Specifics of cystic fibrosis genetic spectrum in Georgia

Abstract

Cystic fibrosis (CF) is a life-threatening autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). F508del is the most common mutation in the world. Other mutations are rare and population specific. The study aimed to comprehensively analyze the distribution of CFTR mutations in Georgian CF patients. Knowing the prevalence and characteristics of specific mutations can be reflected in genetic counseling and management strategies. We reviewed the data of 129 CF patients, aged < 18 years, from all parts of Georgia. 91 patients with a clinically confirmed CF diagnosis were tested for CF-causing mutations (constituting 70.5% of all currently registered CF patients in the country). These patients have been analyzed for rare CFTR variants by massively parallel sequencing of the entire CFTR coding region and adjacent introns combined with the analysis of intra-CFTR rearrangements.  CFTR gene analysis revealed 29 mutations in Georgian CF patients. The most common mutation was c.1545_1546delTA (1677delTA) with a frequency of 42.7%, while the second most common mutation, W1282X, was detected in 11.2% of all CF alleles. Another 27 CFTR mutations have low frequency, including F508del (6.7% of alleles). 3 novel mutations were found (c.708dupT; CFTRdele16_17; c.3170C>G) and reported to CFTR2 database.According to the data, the distribution of CFTR mutations in the Georgian CF population differs regarding the high frequency of mutation c.1545_1546delTA (1677delTA) and the low frequency of the predominant F508del mutation. Compared to patients with F508 del and W1282X mutations, patients with 1677delTA have typical manifestations and complications; however, the frequency of growth retardation and liver damage is 3 times, and the frequency of chronic respiratory manifestations and chronic malnutrition is 2 times lower, though pancreatic insufficiency is more severe in patients with 1677delTa. CF-associated diabetes, distal intestinal obstruction syndrome, and hemoptysis were only observed in patients with the 1677delTA mutation. The mortality rate is lower compared to patients with F508del and W1282X mutations.