DDX3Y loss-of-function variant in AZFa-like non-obstructive azoospermia highlights gaps in current Y-chromosome microdeletion testing.

چکیده اصلی

ABSTRACT: Non-obstructive azoospermia (NOA) due to spermatogenic failure is one of the most challenging conditions for surgical sperm retrieval (SSR). Complete AZFa deletions on Yq11 typically lead to a uniform Sertoli-cell-only (SCO) phenotype, rendering testicular sperm extraction futile. Current EAA/EMQN guidelines rely on sequence-tagged site (STS)-based PCR to detect multi-kilobase AZFa deletions; however, by design, they do not capture intragenic loss-of-function (LoF) variants in key AZFa genes. Recent exome studies have identified DDX3Y as the critical spermatogenic factor within AZFa, showing that isolated DDX3Y LoF variants can reproduce the classical AZFa-like SCO phenotype despite an apparently normal AZFa STS profile. We present a case of a man with idiopathic NOA and an AZFa-like phenotype; elevated FSH, normal karyotype, negative standard AZFa/b/c STS testing, and microdissection testicular sperm extraction (micro-TESE) showed complete SCO syndrome with no sperm retrieved. Whole exome sequencing (WES) subsequently revealed a novel likely pathogenic LoF variant in DDX3Y in one of its coding exons, a defect not detectable by routine AZFa PCR. This case adds to the small number of published DDX3Y loss-of-function variants associated with NOA and SCO syndrome and illustrates an important diagnostic limitation of STS-based AZF testing. We suggest that DDX3Y should be considered in exome or targeted-panel interpretation for selected men with NOA and an AZFa-like presentation despite negative microdeletion testing. Prospective cohorts are required before routine testing algorithms, SSR contraindications, or cost-effectiveness conclusions can be established. Upon validation, such an approach would avoid unnecessary, low-yield SSR while enhancing prognostic counseling and resource utilization. LAY SUMMARY: 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.

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