Y Chromosome Infertility

Clinical characteristics: Y chromosome infertility is characterized by azoospermia (absence of sperm), severe oligozoospermia (<1 x 10⁶ sperm/mL semen), moderate oligozoospermia (1-5 x 10⁶ sperm/mL semen), or mild oligozoospermia (5-20 x 10⁶ sperm/mL semen). Males with Y chromosome infertility usually have no obvious symptoms, although physical examination may reveal small testes.

Diagnosis/testing: The diagnosis of Y chromosome infertility is established in a male with characteristic clinical and laboratory features and by identification of a hemizygous deletion of Yq involving the AZF regions or identification of a heterozygous pathogenic variant involving USP9Y (located within AZFa).

Management: Treatment of manifestations: Pregnancies may be achieved by in vitro fertilization using intracytoplasmic sperm injection (ICSI), an in vitro fertilization procedure in which spermatozoa retrieved from ejaculate (in males with oligozoospermia) or extracted from testicular biopsies (in males with azoospermia) are injected into an egg harvested from the reproductive partner.

Other: Testicular sperm retrieval for in vitro fertilization is ineffective for males with AZFb and AZFa deletions, but has been successful for most males with AZFc deletions; in males with retrievable spermatozoa, the presence or absence of deletion of the long arm of the Y chromosome has no apparent effect on the fertilization or pregnancy rates; the risk for birth defects is the same as for any infertile couple that achieves a pregnancy using assisted reproductive technology.

Genetic counseling: Y chromosome infertility is inherited in a Y-linked manner. Because males with Y chromosome deletions are infertile, the deletions are usually de novo and therefore not present in the father of the proband. Despite their severely impaired spermatogenesis, some males with deletion of the AZF regions have occasionally spontaneously fathered sons, who are infertile. This will occur in about 4% of couples with severe oligospermia if the female partner is young and very fertile. In pregnancies achieved using ICSI, male offspring have the same deletion as their father, with a high risk of male infertility. Note that certain Y deletions, including the most common Y deletions (gr/gr), do not necessarily cause infertility, but are only a risk factor for infertility. Female fetuses from a father with a Y chromosome deletion have no increased risk of congenital abnormalities or infertility. In pregnancies conceived through assisted reproductive technology (ART) and known to be at risk of resulting in a male with Y chromosome deletion, specific prenatal testing or preimplantation testing could be performed to determine the sex of the fetus and/or the presence of the Y chromosome deletion.