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 a n autosomal recessive disorder which has recently been shown to be ass ociated with cystic fibrosis (CF) mutations, As part of an effort to u nderstanding the genetic basis of this disorder, we have analysed the entire coding sequence and all the intron/exon boundaries of the cysti c fibrosis transmembrane conductance regulator (CFTR) gene from 45 azo ospermic individuals with this phenotype. We were able to detect a CFT R gene defect in 86% of chromosomes from these subjects, In addition t o identifying 9 novel CFTR gene mutations, we found that a surprisingl y high proportion (84%) of men with CBAVD who are heterozygous for a C F mutation carry the intron 8 polypyrimidine 5T CFTR allele on one chr omosome, We hypothesise that this tight and significant (p < 10(-6)) l inkage reflects the very mild impact of this mutation on CFTR gene exp ression, Although genetic heterogeneity cannot be excluded, CBAVD pati ents in whom no CFTR mutation has been detected are likely to harbour additional unidentified mild mutations, These observations have implic ations for the genetic counselling of CBAVD patients and CF families, and couples undergoing in vitro fertilisation procedures.