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Extensive evidence from multiple studies supports a strong association between variants in ZP2 and female infertility. Several independent case reports and multi‐patient studies have identified both heterozygous and homozygous mutations in ZP2 in affected individuals, with evidence of segregation in familial cases. For instance, one study reported a heterozygous missense mutation that impaired protein expression and secretion, leading to defective zona pellucida formation and infertility (PMID:37736051). In addition, other reports have documented recurrent variants and compound heterozygous changes that further consolidate the link between ZP2 disruption and the infertility phenotype.
Genetic evidence has emerged from various families where affected individuals harbor pathogenic variants in ZP2. The mutation spectrum includes missense, frameshift, and splice site variants. One representative variant, reported as c.1859G>A (p.Cys620Tyr), has been identified in unrelated patients and underscores the significance of missense changes in disrupting zona pellucida assembly (PMID:35595959). Segregation analyses across these families demonstrate the co‐segregation of the variant with the infertility phenotype, lending further weight to its clinical relevance.
Functional studies have been instrumental in validating the pathogenicity of ZP2 variants. In vitro analyses using CHO cells have shown that mutant ZP2 proteins exhibit reduced expression and impaired interaction with other zona pellucida components. Moreover, mouse models engineered to carry the human mutations recapitulate key features of the disease, such as abnormal zona pellucida structure and resultant infertility. These experimental findings provide a mechanistic explanation linking ZP2 variants to the compromised oocyte environment observed in affected individuals.
While some studies report autosomal recessive inheritance in consanguineous families, a number of cases demonstrate a dominant effect of heterozygous variants. This dosage effect highlights the complexity of the genetic architecture underlying female infertility associated with ZP2, and suggests that even single allele disruption can lead to a clinically significant phenotype.
Taken together, the combined genetic and functional data provide a coherent narrative in which ZP2 variants disrupt the formation and function of the zona pellucida. This disruption compromises oocyte viability and fertilization, thereby manifesting as female infertility. The broad spectrum of variants, supported by robust functional and segregation evidence, underlines the clinical utility of ZP2 genetic testing in patients with infertility.
Key take‑home message: ZP2 variants represent a strongly supported genetic etiology for female infertility, and integrating molecular diagnostics with functional assessment is essential for precise clinical management and personalized treatment strategies.
Gene–Disease AssociationStrongMultiple independent studies have identified pathogenic ZP2 variants in approximately 14 unrelated probands with familial segregation and concordant functional findings demonstrating disrupted zona pellucida formation (PMID:37736051, PMID:35595959). Genetic EvidenceStrongThe identification of diverse variant classes—including the recurrent missense variant c.1859G>A (p.Cys620Tyr) in unrelated patients—coupled with segregation data across multiple families underpins robust genetic evidence. Functional EvidenceModerateIn vitro cell models and in vivo mouse models consistently demonstrate that ZP2 variants result in reduced protein expression and impaired zona pellucida assembly, aligning with the observed infertility phenotype. |