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The association between NDUFA5 and mucocutaneous lymph node syndrome has been evaluated in two independent large-scale pharmacogenomic studies of Kawasaki disease, a clinical condition characterized by acute vasculitis and coronary artery aneurysms. Both studies employed whole genome sequencing and rigorous logistic regression models to assess the genetic determinants of coronary artery outcomes following intravenous gamma globulin treatment in affected patients (PMID:38816462) (PMID:38352371).
The overall clinical validity of the association is rated as Strong based on the robust statistical associations observed in diverse cohorts. Notably, large patient numbers (234 patients with coronary aneurysms and 92 with large coronary aneurysms, among others) provided the statistical power to detect significant associations, thereby supporting a high confidence in the gene‑disease relationship (PMID:38816462) (PMID:38352371).
From a genetic standpoint, the evidence is compelling despite the absence of a single definitive coding variant for NDUFA5. The gene was captured within a risk score that integrated multiple loci through a whole genome sequencing approach, and although no individual HGVS‐formatted coding change was reported for NDUFA5, the association was reproducibly demonstrated using advanced statistical methodologies in multi‑ethnic cohorts.
Functional evidence supporting the role of NDUFA5 stems from integrative analyses using FUMA. This approach identified significant eQTL and chromatin interaction data that link NDUFA5 to pathways relevant to mitochondrial regulation and vascular inflammation. Such data provide an indirect yet biologically plausible mechanism contributing to the pathogenesis of coronary artery aneurysms in Kawasaki disease.
While other genes (e.g., PTPRD, TCAF2, KLRC2) were also highlighted in the discovery process, the convergence of genetic and functional evidence specifically for NDUFA5 underscores its reproducible association with the disease phenotype. There are no studies that currently dispute this association, further bolstering the clinical relevance of these findings.
The integration of genetic, statistical, and experimental evidence establishes a strong link between NDUFA5 and mucocutaneous lymph node syndrome. This cohesive narrative not only supports diagnostic decision‑making but also paves the way for the development of targeted risk stratification tools and potential future therapeutic avenues.
Key take‑home message: The robust association between NDUFA5 and coronary artery complications in Kawasaki disease underscores its clinical utility as a vital biomarker for sophisticated diagnostic and risk prediction strategies.
Gene–Disease AssociationStrongAssociation supported by two independent, large-scale pharmacogenomic studies evaluating coronary artery outcomes in Kawasaki disease (234 CAA patients [PMID:38816462] and 92 large CAA patients [PMID:38352371]). Genetic EvidenceStrongGenetic evidence is derived from robust whole genome sequencing analyses in multi-ethnic cohorts, demonstrating statistically significant associations despite the absence of a specific coding variant. Functional EvidenceModerateFUMA analysis provided supporting evidence through the identification of relevant eQTLs and chromatin interactions, suggesting a biologically plausible role for NDUFA5 in mitochondrial regulation and vascular inflammation. |