None of the CFTR mutations were observed in patients with azoospermia without CAVD or with severe oligozoospermia and the frequency of allele 5T was 3.6% (three out of 78 alleles) and 1.35% (one out of 74 alleles) respectively.
In a subset of infertile men, a spectrum of spermatogenic defects ranging from a complete absence of germ cells (sertoli cell only) to oligozoospermia is associated with microdeletions of the DAZ (deleted in azoospermia) gene cluster on human distal Yq.
This procedure could be particularly useful in screening for the DAZ locus in the diagnostic workup of nonobstructive azoospermia and severe oligoasthenoteratozoospermia.
Deletions in the AZFc region involving the DAZ gene were the most frequent finding and they were more often observed in severe hypospermatogenesis than in Sertoli cell-only syndrome, suggesting that deletions of this region are not sufficient to cause complete loss of the spermatogenic line.
Finally, neither the frequency of CFTR mutations nor the frequency of the TG12-T5 variants differed between patients with mild oligospermia (74 cases) and patients with ovulatory sterility (30 cases) compared with the general population.
We conclude that partial deletions of the DAZ genes are associated with oligozoospermia but not with azoospermia; however, an increased number of DAZ genes does not seem to be a statistically significant risk factor for spermatogenic failure.
Therefore, screening for the IVS8-5T mutation in the CFTR gene may be recommended for men with NOA or severe oligozoospermia seeking assisted reproductive technology (ART).
Twelve of 101 patients (12%) with the AZFc/DAZ microdeletion were found, including 8 with azoospermia (11%) and 4 with severe oligozoospermia (14.3%), and 1 patient had a AZFb and AZFc/DAZ double deletion.
Five individuals with heterozygous pathogenic CFTR variants were identified using targeted NGS in a cohort of 1112 idiopathic infertile men with azoospermia or severe oligozoospermia.
Chromosome aberrations, Y chromosome microdeletions and CFTR (cystic fibrosis transmembrane conductance regulator) mutations alone may explain up to 25% of azoospermia and severe oligozoospermia.
Copy deletion screening of DAZ gene family on the Y chromosome in 485 patients with idiopathic azoospermia or oligozoospermia and 236 fertile men revealed that the prevalence of deletion patterns of the entire DAZ gene and DAZ1/DAZ2 gene were significantly higher in the patients than in fertile men.
With these diagnostic tools, 63 DNA samples from men with idiopathic oligozoospermia and 107 DNA samples from men with proven fertility were analysed for the presence of the complete DAZ gene locus, encompassing the four DAZ gene copies.
More interestingly, partial DAZ1/2 deletion was associated with azoospermia (ORs=2.63, 95%CI: 1.19-5.81, I(2)=64.7%) and oligozoospermia (ORs=2.53, 95%CI: 1.40-4.57, I(2)=51.8%), but partial DAZ3/4 deletion was not associated with azoospermia (ORs=0.71, 95%CI: 0.23-2.22, I(2)=71.7%,) and oligozoospermia (ORs=1.21, 95%CI: 0.65-2.24, I(2)=55.5%).
Maturation arrest and hypospermatogenesis tissues expressed significantly low levels of DDX3Y testicular transcript (P < 0.001), while the mRNA levels of the other genes were similar to that in tissues from the normal spermatogenesis group.
The expression of DBY in a cell line from this latter patient is unaltered; this shows that it is the loss of genes lying within the deletion that is responsible for the observed oligozoospermia.
While deletions or even smaller mutations in USP9Y seem to be associated with a testicular phenotype of severe hypospermatogenesis, patients with deletions of DBY may present both Sertoli cell-only syndrome and severe hypospermatogenesis.
One of these two patients had DFFRY deletion and the other had DBY deletion; their testicular phenotypes were Sertoli cell-only syndrome and hypospermatogenesis, respectively.
Deletions in the azoospermia factor region AZFa on the human Y chromosome and, more specifically, in the region that encompasses the ubiquitin-specific peptidase 9, Y-linked gene USP9Y have been implicated in infertility associated with oligospermia and azoospermia.
While deletions or even smaller mutations in USP9Y seem to be associated with a testicular phenotype of severe hypospermatogenesis, patients with deletions of DBY may present both Sertoli cell-only syndrome and severe hypospermatogenesis.
To uncover the functional contribution of DAZ to human spermatogenesis, a DAZ gene copy-specific deletion analysis was previously established and showed that DAZ1/DAZ2 deletions associate with oligozoospermia.
Analysis of DAZ gene copies in Tunisian population, suggested that the simultaneous deletion of DAZ2 and DAZ4 gene copies is associated with male infertility, and that oligospermia seems to be promoted by removing DAZ4 copy.