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Recent studies have delineated the role of deleterious variants in RHOXF1 in the etiology of oligospermia, a common phenotype of male infertility. The evidence derives from a cohort study of 1201 infertile men, wherein four unrelated probands were identified with hemizygous variants in RHOXF1 (PMID:38258527).
The genetic evidence is robust, with the identification of four distinct hemizygous variants – three missense and one nonsense – consistently observed in patients presenting with oligospermia. Notably, one representative variant is c.478C>T (p.Arg160Ter), which meets the criteria for a complete coding change and underscores the potential deleterious effects on the protein product (PMID:38258527).
Although explicit segregation data of additional affected relatives were not provided, the recurrent observation of these variants in unrelated cases strengthens the causal link between RHOXF1 and oligospermia. This pattern is further supported by the comprehensive evaluation of variant classes in the study (PMID:38258527).
In parallel, functional studies have demonstrated that these RHOXF1 variants result in a significant reduction in RHOXF1 protein levels and aberrant intracellular protein aggregation. Moreover, luciferase assays revealed that especially the p.Arg160Ter variant disrupts DMRT1 promoter activity, thereby impairing downstream spermatogenic processes (PMID:38258527).
Integrating the genetic and functional data, the evidence strongly supports a causal role for RHOXF1 variants in oligospermia. The convergence of multi‐patient genetic findings with concordant in vitro functional assays offers a reliable foundation for diagnostic decision‑making and potential commercial test development.
Key take‑home: Analysis of RHOXF1 mutations is a clinically useful approach to diagnose oligospermia and to guide therapeutic strategies in affected males.
Gene–Disease AssociationStrongFour unrelated probands ([PMID:38258527]) showing consistent oligospermia phenotypes support a strong gene-disease association. Genetic EvidenceStrongDetection of four hemizygous variants, including the representative c.478C>T (p.Arg160Ter), in a well‐defined patient cohort ([PMID:38258527]) underlines the genetic causality. Functional EvidenceModerateIn vitro analyses demonstrating decreased RHOXF1 protein levels and disrupted DMRT1 promoter activity substantiate the pathogenic mechanism ([PMID:38258527]). |