What are the genetic reasons of infertility?

Infertility which 30-40% of couples suffer is caused by males. At the end of the result of studies regarding male infertility (anamnesis, physical treatment, hormonal, serologic, immunologic tests, ultrasonography and doppler checking) it is not possible to define etiolation. But the recent developments of molecular genetic provide us to obtain detailed information about the root of genetic infertility.

Acute male factor is mainly related the problems of genetic. It is known that Spermatogenesis is leaded by genes or gene groups located certain chromosomes, and the problems in this regions cause some irregularities on the stages of sperm concentration, sperm maturation or diversion. These diversions both in number and in structure on chromosomes, and the distortions in genes on the molecular level impose the spermatogenesis for the worse.

It is realized that , in the cases  which sperm concentration on ejaculatory system is less then 5 million, the risk of seeing karyotype anomaly is four times higher than those in fertile population. In acute OAT cases it is also defined that various karyotype anomalies have occurred and some structural chromosome anomalies like translocation or deletion are exists. Although in people who carry translocation spermatogenesis is affected badly, sometimes normal sperm parameters are observed. In these situations the reason of couples problems can be repetitive pregnancy loses.

In non-obstructive azoospermia cases, the probability of being seen chromosome anomalies is higher and anomaly risk is as fifteen times higher as those in fertile population.

For non- obstructive azoospremia patients anomalies especially cover sexual chromosomes. Komplet or Mosaic 47, XXY (Klinefelter Syndrome) is the best known sexual chromosome anomaly. Furthermore in these cases some structural distortions such as translocation, deletion, inversion on sexual chromosomes including 46,XX, 47,XXY or 46,XY/45,X. Sperm parameters are also affected at different levels. Beside sexual chromosomes  structural distortions on autosomal chromosomes also result in azoospermia.

The critical role of the genes of Y chromosome and gene families on testis determination and diversion has already been found. In Oligospermia or azoospermia microdeletions found the certain areas of Y chromosome prove how important these genes on spermatogenesis are. Analysis realized on azoospermia males shows that the cause is microdeletions located on the longer branch of the chromosome. Nowadays the responsible of azoospermia called AZF area is divided different zones ( AZFa, AZFb, AZFc and AZFd) by mapping.

While deletions are mostly observed in the area of AZFc, some deletions are also detected in other areas. These syndromes, cell-only syndrome, can show varied phenotype to spermatogenesis recession and hipospermatogenesis. In our center with the method of PCR, 20 locuses is scanned for microdeletions.to increase the number of locus increases the safety of diagnosis instead of increasing the microdeletion incidence.

Knowing the prognostic importance of obtaining sperm of Y microdeletion area is important and in the aspect of information before the process. For example It is shown that it could not be obtained sperm in the vast deletions including the area of AZFc ( AZFb+c and AZFa+b+c). On the contrary On limited deletions including solely AZFc area, it is possible to get mature spermatozoon from 50% of the patients. On the table below there is a compare of Y deletion areas of both sperm-obtained and not obtained cases.

In the cases of being defined of Y deletions, It is absolutely certain that these deletions will be conveyed to the male baby via Y chromosomes, and these babies will face the same problems in their maturation. Thus families should be informed about the problem beforehand.

Congenital bilateral/unilateral absence of vaz differences (CBAVD), causes obstructive azoospermia,  is responsible for 1-2% of male infertility and 6% of obstructive azoospermia. These patients have mutations of the gene of cystic fibrosis transmembrane conductor regulator (CFTR). Many syptoms show heterozygotic mutations.

The disease of cystic fibrosis occurred on people who is inherited autosomal recessive and carrying the mutation as homozygot does not show the same symptoms of characteristic lung and pancreas symptoms. Atypical symptoms (often monosymptomatic) can be found together with either bilateral ejaculatory ductus obstruction or obstruction inside the epididymis, vaz deference agenezy (bilateral or unilateral ) or alone.  In some cases subclinical symptoms (increased color concentration and sinusitis ) can be detected. Apart from that there are also patients having homozygot mutations and showing soft phenotype. Till now it has been encountered more than a hundred different mutations.

In the cases defined vaz deference agenezy related to cystic fibrosis carriage, Because of the high frequency of carriers and the high degree of marriage between relatives (20-40%), Controls and tests are also realize on partners too. The couples are informed about diseases on embryos, and the risks of carrying diseases, and PGT should be advised if needed.