Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia

Context Infertile men with obstructive azoospermia may have mutations in th e cystic fibrosis transmembrane conductance regulator (CFTR) gene, many of which are rare in classic cystic fibrosis and not evaluated in most routine mutation screening. Objective To assess how often CFTR mutations or sequence alterations undete cted by routine screening are detected with more extensive screening in obs tructive azoospermia, Design Routine screening for the 31 most common CFTR mutations associated w ith the CF phenotype in white populations, testing for the 5-thymidine vari ant of the polythymidine tract of intron 8 (IVS8-5T) by allele-specific oli gonucleotide hybridization, and screening of all exons through multiplex he teroduplex shift analysis followed by direct DNA sequencing. Setting Male infertility clinic of a Canadian university-affiliate hospital . Subjects Of 198 men with obstructive (n = 149) or nonobstructive (n = 49; c ontrol group) azoospermia, 64 had congenital bilateral absence of the vas d eferens (CBAVD), 10 had congenital unilateral absence of the vas deferens ( CUAVD), and 75 had epididymal obstruction (56/75 were idiopathic), Main Outcome Measure Frequency of mutations found by routine and nonroutine tests in men with obstructive vs nonobstructive azoospermia, Results Frequency of mutations and the IVS8-5T variant in the nonobstructiv e azoospermia group (controls) (2% and 5.1% allele frequency, respectively) did not differ significantly from that in the general population (2% and 5 ,2%, respectively), In the CBAVD group, 72 mutations were found by DNA sequ encing and IVS8-5T testing (47 and 25, respectively; P<.001 and P=.002 vs c ontrols) vs 39 by the routine panel (P<.001 vs controls). In the idiopathic epididymal obstruction group, 24 mutations were found by DNA sequencing an d IVS8-5T testing (12 each; P=.01 and P=.14 vs controls) vs 5 by the routin e panel (P=.33 vs controls). In the CUAVD group, 2 mutations were found by routine testing (P=.07 vs controls) vs 4 (2 each, respectively; P=.07 and P =.40 vs controls) by DNA sequencing and IVS8-5T testing. The routine panel did not identify 33 (46%) of 72, 2 (50%) of 4, and 19 (79%) of 24 detectabl e CFTR mutations and IVS8-5T in the CBAVD, CUAVD, and idiopathic epididymal obstruction groups, respectively. Conclusions Routine testing for CFTR mutations may miss mild or rare gene a lterations. The barrier to conception for men with obstructive infertility has been overcome by assisted reproductive technologies, thus raising the c oncern of iatrogenically transmitting pathogenic CFTR mutations to the prog eny.