DDX3Y Loss-of-Function Variant in AZFa-Like Non-Obstructive Azoospermia Highlights Gaps in Current Y-Chromosome Microdeletion Testing.

Some men have no sperm in the semen because sperm production in the testis has failed. In selected patients, surgical sperm retrieval may be performed, in which small pieces of testicular tissue are examined to look for rare sperm that could be used for intracytoplasmic sperm injection, a form of IVF in which a single sperm is injected into an egg. Before surgery, men are usually tested for large missing regions on the Y chromosome, including the AZFa region. Complete AZFa deletions are associated with a very poor chance of finding sperm. In this case report, we describe a man with no sperm in the semen, negative standard AZF deletion testing, and no sperm found during microdissection testicular sperm extraction. Later exome sequencing identified a previously unreported stop-gain variant in DDX3Y, a gene located within AZFa and now considered to have moderate evidence for involvement in severe sperm-production failure. Together with previously published cases, this finding illustrates a limitation of standard deletion testing: it cannot detect small gene-level variants. In carefully selected men with an AZFa-like clinical picture, DDX3Y sequence analysis may improve counseling and may help avoid low-yield surgery, but larger studies and economic evaluation are needed.