变表型的巴基斯坦CF患者的CFTR基因变异。
方法：对25例疑似CF（CF1-CF25）进行临床鉴定后，进行临床外显子组和Sanger测序。遵循ACMG指南来解释鉴定的变体的临床意义。
结果：临床调查显示常见的表型，如胰腺功能不全，胸部感染,慢性肝脏和肺部疾病。一些患者还表现出胃食管反流病（GERD）等症状，新生儿胆汁淤积,肢端皮炎,糖尿病,和异常吸收不良的粪便。25名CF患者的遗传分析鉴定了CFTR基因中的有害变体。值得注意的是,12%的患者出现复合杂合变异，而88%有纯合变异。最普遍的变体是p。（Met1Thr或Met1？）为24％，以前在巴基斯坦人口中没有报道。第二最常见的变体是16%的p.(Phe508del)。其他变体,包括p.(Leu218*)，p.（Tyr569Asp），p.(Glu585Ter),和p.(Arg1162*)也在本研究中鉴定。对其中一名患者的遗传分析显示，除CFTR外，G6PD中还存在致病性变异。
结论：该研究报告了具有不同表型的巴基斯坦人群中CF患者CFTR基因的新变异。它还强调筛查疑似巴基斯坦CF患者的p。（Met1Thr）变异，因为它在研究中的观察和患病率增加。此外，这些发现还意味着在CF患者的基因组中寻找其他致病变异，这可能会改变表型。这些发现为诊断提供了有价值的信息，遗传咨询,以及巴基斯坦CF患者的潜在治疗策略。
方法：对25例疑似CF（CF1-CF25）进行临床鉴定后，进行临床外显子组和Sanger测序。遵循ACMG指南来解释鉴定的变体的临床意义。
结果：临床调查显示常见的表型，如胰腺功能不全，胸部感染,慢性肝脏和肺部疾病。一些患者还表现出胃食管反流病（GERD）等症状，新生儿胆汁淤积,肢端皮炎,糖尿病,和异常吸收不良的粪便。25名CF患者的遗传分析鉴定了CFTR基因中的有害变体。值得注意的是,12%的患者出现复合杂合变异，而88%有纯合变异。最普遍的变体是p。（Met1Thr或Met1？）为24％，以前在巴基斯坦人口中没有报道。第二最常见的变体是16%的p.(Phe508del)。其他变体,包括p.(Leu218*)，p.（Tyr569Asp），p.(Glu585Ter),和p.(Arg1162*)也在本研究中鉴定。对其中一名患者的遗传分析显示，除CFTR外，G6PD中还存在致病性变异。
结论：该研究报告了具有不同表型的巴基斯坦人群中CF患者CFTR基因的新变异。它还强调筛查疑似巴基斯坦CF患者的p。（Met1Thr）变异，因为它在研究中的观察和患病率增加。此外，这些发现还意味着在CF患者的基因组中寻找其他致病变异，这可能会改变表型。这些发现为诊断提供了有价值的信息，遗传咨询,以及巴基斯坦CF患者的潜在治疗策略。
