- Consequential micro-deletions may be detected within three regions of the long arm of the Y chromosome, designated as AZF (Azoospermic Factor) a, b, and c.
- Y chromosome micro-deletions are identified in 3–13% of infertile men.
- Too small to be identified by karyotype analysis alone, micro-deletions are identified by a polymerase chain reaction-based technique using multiple sequence-tagged sites.
- Deletions of the different regions are associated with different capacities for sperm production.
- Approximately one third of men with deletions of the AZFc region may have sufficient spermatogenesis to produce spermatozoa within the ejaculate;
- For those who are azoospermic, sperm may be retrieved by TESE (to be used for ICSI) in the majority of these men.
In addition to the men whose infertility is connected with genetic disease, there are genetic defects that seem to carry no ill consequences for general health but do cause severe and heritable infertility in men.
Chief among these are the azoospermia factor (AZF) micro-deletions in three spots on the Y chromosome, termed the AZFa, AZFb, and AZFc regions, which are found in up to 15 percent of men with very few sperm.
In the stark language of geneticists, these mutations are “genetically lethal” — that is, these are mutations that would naturally preclude fathering offspring.
The fertility treatment ICSI has changed the outlook:
Intracytoplasmic Sperm Injection (ICSI) is often recommended in cases of male infertility. This procedure consists of extracting a spermatozoon from a sample of semen or by testicular biopsy to select the most appropriate sperm.
ICSI has changed the prospects for most of these men, as men with micro-deletions in the AZFc region, the most common of the three, harbor enough sperm that it is possible for them to father children.
Micro-deletions in the AZFa and AZFb regions, which are comparatively rare, result in such complete infertility that TESE cannot yield enough sperm to allow ICSI.
Genetic testing on the ICSI-produced sons of men with AZFc micro-deletions shows that the mutation is invariably passed down. A new generation of boys who will inherit their fathers’ infertility is being born.
Choosing the right lab for testing is important:
Because micro-deletion testing is not standardized, selection of an experienced laboratory that thoroughly tests for deletion of entire regions (not just partial deletion) is important, as clinically relevant prognostic information can only be applied to patients with complete deletion of one or more regions.
Passing down genes to male offspring:
Patients with infertility due to an AZF micro-deletion are thus required to make a choice to proceed with ICSI knowing the consequences for their male children. Many parents are not dissuaded from proceeding with ICSI by the knowledge that any sons will inherit their fathers’ infertility: one study conducted in Belgium and the Netherlands found that four-fifths of prospective parents went ahead with ICSI after the man received a diagnosis of a micro-deletion in the AZFc region. Most parents who choose ICSI in spite of a father’s AZFc micro-deletion likely reason that a son could use ICSI to father children just as they have done. The one-fifth of prospective parents who received a diagnosis of AZFc micro-deletion and then abandoned their efforts to have a child genetically related to the father perhaps believed that there is something wrong with counting on ICSI to begin a line of sterile male descendants. Of the prospective parents who did not choose ICSI, more discontinued their fertility treatment than opted for donor sperm — suggesting that they would rather adopt a child or remain childless than have a child genetically related only to the mother.
The PGD method:
The technique of preimplantation genetic diagnosis (PGD) is commonly explained as a way of checking the genes of embryos produced by IVF for serious genetic diseases.
It is possible to avoid the birth of infertile males by employing the PGD method [L]. In the case of AFZc deletions, PGD could be used to select for female embryos, although none of the clinics that participated in the study [L] mentioned above offered sex selection in the case of AZFc micro-deletions. In the past, sex selection through PGD was used only for couples who risked passing along the genes for serious diseases, such as:
- Duchenne/Becker muscular dystrophy,
- and fragile X syndrome.
Since men with AZFc micro-deletions typically enjoy good health apart from their infertility, the possibility of using PGD to select against male embryos who would carry this mutation reopens troubling questions about what kind of criteria society will accept as reason enough to eliminate a nascent life.
Test results may vary depending on your age, gender, health history, the method used for the test, and other things. Your test results may not mean you have a problem. Ask your healthcare provider what your test results mean for you.
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