Y Chromosome Deletion Analysis

Y chromosome deletions are typically characterized by azoospermia, severe to moderate oligozoospermia, and/or abnormal sperm morphology/motility. Males with Y chromosome deletions usually have no obvious symptoms, although physical examination may reveal small testes. Y chromosome deletions are the most frequent cause of spermatogenic failure in infertile men with normal cytogenetic chromosomes. Incidence of these deletions in infertile men is about 3-10% (Silber and Disteche 2012).

A portion of the Y chromosome has been subdivided in three AZF (Azoospermia Factor) regions: AZFa, AZFb and AZFc. Each AZF region contains several genes associated with normal spermatogenesis. AZFa deletions are rare and usually produce the severe phenotype of Sertoli-cell-only syndrome (SCOS). AZFb and/or AZFb/c deletions are uncommon and usually result in severe azoospermia. AZFc deletions are relatively common and result in a variable infertility phenotype, ranging from azoospermia and SCOS to severe or mild oligozoospermia (Silber 2011).

The correct diagnosis of the genetic cause of infertility is important for the further treatment of patients. Furthermore, Y chromosome deletion testing is recommended before a couple undergoes assisted reproduction in order to prevent the possible transmission of the genetic lesion to the next generation.

Y chromosome deletions inherited in a Y-linked manner. Cases of Y chromosome microdeletions usually occur de novo, and due to the infertile phenotype, they are typically not transmitted. Despite their severely impaired spermatogenesis, some males with deletions in the AZF regions have occasionally spontaneously fathered sons who are infertile. In cases where assisted reproductive technology is used to achieve pregnancy, male offspring have the same deletion as their father, with a high risk of male infertility (Silber 2012).

The AZFa region is about 1100 kb long and contains two single-copy genes USP9Y and DDX3Y. Complete deletion of the AZFa region removes both genes. The AZFb and AZFc regions together encompass 24 genes, most of which are present in multiple copies for a total of 46 copies. Complete deletion of AZFb removes 6.2 Mb (including 32 copies of genes). The AZFc region includes 12 genes, each present in a variable number of copies making a total of 32 copies. The classical complete deletion of AZFc, the most frequent pattern among men with deletions of the Y chromosome, removes 3.5 Mb (Krausz 2014).

Y chromosome deletions are estimated in 5%-15% of men with non-obstructive azoospermia or severe oligospermia (Silber and Disteche 2012).

Testing for deletions involves investigating for the presence or absence of markers located within nonpolymorphic regions of the AZFa, AZFb, and AZFc regions. Y chromosome deletions are detected by multiplex PCR amplification. Over 99% of the five common microdeletions AZFa, AZFb, AZFbc and AZFabc will be detected by this assay (Krausz 2014).