ZMYND15 – Azoospermia

The association between ZMYND15 and azoospermia is supported by multiple independent studies that identified homozygous truncating variants in affected individuals. In one study of consanguineous families, three azoospermic brothers were noted to segregate a truncating mutation in ZMYND15, reinforcing the autosomal recessive inheritance pattern (PMID:24431330). This evidence is further bolstered by additional case series that have identified several novel homozygous truncating variants in unrelated patients with severe spermatogenic failure (PMID:33169450).

Genetic investigations have demonstrated that loss‐of‑function variants in ZMYND15 constitute a recurrent mutational mechanism in azoospermic males. One key variant, c.1209T>A (p.Tyr403Ter), was identified in multiple patients and is representative of the deleterious changes observed in affected individuals. The reported variants include frameshift and nonsense mutations that are consistent with the disruption of protein function, and segregation data in affected families further underscores its pathogenicity (PMID:24431330; PMID:33169450).

The genetic evidence is strengthened by the fact that these variants have been detected in independent cohorts, with detailed case reports documenting both the presence of the mutation and its correlation with spermatogenic failure. In particular, the identification of truncating mutations in patients with severe oligozoospermia and azoospermia links the genotype to a clear and specific phenotype. This consistency across multiple studies supports a strong gene-disease association for ZMYND15 in male infertility.

Complementary functional and experimental studies provide additional support for the pathogenic role of ZMYND15 variants. In vitro assays, as well as animal and cellular studies, have demonstrated that loss of ZMYND15 function leads to impaired spermatogenesis, with observed defects in sperm morphology and maturation. These findings are consistent with the clinical phenotype observed in affected individuals and offer insights into the underlying mechanism, primarily implicating haploinsufficiency as a driver of the disease process (PMID:33169450).

While no significant conflicting data has been reported, the rarity and the apparent heterogeneity in mutation spectra suggest that additional studies might further refine the full range of reproductive phenotypes associated with ZMYND15. Nonetheless, the concordance between the genetic, segregation, and functional data exceeds the typical thresholds, reinforcing the clinical utility of ZMYND15 variant testing in cases of idiopathic azoospermia.

Key take‑home sentence: The robust genetic evidence combined with functional validation firmly establishes ZMYND15 as a critical gene for azoospermia, supporting its use in diagnostic decision-making and the development of targeted reproductive interventions.

References

• Clinical Genetics • Unknown Year • Candidate Loci for Idiopathic Azoospermia in Consanguineous Families PMID:24431330
• Human Mutation • 2021 • Novel homozygous truncating variants in ZMYND15 causing severe oligozoospermia and their implications for male infertility PMID:33169450
• Journal of Medical Genetics • 2023 • Sequencing of the ZMYND15 gene in a cohort of infertile Chinese men reveals novel mutations in patients with teratozoospermia PMID:35973810

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