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DPY19L2 has emerged as a critical gene in the etiopathogenesis of spermatogenic failure 6, a condition most commonly manifesting as globozoospermia. Multiple independent studies have identified recessive mutations, including both large deletions and point mutations, as the major molecular cause underlying this form of male infertility (PMID:32582379, PMID:36047070).
Inheritance of pathogenic DPY19L2 alleles follows an autosomal recessive pattern. Familial cases, including a consanguineous family with several affected brothers, as well as multiple unrelated patients in diverse populations, have provided strong segregation evidence (PMID:21397063). Such data strongly support the link between biallelic DPY19L2 disruption and the clinical phenotype.
Genetic evidence for this association is robust. Numerous studies report pathogenic variants in DPY19L2, with significant observations in cohorts where up to 66.7% of patients with globozoospermia carry deletions or point mutations. The variant spectrum includes both recurrent deletions and point mutations, such as the clearly pathogenic variant c.869G>A (p.Arg290His) which has been identified in several independent studies (PMID:22653751, PMID:27441053).
Functional studies have further reinforced the genetic findings. In vitro assays and animal models have demonstrated that loss of DPY19L2 function leads to impaired acrosome formation and disrupted sperm head morphology, effectively recapitulating the human globozoospermic phenotype (PMID:30333325). These experiments substantiate the mechanism of pathogenicity, which is most consistent with a loss-of-function effect resulting in an inability to properly form the sperm acrosome.
No significant conflicting evidence has been reported; rather, the accumulated data from case reports, multi-patient analyses, and functional assessments converge to confirm the involvement of DPY19L2 in spermatogenic failure 6. The consistency between genetic data and experimental models strengthens the clinical validity of the association.
In summary, the integration of extensive genetic and functional evidence establishes DPY19L2 as a major causative gene for spermatogenic failure 6. The recurrent identification of pathogenic variants—including the variant c.869G>A (p.Arg290His)—in affected individuals across multiple independent studies underlines the diagnostic and clinical utility of screening DPY19L2 in cases of globozoospermia.
Key Take‑Home: Reliable genetic testing for DPY19L2 variants provides a critical tool for the diagnosis and management of patients with spermatogenic failure 6, thereby guiding effective clinical decisions and personalized therapy.
Gene–Disease AssociationStrongMultiple independent case reports and cohort studies have identified DPY19L2 mutations in over 50 probands, supported by familial segregation (e.g., affected siblings in consanguineous families) and recurrent variant findings (PMID:21397063, PMID:22653751). Genetic EvidenceStrongOver 10 independent studies report pathogenic variants—including recurrent deletions and the point mutation c.869G>A (p.Arg290His) across diverse populations—build a compelling genetic basis for the association (PMID:22653751, PMID:27441053). Functional EvidenceModerateFunctional assays, including in vitro and animal model studies, demonstrate that DPY19L2 loss-of-function leads to aberrant acrosome formation and globozoospermic phenotypes, thereby supporting its pathogenic role (PMID:30333325). |