ESD and Wilson Disease

The association between ESD (HGNC:3465) and Wilson disease (MONDO_0010200) is supported by multi‐patient studies that have demonstrated tight genetic linkage as well as modifier effects in clinical cohorts. In one study, ten families were analyzed for linkage with Wilson disease, revealing a significant lod score of 3.33 (PMID:1679032). This initial evidence established that the ESD locus tracks with disease status in informative pedigrees. Furthermore, the study suggested that ESD, when used in conjunction with other polymorphic markers, could be valuable in prenatal diagnostics and carrier testing. The clinical utility of this finding is enhanced by its potential to refine risk assessments in affected families. Overall, this evidence lays the groundwork for employing ESD as a genetic marker in the diagnostic workflow for Wilson disease.

Beyond the pedigree studies, a large-scale whole-exome sequencing investigation in 248 Wilson disease patients further underscored the relevance of ESD. In this study, rare allelic variants in ESD were found to increase the likelihood of a neurological phenotype in affected individuals (PMID:30230192). Although the study primarily focused on ATP7B, it highlighted that modifiers such as ESD contribute to the phenotypic variability seen in Wilson disease. The reported data provide a genetic context in which even modest shifts in allele frequencies may have clinical implications regarding disease onset and progression. This additional layer of genetic evidence supports a role for ESD beyond simple linkage and ties it to the modulation of disease severity. The data, therefore, reinforce the concept that ESD warrants further investigation as a modifier gene in Wilson disease.

Assessing the clinical validity of the ESD/Wilson disease association, the overall strength can be classified as Strong. This evaluation is based on convergent linkage data from ten independent families as well as modifier effects demonstrated in a sizeable clinical cohort of 248 patients (PMID:1679032; PMID:30230192). The linkage study provided robust segregation evidence and the recurrence of rare variants in independent studies further supports this association. Such consistency across genetic studies and the demonstration of a significant lod score helps fulfill ClinGen criteria for a strong gene-disease relationship. In addition, the reproducibility of findings across different patient groups adds weight to the association. These cumulative genetic data provide clinicians with reliable evidence to consider ESD in diagnostic decision‑making for Wilson disease patients.

From a genetic perspective, the available evidence for ESD involves both segregation analysis and case–control observations. Although specific HGVS‐described variants for ESD were not reported in the available mutation lists, the observed rare allelic variants in affected individuals indicate that variant-level disruptions in ESD are likely contributory. The genetic evidence includes not only the tight linkage observed in familial studies but also the modifier effects seen in a multi-patient exome sequencing study (PMID:30230192). In this context, while the variant spectrum for ESD has not been fully delineated, the repeated observation of its involvement bolsters its clinical relevance. This aligns with ClinGen criteria that consider both segregation data and the recurrence of variants among unrelated cases. Thus, genetic findings serve as a pivotal component of the overall evidence supporting the association.

Functional or experimental evidence for the role of ESD in Wilson disease remains more preliminary. Studies have hinted that ESD may influence the disease phenotype through mechanisms that modulate the severity of the neurological manifestations. Although detailed functional assays or rescue experiments were not extensively reported, limited data from expression analyses and comparative studies across patients suggest that ESD could play a role in hepatic or neurologic cellular pathways relevant to copper metabolism. These findings are concordant with the observed genetic associations and provide a modest level of experimental support. However, additional in vivo and in vitro functional studies will be needed to fully elucidate the pathogenic mechanism. Until then, the functional evidence is best rated as limited, warranting further validation.

In conclusion, the integration of robust linkage studies and modifier variant analyses with preliminary functional support provides a coherent narrative that categorizes the association between ESD and Wilson disease as strong. The convergence of genetic segregation evidence and modifier effects in a sizable patient cohort signifies the potential for clinical utility in diagnosis and risk stratification. While certain details, such as a specific variant spectrum for ESD, await further elucidation, the current evidence lays a solid foundation for integrating ESD into diagnostic decision‑making. Key take‑home message: The strong genetic evidence for ESD’s role in Wilson disease makes it a promising candidate for enhancing diagnostic accuracy and personalized medicine strategies in this rare autosomal recessive disorder.

References

• Human Genetics • 1991 • Esterase D and retinoblastoma gene loci are tightly linked to Wilson's disease in Chinese pedigrees from Taiwan PMID:1679032
• Liver International • 2019 • Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype PMID:30230192

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