MUTATIONS IN THE CYSTIC FIBROSIS GENE IN PATIENTS WITH CONGENITAL ABSENCE OF THE VAS DEFERENS

Background. Congenital bilateral absence of the vas deferens (CBAVD) is a form of male infertility in which mutations in the cystic fibrosis transmembrane con- ductance regulator (CFTR) gene have been identified. The molecular basis of CBAVD is not completely under- stood. Although patients with cystic fibrosis have muta- tions in both copies of the CFTR gene, most patients with CBAVD have mutations in only one copy of the gene. Methods. To investigate CBAVD at the molecular lev- el, we have characterized the mutations in the CFTR gene in 102 patients with this condition. None had clini- cal manifestations of cystic fibrosis. We also analyzed a DNA variant (the 5T allele) in a noncoding region of CFTR that causes reduced levels of the normal CFTR protein. Parents of patients with cystic fibrosis, patients with types of infertility other than CBAVD, and normal subjects were studied as controls. Results. Nineteen of the 102 patients with CBAVD had mutations in both copies of the CFTR gene, and none of them had the 5T allele. Fifty-four patients had a mutation in one copy of CFTR, and 34 of them (63 per- cent) had the 5T allele in the other CFTR gene. In 29 patients no CFTR mutations were found, but 7 of them (24 percent) had the 5T allele. In contrast, the fre- quency of this allele in the general population was about 5 percent. Conclusions. Most patients with CBAVD have muta- tions in the CFTR gene. The combination of the 5T allele in one copy of the CFTR gene with a cystic fibrosis mu- tation in the other copy is the most common cause of CBAVD. The 5T allele mutation has a wide range of clin- ical presentations, occurring in patients with CBAVD or moderate forms of cystic fibrosis and in fertile men. (N Engl J Med 1995;332:1475-80.)