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

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.

L138ins Variant of the CFTR Gene in Russian Infertile Men.

(1) Introduction: Pathogenic variants in the CFTR (Cystic Fibrosis Transmembrane conductance Regulator, OMIM: 602421) gene cause Cystic Fibrosis (CF, OMIM: 219700) and CF-related disorders (CF-RD), often accompanied by obstructive azoospermia due to congenital bilateral aplasia of vas deferens (CBAVD, OMIM: 277180) in male patients. The L138ins (c.413_415dup; p. (Leu138dup)) is a mild variant in the CFTR gene that is relatively common among CF-patients in Slavic populations. The frequency of this variant in Russian infertile men has not been sufficiently studied; (2) Materials and Methods: The sample consisted of 6033 Russian infertile men. The patients were tested for 22 common in Russian populations pathogenic variants of the CFTR gene and the IVS9Tn-polymorphic locus of the intron 9. Molecular-genetic studies were performed using amplified fragment length polymorphism (AFLP-PCR), multiplex ligation-dependent probe amplification (MLPA), and nested PCR (for analysis of the IVS9Tn-polymorphic locus); (3) Results: Pathogenic variants in the CFTR were detected in 3.9% of patients. The most frequent variants were F508del and CFTRdele2.3(21kb), accounted for 61.0% and 7.1% of detected variants, respectively. The L138ins variant was detected in 17 (0.28%) individuals: one of them was homozygous, 10 patients were heterozygous, and 6 patients were compound-heterozygous (F508del/L138ins, n = 4; L138ins/N1303K, n = 1; L138ins/5T, n = 1). Two pathogenic CF-causing variants in the CFTR gene were detected in 8 patients, including 7 compound heterozygous (F508del/L138ins, n = 4; F508del/N1303K, n = 1; 2184insA/E92K, n = 1; 3849+10kbC>T/E92K, n = 1) and one homozygous (L138ins/L138ins). The L138ins variant was found in 7 out of 16 (43.75%) chromosomes in six of these patients. The most common pathogenic variant, F508del, was identified in five out of them, in 5 of 16 (31.25%) chromosomes. The allele frequency (AF) of the L138ins variant in the sample has been found to be 0.0014.; (4) Conclusions: The L138ins variant of the CFTR gene is the third most common variant after F508del and CFTRdele2.3(kb) among Russian infertile men.

Comprehensive semen examination in patients with pancreatic-sufficient and pancreatic-insufficient cystic fibrosis.

We examined a cohort of 93 cystic fibrosis (CF) male patients who were pancreatic-sufficient (PS-CF; n=40) or pancreatic-insufficient (PI-CF; n = 53). Complex semen examination was performed, including standard semen analysis, quantitative karyological analysis (QKA) of immature germ cells (IGCs), transmission electronic microscopy (TEM), biochemical analysis, and sperm DNA fragmentation by terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling (TUNEL) assay. Azoospermia was diagnosed in 83 (89.2%) patients. The other 10 (10.8%) patients were found to be nonazoospermic and showed various spermatological diagnoses (asthenozoospermia, n = 2; asthenoteratozoospermia, n = 3; oligoasthenozoospermia, n = 1; oligoasthenoteratozoospermia, n = 3; and normozoospermia, n = 1) with no specific morphological abnormalities. Oligospermia was detected in 89.2% azoospermic and 30.0% nonazoospermic patients. Low seminal pH (<7.0) was found in 74 (89.2%) of 83 azoospermic patients. Moderate leukocytospermia (2.0 × 10 6 -2.2 × 10 6 ml -1 ) was revealed in 2.4% azoospermic and 40.0% nonazoospermic semen samples. The signs of partial meiotic arrest at prophase I were found in 4 of 6 nonazoospermic patients examined by QKA of IGCs. The content of fructose and citrate was low in oligospermic and normal in nonoligospermic semen samples. An increased percentage (>30%) of spermatozoa with noncondensed ("immature") chromatin was revealed in 2 of 6 nonazoospermic semen samples analyzed by TEM.