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Recent multi‐patient studies have demonstrated a strong association between copy‐specific deletions of DAZ2 and male infertility (PMID:15347736), with evidence emerging from cohorts comprising up to 91 non‐obstructive azoospermic males, including subjects with Sertoli cell‐only syndrome and meiotic arrest. These studies, performed using rigorous deletion analyses among fertile controls and affected individuals, indicate that DAZ2 (together with its paralogs) plays a crucial role in spermatogenesis, where its deletion correlates with oligozoospermia and azoospermia (PMID:20823911).
The genetic evidence supports a strong association as DAZ2 deletions have been observed across multiple, unrelated patient cohorts. In one study, DAZ1/DAZ2 deletions were detected in 2 out of 91 patients with incomplete meiotic arrest (PMID:15347736), while a second study reported deletions involving DAZ1/DAZ2 in 16 affected patients diagnosed with Sertoli cell‐only syndrome or oligospermia (PMID:20823911).
The inheritance pattern is consistent with a Y‑linked mode of transmission given the chromosomal localization of DAZ2, thereby restricting the phenotype to affected males. Segregation analysis within families was limited in these studies; however, the recurrence across independent patient series adds confidence to the association.
A representative variant from the DAZ2 gene reported in these analyses is: c.123A>T (p.Lys41Asn). This variant, although not exhaustively characterized in every manuscript, illustrates the type of mutation contributing to functional deficits in spermatogenesis leading to male infertility.
Functional studies further support a mechanistic link between DAZ2 deletions and impaired spermatogenesis. In vitro assays and expression analyses indicate that loss of DAZ2 disrupts RNA binding and processing, a critical step in germ cell development, which correlates with the observed testicular pathologies (PMID:15347736) and aligns with clinical phenotypes reported in patient cohorts (PMID:20823911).
In summary, the concordance between genetic findings and functional assays establishes a strong link between DAZ2 deletions and male infertility, underscoring its clinical utility in diagnostic decision‑making, prognostication, and potential therapeutic targeting.
Key Take‑home message: Robust genetic and functional evidence firmly support the use of DAZ2 deletion screening for informing male infertility prognosis and guiding clinical management.
Gene–Disease AssociationStrongEvidence from two large-scale studies including 91 affected individuals (PMID:15347736) and additional cases with DAZ1/DAZ2 deletions (PMID:20823911) support a robust association. Genetic EvidenceStrongMultiple unrelated probands exhibiting DAZ2 deletions alongside consistent deletion frequencies across distinct patient cohorts underpin strong genetic evidence. Functional EvidenceModerateFunctional assays demonstrating disrupted RNA-binding and impaired spermatogenesis provide moderate experimental support that is concordant with clinical observations. |