I. Disease
Male infertility concerns around 10 % of the human population. It is often related to the quantity, mobility and morphology or functioning of spermatozoa.
II. Causes
The causes of male infertility are multiple (endocrine, obstructive, infectious, congenital, genetic, medicinal, other). The etiology can be identified in 50-60 % of cases, following a series of examinations.
III. Epidemiology
Microdeletions are a genetic cause to the male infertility.They are found in 15 -20 % of men presenting an azoospermia and around 5 – 7 % of men presenting an oligozoospermia. It is estimated that 1/1000 male births carry a Yq de novo (when none of the parents carries the microdeletion).
IV. Genetics
Some facts :
- Inheritance is Y-linked.
- Y chromosome microdeletions typically occur de novo. Rarely, men carrying a microdeletion may be fertile and father infertile sons.
- Penetrance is near 100 percent in affected males.
- Microdeletions of the azoospermia factor (AZF) regions on the q arm of the Y chromosome are present in 5–10 percent of males with non-obstructive azoospermia or severe oligospermia.
- Routine karyotype will detect abnormalities in 5–10 percent of infertile males. Cytogenetic analysis cannot detect Y chromosome deletions, interstitial deletions of the AZF regions, or whether a visible Y chromosome deletion includes the AZF regions.
Depending on the deleted region, the phenotypical profile will be different:
- A deletion in region AZFa is associated to the syndrome of « Sertoli cell only type I » (SCOS1) with total absence of germinal cells.
- A deletion in the region AZFb is associated to a blockage in the spermatogenesis at spermatozoa level.
- A deletion in region AZFc is associated to various phenotypes, from azoospermia with presence of few germinal cells (seen at the testis biopsy), to oligozoospermia.
Several regions can be simultaneously deleted, modifying even more the phenotype. Besides complete deletions, we can also observe partial deletions, which concern just a part of the region. The correlation phenotype/genotype becomes then difficult.The severity of the infertility depends on the function of the deleted region. It is possible to evaluate the success chance of the medically assisted techniques of procreation (eg : ICSI,. First, the microdeletions will allow evaluating the probability of finding spermatozoids – by a testicular biopsy (TESE,Testicular Sperm Extraction). Indeed, a deletion in the region AZFb will always be a bad prognosis, while a patient presenting a deletion in region AZFc will have 50 % of chances of having spermatozoids at the biopsy.
V. Diagnosis
Before a Yq search of microdeletions, the first step of diagnosis starts by a spermogramme. In the case of severe oligospermia; the analyses have to be completed by a FSH dosage and a karyotype. If the karyotype is normal; a molecular analysis of Y chromosome can be considered. The genetic diagnosis will search deletions in the three regions of Y chromosome (long arm in Y chromosome) concerned, AZFa, AZFb et AZFc, these regions including the spermatogenesis genes.
VI. Genetic analysis – Technique
Biological sample: saliva on FTA cardAnalysis of the following mutations:Search of microdeletions in Y chromosome (regions AZFa, AZFb and AZFc)Analysis description: PCR multiplex: amplification of loci ZFY, SRY, sY127, sY254, sY84, sY134 and sY255.
VII. Solutions
Thanks to the ICSI (Intra Cytoplasmic Sperm Injection), men carrier of certain microdeletions in Y chromosome can have children. However, these microdeletions will be inevitably passed on to their children, which will also have a strong probability of being infertile.