Pathogenic Variants and Genotypes of the CFTR Gene in Russian Men with Cystic Fibrosis and CBAVD Syndrome

Abstract

Pathogenic CFTR variants cause cystic fibrosis (CF), and CF-related disorders (CF-RD), including bilateral aplasia of the vas deferens (CBAVD). The spectrum of clinical manifestations depends on the CFTR genotype. The frequency and spectrum of the CFTR variants vary between populations and clinical groups. CFTR variants and genotypes were analyzed in Russian men with CF (n = 546) and CBAVD syndrome (n = 125). Pathogenic variants were detected in 93.95% and 39.2% of the CF and CBAVD alleles, respectively. The most frequent c.1521_1523del (F508del; p.Phe508del) variant was found in 541 (49.5%) CF alleles. A total of 162 CFTR genotypes were revealed in CF patients, including 152 homozygous and 394 compound-heterozygous. The most common CF-genotype was F508del/F508del (24.9%). Other frequent CF-genotypes were F508del/3849+10kbC>T, F508del/CFTRdele2,3, and F508del/E92K. CF-causing variants and/or 5T allele were found in 88% of CBAVD patients: 5T/CFTRmut (48.0%), CFTRmut/N (17.6%), CFTRmut/CFTRmut (6.4%), 5T/5T (10.4%), 5T/N (5.6%) and N/N (12.0%), with the most common CBAVD-genotype being F508del/5T (29.6%). The allele frequencies of F508del, CFTRdele2,3 394delTT, and 3849+10kbC>T were significantly higher in CF patients. L138ins/L138ins, 2184insA/E92K, and L138ins/N genotypes were found in CBAVD, but not in CF patients. The results indicate certain differences in the frequency of some CFTR variants and genotypes in Russian CF and CBAVD patients.

Russian Regional Differences in Allele Frequencies of CFTR Gene Variants: Genetic Monitoring of Infertile Couples

“…Interestingly, the total frequency of the 11 variants was also substantially higher among infertile men compared with either source of population AFs (0.0240 compared to the maximum value of 0.0117 for the healthy individuals from RUSeq), but lower in infertile Russian men without CBAVD syndrome (AF = 0.0164) (chi-squared = 100.19, df = 2, p-value < 2.2 × 10 −16 ). This finding corroborated previous studies [12], reinforcing the significance of CFTR gene variants in male infertility monitoring. However, due to the low carrier rate of other variants in the population data, definitive conclusions regarding these variants could not be drawn.…”

“…Remarkably, despite the high prevalence of obstructive azoospermia in individuals with CF, prior investigations have demonstrated distinct spectrum and frequencies of CFTR variants among CF patient cohorts compared with those with CBAVD without CF. In a cohort of infertile Russian men without CF, the most commonly identified variants were F508del, CFTRdele2,3(21kb), and L138ins (c.413_415dup; p.Leu138dup) [12].…”