ETIOLOGY OF CONGENITAL ABSENCE OF VAS-DEFERENS - GENETIC-STUDY OF 3 GENERATIONS

Bilateral congenital absence of the vas deferens (CAVD) is a form of male sterility (found in otherwise normal men) of unknown aetiology. Because males with cystic fibrosis (CF) almost invariably have CAVD as well, we investigated the hypothesis that men with isolated CAVD might share a common genetic background with mates with CF. Genetic testing for CF was carried out in three generations of subjects: 44 patients with CAVD and their wives, 24 of their parents, and 13 of their offspring generated by microsurgical epididymal sperm aspiration (MESA) and in-vitro fertilization (IVF). DNA extracted from peripheral lymphocytes was amplified by the polymerase chain reaction (PCR) and then analysed for 12 mutations in the cystic fibrosis transmembrane conductance regulatory (CFTR) gene. Among 44 patients tested with CAVD, 26 (59%) were positive for at least one CF mutation, while the carrier frequency for CF mutations in the general population is only 4%. Four patients were found to be compound heterozygotes, three with genotypes Delta F-508/R117H, one with R553X/R117H. Among 24 parents tested, 15 (seven fathers, eight mothers) had sons with CAVD who were positive for CF mutations. Of these, nine (four fathers and five mothers) were found to be carriers for CF mutations. These four fathers, although carriers of CF mutations, were obviously fertile. Of the 13 offspring tested, six (three boys and three girls) had CF positive fathers. Of these, three (two girls and one boy) were found to be carriers for CF mutations. These MESA/IVF children are the first offspring to whom men with CAVD have been able to transmit CF mutations. All of the MESA/IVF male offspring (like their grandfathers) had a normal vas deferens bilaterally, including one carrier for Delta F-508. This study revealed, by genetic testing of otherwise normal men with sterility caused by CAVD, a new population of patients with a variant form of CF and highlighted the possibility that carrier frequency for CF is higher than previously thought. Compound heterozygosity for CF mutations and not carrier condition is associated with isolated CAVD. It is concluded that genetic counselling and screening for CF should be offered to couples undergoing sperm aspiration and IVF procedures when CAVD is a factor in their infertility.