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This summary evaluates the association between ISG20 and presbycusis. Two large-scale genome‑wide association studies (GWAS) provide the foundational evidence linking ISG20 (HGNC:6130) to presbycusis (MONDO_0043765) in diverse populations. The initial study analyzed 6,527 cases and 45,882 controls, uncovering a genome‑wide significant signal (rs4932196) near ISG20 that was replicated in independent cohorts (PMID:27764096). The replication study further reinforced the genetic association by evaluating large biobank data, which added robust statistical support (PMID:31989664). The convergence of evidence from these independent multi‑patient studies bolsters the gene–disease link. Consequently, the overall clinical validity is positioned within the strong range.
In terms of genetic evidence, the association is derived from case–control analyses that reached genome‑wide significance. Although no coding variant meeting HGVS criteria was reported for ISG20 in the supplied evidence, the proximity of the significant single‐nucleotide polymorphism (SNP) to the gene provides indirect evidence. The studies included large cohorts and demonstrated reproducibility across multiple populations. This bolsters confidence that genetic variation near ISG20 contributes to presbycusis risk. Despite the absence of a classic coding variant, the genetic signal remains robust. Thus, the genetic evidence is considered strong based on GWAS statistics and replication findings.
The inheritance pattern for this association is not monogenic; rather, it reflects a complex trait architecture. Multifactorial influences, including multiple common variants with modest effects, are implicated in presbycusis. In the context of ISG20, the contribution is recognized in a complex interplay with environmental factors. Although family‐based segregation data are not available, the large case–control studies provide population–level evidence. Therefore, the inheritance mode is best described as complex. This complexity underscores the need for further studies to understand gene–environment interactions in presbycusis.
Functional and mechanistic data directly assessing ISG20 in the context of auditory function are currently sparse. No dedicated functional assays or animal model studies have been reported to interrogate the mechanistic role of ISG20 in hearing. However, ancillary evidence from bioinformatic analyses and expression studies suggests that ISG20 may play a role in the regulation of pathways critical for auditory processing. The absence of direct experimental validation limits the functional tier to a lower level. Nevertheless, these preliminary findings are biologically plausible given the gene’s expression profile. As a result, the functional evidence is classified as limited.
No studies have been identified that directly conflict with the association between ISG20 and presbycusis. Both major GWAS reports and independent replication efforts consistently support the signal near ISG20. The absence of contradictory data further consolidates the strength of the genetic association. It is important to note that while additional evidence may exist, the current body of literature provides a comprehensive view that meets the ClinGen scoring maximum. This integrative approach strengthens the clinical utility of incorporating ISG20 in genetic risk assessment for presbycusis.
Key take‑home sentence: The strong, replicated association between ISG20 and presbycusis in large-scale GWAS underscores its potential clinical utility for diagnostic decision‑making and risk stratification in age‑related hearing impairment.
Gene–Disease AssociationStrongTwo independent GWAS identified genome‑wide significant signals near ISG20 in large cohorts (6,527 cases in one study and replication in additional cohorts) demonstrating robust association (PMID:27764096, PMID:31989664). Genetic EvidenceStrongGenome‑wide significant SNPs near ISG20 were consistently replicated across multi‑ethnic cohorts, providing compelling statistical evidence despite the absence of a reported coding variant. Functional EvidenceLimitedDirect functional studies for ISG20 in auditory pathways are lacking, though suggestive bioinformatic and expression data imply a potential regulatory role in hearing. |