title: Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia.
abstract: BACKGROUND
  Infertile men with obstructive azoospermia may have mutations in the 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 undetected by routine screening are detected with more extensive screening in obstructive azoospermia.
  
  
  METHODS
  Routine screening for the 31 most common CFTR mutations associated with the CF phenotype in white populations, testing for the 5-thymidine variant of the polythymidine tract of intron 8 (IVS8-5T) by allele-specific oligonucleotide hybridization, and screening of all exons through multiplex heteroduplex shift analysis followed by direct DNA sequencing.
  
  
  METHODS
  Male infertility clinic of a Canadian university-affiliated hospital.
  
  
  METHODS
  Of 198 men with obstructive (n = 149) or nonobstructive (n = 49; control group) azoospermia, 64 had congenital bilateral absence of the vas deferens (CBAVD), 10 had congenital unilateral absence of the vas deferens (CUAVD), and 75 had epididymal obstruction (56/75 were idiopathic).
  
  
  METHODS
  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 nonobstructive 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 sequencing and IVS8-5T testing (47 and 25, respectively; P<.001 and P = .002 vs controls) vs 39 by the routine panel (P<.001 vs controls). In the idiopathic epididymal obstruction group, 24 mutations were found by DNA sequencing and IVS8-5T testing (12 each; P=.01 and P=.14 vs controls) vs 5 by the routine 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 detectable 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 alterations. The barrier to conception for men with obstructive infertility has been overcome by assisted reproductive technologies, thus raising the concern of iatrogenically transmitting pathogenic CFTR mutations to the progeny.
authors.affiliation: Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Mak
authors.forename: J
authors.initials: J
authors.lastname: Zielenski
authors.forename: L C
authors.initials: LC
authors.lastname: Tsui
authors.forename: P
authors.initials: P
authors.lastname: Durie
authors.forename: A
authors.initials: A
authors.lastname: Zini
authors.forename: S
authors.initials: S
authors.lastname: Martin
authors.forename: T B
authors.initials: TB
authors.lastname: Longley
authors.forename: K A
authors.initials: KA
authors.lastname: Jarvi
mesh_terms: D000328:Adult; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D005820:Genetic Testing; D006801:Humans; D008297:Male; D009154:Mutation; D009845:Oligospermia / Q000235:genetics*
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator