Genetic Heterogeneity Correlated with Phenotypic Variability in 48 Patients with Cystic Fibrosis

Cystic fibrosis (CF) is a rare autosomal recessive genetic disease that has a progressive and multisystemic course. The spectrum and frequency of mutations in the gene enco-ding the cystic fibrosis transmembrane conductance regulator (CFTR) varies both in European countries and in other geographical regions. The aim of the our retrospective study was to present the genetic variants identified in a group of 48 patients with CF patients from the Moldova region (Romania), as well as to establish genotype-phenotype correlations. Genetic testing was initially performed for 38 CFTR mutations, and in heterozygous patients or in whom no mutation was detected, CFTR gene sequencing (NGS) was performed.The compound heterozygous genotype was identified in 26 (54.16%) of the patients (one of the alleles being F508del), while 22 (45.83%) patients had the homozygous F508del genotype. The F508del variant was the most frequent (69.79%), followed by: G542X (6.25%, 6/96), c.621 +1G>T (3.12%, 3/96), 1677delTA (3.12%, 3/96), 185+1G->T (3.12%, 3/96), 2184insA (2.08%, 2/96), c.917dupA (2.08%, 2/96) and 3849G>A (2.08%, 2/96). Several new variants were also identified, which had not been reported in other studies from Romania (R1158X, K598*, R347H, c.2589_2599del, R496H, and CFTRdele2). We compared the results obtained with data from the literature and correlated the detected CFTR variant (genotype) with the phenotypic manifestations, highlighting certain particularities present in some patients. Genetic testing allows for early diagnosis and adapted management, including personalized treatment for each patient. Identification of novel unclassified CFTR variants still remains a challenge for clinicians. NGS-based screening of heterozygous healthy carriers is important for both genetic counseling and prenatal diagnosis.