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The association between PYGO2 and male infertility is supported by robust genetic evidence derived from two independent case‑control studies. Both studies evaluated non‑synonymous single nucleotide polymorphisms (SNPs) in the coding region of PYGO2 in cohorts of patients with idiopathic oligospermia and azoospermia. In one study, sequencing of 178 patients revealed three coding SNPs that were exclusively present in subjects with severe spermatogenic defects (PMID:26345837). This study emphasized that specific missense mutations may impair the protein’s role during chromatin remodeling in elongating spermatids, potentially leading to male infertility.
A second independent investigation analyzing 120 affected individuals alongside 120 fertile controls further established a statistically significant association for one specific SNP. Notably, the heterozygous state for PYGO2 rs141722381, corresponding to the missense change c.718A>G (p.Asn240Ile), was correlated with an increased risk of azoospermia (PMID:36197138). The study documented an over‑dominance effect with an odds ratio exceeding 2.6, underscoring the variant’s potential contribution to the disease phenotype.
Collectively, the genetic evidence is bolstered by the identification of recurrent missense variants in independent cohorts. The comprehensive analyses in these studies, which included both conventional case‑control approaches and bioinformatic predictions of protein structural disruption, provide a strong argument for the clinical relevance of PYGO2 mutations in male infertility. The reported cumulative patient numbers (178 in one study and 120 in another) further reinforce the robustness of the association (PMID:26345837, PMID:36197138).
Despite the solid genetic correlation, the current evidence lacks direct functional or experimental assessments to elucidate the precise biological mechanism linking PYGO2 variants with spermatogenic failure. No animal models, in vitro assays, or rescue experiments were provided to further confirm the pathogenicity beyond statistical association. This emphasizes the need for additional studies to explore the molecular underpinnings of how these missense changes might disrupt chromatin remodeling during sperm development.
In summary, while the genetic data from independent studies consistently point to a strong association between PYGO2 variants and male infertility, functional investigations remain limited. The current evidence supports a pathogenic role for coding SNPs such as c.718A>G (p.Asn240Ile) in altering protein function, albeit without direct experimental verification of the mechanism.
Key take‑home: PYGO2 is a compelling genetic candidate for male infertility, with robust association data underscoring its clinical utility in diagnostic decision‑making, despite an acknowledged gap in functional validation.
Gene–Disease AssociationStrongTwo independent studies involving 178 (PMID:26345837) and 120 cases (PMID:36197138) demonstrated a statistically significant association between PYGO2 variants and male infertility. Genetic EvidenceStrongThe reported recurrent missense variants, including c.718A>G (p.Asn240Ile), in well‐characterized patient cohorts confirm robust genetic evidence for the association. Functional EvidenceLimitedNo direct functional assays or experimental models were provided; the association is supported solely by genetic epidemiological data. |