Chromosome Y microdeletion (ORPHA:1646)
A genetic male infertility characterized by azoospermia or oligozoospermia due to chromosome Y microdeletion.
Epidemiology
Estimated prevalence is 1/2500.
Clinical description
The diagnosis is usually made in adulthood, in the context of a couple's infertility. The spermogram shows non-obstructive azoospermia or oligozoospermia of variable intensity, usually severe.
Etiology
5 to 10% of cases of azoospermia (absent sperm) or severe secretory-type oligospermia (<1 million spermatozoa/mL semen) are associated with microdeletions in the euchromatic portion of the Y-chromosome long arm, at the AZF locus (azoospermia factor). Several subregions are distinguished in the AZF locus. In this region, the structure of the Y-chromosome is rich in repeated palindromes and recombination between two flanking sequences sharing a high degree of homology leads to various deletions: i) AZFa deletions (recombination between the sequences HERV15yq1 and HERV15yq2); the rarest - ii) AZFb or P5/proximal-P1 deletions, iii) AZFb+c deletions, of which two types are distinguished: P5/distal-P1 or P4/distal-P1 and iv) AZFc deletions caused by recombination between palindromes b2 and b4.
Diagnostic methods
Diagnosis is made on the basis of azoospermia or oligozoospermia in otherwise healthy males after exclusion of other causes of infertility. Molecular diagnosis is made by PCR amplification of STS type sequences (sequence-tagged sites) from the AZFa, b, and c regions. AZFc deletions are the most frequent; they are associated with azoospermia or oligospermia, usually severe. Complete deletions of AZFa, AZFb+c and AZFb regions are always associated with azoospermia: testicular histology shows either total lack of germline cells (SCOS or Sertoli cell only syndrome) or more or less systematized arrested maturation of cells from the spermatogenetic cell lineage.
Differential diagnosis
The differential diagnosis includes multiple causes of non-obstructive azoospermia, the most frequent being 47,XXY syndrome, other genetic hypogonadisms like Kallmann syndrome, testis inflammation (orchitis), infectious diseases (i.e. mumps after puberty), treatment (cancer chemotherapy), cryptorchidism, etc. Recent studies have identified numerous variants in multiple genes leading to azoo- or oligozoospermia.
Genetic counseling
Most Y chromosome microdeletions are de novo. Transmission is Y-linked. In case of spontaneous or following assisted reproductive techniques, male offsprings will inherit the paternal deletion.
Management and treatment
All chromosome Y microdeletions do not necessarily lead to infertility: firstly, some deletions (especially some partial deletions) do not result in spermatogenesis defects; secondly, among men with severe oligospermia, some can father children without infertility treatment. Finally, when mature spermatozoa are found in the sperm or in the testicles, the infertility problem can be solved with medically assisted procreation techniques such as TESE (testicular sperm extraction)-ICSI (intracytoplasmic sperm injection). However, there is a risk of transmitting the microdeletion to every male infant.
Prognosis
The condition has no impact on life expectancy. Some patients may be psychologically impacted by learning that their infertility is due to a genetic abnormality.

                            Last update: 
                            July 2023


                            - Expert reviewer(s): 
                            Dr Florence FELLMANN  - Dr James LESPINASSE