Frequent occurrence of the CFTR intron 8 (TG)n 5T allele in men with congenital bilateral absence of the vas deferens.

Isolated congenital bilateral absence of the vas deferens (CBAVD) is an autosomal recessive disorder which has recently been shown to be associated with cystic fibrosis (CF) mutations. As part of an effort to understanding the genetic basis of this disorder, we have analysed the entire coding sequence and all the intron/exon boundaries of the cystic fibrosis transmembrane conductance regulator (CFTR) gene from 45 azoospermic individuals with this phenotype. We were able to detect a CFTR gene defect in 86% of chromosomes from these subjects. In addition to identifying 9 novel CFTR gene mutations, we found that a surprisingly high proportion (84%) of men with CBAVD who are heterozygous for a CF mutation carry the intron 8 polypyrimidine 5T CFTR allele on one chromosome. We hypothesise that this tight and significant (p < 10−6) linkage reflects the very mild impact of this mutation on CFTR gene expression. Although genetic heterogeneity cannot be excluded, CBAVD patients in whom no CFTR mutation has been detected are likely to harbour additional unidentified mild mutations. These observations have implications for the genetic counselling of CBAVD patients and CF families, and couples undergoing in vitro fertilisation procedures.