Mutational spectrum of CFTR in cystic fibrosis patients with gastrointestinal and hepatobiliary manifestations.

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.

CONCLUSION: 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.