Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
PYGO2 has been implicated in the pathogenesis of azoospermia, a condition characterized by the absence of sperm and consequent male infertility. Recent multi‐patient studies have examined the association of non‑synonymous SNPs in PYGO2 with idiopathic azoospermia. Two independent studies provided evidence by comparing cohorts of affected individuals with control groups, establishing a statistically significant correlation between PYGO2 variants and the azoospermia phenotype (PMID:26345837, PMID:36688188). This report integrates these findings to support diagnostic decision‑making while underscoring avenues for future research. The convergence of genetic data with in silico analyses offers a moderate degree of clinical evidence.
Genetic assessments have identified recurrent missense variants in PYGO2 among cohorts of affected men. One study analyzed 178 patients with a range of spermatogenic defects, and another compared 100 infertile patients with 100 normozoospermic controls. These independent investigations consistently reported non‑synonymous SNPs, lending statistical support to PYGO2 involvement in azoospermia. The standardized variant reporting, including use of HGVS nomenclature, facilitates interpretation and comparison across studies (PMID:26345837, PMID:36688188). The genetic evidence from these studies substantiates a moderate gene‑disease association.
A representative variant from the reported spectrum is c.421A>G (p.Met141Ile). This variant, reflecting a missense change, is emblematic of the alterations identified by sequencing efforts in azoospermic patients. Its inclusion in the analysis underscores the importance of precise molecular nomenclature, ensuring clarity for clinical laboratories and researchers. The detailed HGVS annotation aids in the aggregation of genetic data across diverse populations and enhances reproducibility in future studies. Such standardized reporting is a cornerstone for variant curation in clinical genomics.
The underlying inheritance pattern for azoospermia in the context of PYGO2 variants appears consistent with an autosomal recessive model. Although explicit family‐based segregation data are limited, the recurrence of PYGO2 missense variants in multiple unrelated probands supports recessive inheritance. The absence of reports detailing extended familial segregation denotes an area for ongoing investigation. Nonetheless, the repeated association in independent case–control cohorts bolsters the inferred genetic model, which is critical for genetic counseling and testing strategies.
Functional evidence for PYGO2’s role in azoospermia is primarily derived from in silico analyses. Computational tools such as SIFT, Polyphen‑2, and Mutation Taster predict that the identified missense variants, including c.421A>G (p.Met141Ile), may disrupt protein tertiary structure and impair chromatin remodeling during spermatogenesis. Although direct experimental validation using cellular or animal models remains forthcoming, these predictive data align with PYGO2’s known biological functions in sperm development. As a result, the functional evidence is considered limited but supportive of the genetic findings.
In conclusion, the integration of genetic association studies and computational analyses yields a moderately robust association between PYGO2 and azoospermia. This evidence base, while inviting further experimental and segregation studies, provides a useful framework for clinical diagnostics in male infertility. Clinicians may consider incorporating PYGO2 variant screening as an adjunct in the diagnostic workup of idiopathic azoospermia. Key take‑home: Comprehensive genetic evaluation, including standardized PYGO2 analysis, can substantially inform diagnosis and management in patients with azoospermia.
Gene–Disease AssociationModerateTwo independent case–control studies involving 178 and 200 individuals respectively demonstrated statistically significant associations between PYGO2 missense variants and azoospermia (PMID:26345837, PMID:36688188). Genetic EvidenceModerateRecurrent non‑synonymous variants, including c.421A>G (p.Met141Ile), were identified across independent studies, supporting the contribution of PYGO2 variants to the azoospermia phenotype. Functional EvidenceLimitedIn silico analyses predict that PYGO2 missense variants may disrupt protein structure and function; however, direct experimental validation is not yet available. |