Y chromosome microdeletion

  • About disease
  • About screening
  • Treatment

Genetically males have two sex chromosomes: one X and one Y chromosome. Y chromosome is made up of three regions: the pseudoautosomal region (PAR 1 and PAR 2), the heterochromatin (structural) and euchromatin (informational) regions. Among them the last two are joined in the MSY, the non-recombination (male-specific) region.

Pseudoautosomal regions make up about 5% of the Y chromosome and may recombine with the X chromosome during meiosis. The remaining 95% of the Y chromosome, representing the male non-recombining region (MSY), does not undergo recombination and does not crossover with the X chromosome.

The male non-recombining region (MSY) consists of a long and short arm connected by a centromere. The short arm itself includes the SRY, ZFY/ZFX regions determining testis development and differentiation. As for the long arm, it contains the AZFa, AZFb, and AZFc regions. Spermatogenesis begins in the AZFa region, continues in the AZFb and ends in the AZFc. These regions are important for normal spermatogenesis. That is why deletions in the AZF region are the most frequent genetic factor in spermatogenesis disorders.

At Gemonics, YCM screening is performed through PCR amplification. According to the European Academy of Andrology (EAA) guidelines, the PCR reaction should utilize specific sequence-tagged sites (STS) surrounding regions of the Y chromosome that are commonly deleted in oligospermic and azoospermic men.

To promote the sensitivity of the analysis, two STS should be amplified in each region. The Y chromosome deletion test is based on the principle of reverse hybridization and detects mutations in 5 regions. Namely: AZFa, AZFb and AZFc, as well as sections of the short arm of the Y chromosome – SRY and ZFY. The Y chromosome deletion test is based on the principle of reverse hybridization and detects mutations in 5 regions, namely: AZFa, AZFb, and AZFc, as well as the SRY and ZFY regions of the Y chromosome short arm.

The test results show:

Presence/absence of 6 STS (sequence tagged sites). These sequences are found in all three regions (AZFa, AZFb, AZFc) of azoospermia factor (AZF) that are required for normal spermatogenesis.

  • AZFa (sY84; sY86) – AZFa microdeletion can cause complete azoospermia and/or testicular fibrosis;
  • AZFb (sY127; sY134) – AZFb is associated with the initiation of the meiosis phase during spermatogenesis, so in case of microdeletion the process may stop at this stage;
  • AZFc (sY254; sY255) – AZFc is the most frequent microdeletion among AZFs. It is the cause of many clinical and histological phenotypes.

This test shows the presence/absence of the following two sequences:

  • ZFY (consists of homologous genes and is used in the test as a kind of control of the DNA extraction and amplification process);
  • SRY (responsible for the determination of the testis, and its mutation can cause abnormalities in the initiation of development and differentiation of the testis).

Screening for YCM in men with infertility problems is an important study, the outcome of which determines the clinical management strategy of the patient using assisted reproductive technologies (TESE, IVF, ICSI).

It should be noted that AZFc is the most frequent deletion type among all microdeletions. It accounts for 60-80% of all deletions. At the same time, in contrast to the AZFa and AZFb microdeletions, in the case of AZFc a man has the highest chances of having a biological child through assisted reproductive technologies. In cases of AZFa and AZFb microdeletions, the probability of pregnancy is very low. Therefore, the results of the YCM study can play an important role in determining the right course of treatment.

When a man has non-obstructive azoospermia (NOA), microsurgical sperm aspiration from the testicle or epididymis is considered the gold standard of treatment. In non-obstructive azoospermia caused by Y chromosome microdeletions, the rate of successful sperm retrieval depends greatly on the region of AZF that is absent. According to the studies, deletions in the AZFc region are associated with the highest sperm retrieval rate amounting to 50-80%, while in cases of AZFa and AZFb there are reported unfavorable sperm retrieval rates and clinical outcomes. Moreover, there may also be simultaneous microdeletions of several AZF regions, for example, AZFbc or AZFabc, resulting in the same unfavorable prognosis. In order to avoid ineffective surgical intervention, surgical sperm aspiration is not recommended for patients with verified presence of deletions in the AZFa, AZFb, AZFabc, or AZFbc regions.

Frequently Asked Questions

Who should undergo Y chromosome deletion screening?

The screening is recommended for men diagnosed with azoospermia (no sperm in the ejaculate) or severe oligospermia (1 million or less sperm in the ejaculate).