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Evidence from two independent genome‑wide association studies in Caribbean Hispanic cohorts has implicated DERL3 in coronary artery disorder. Both studies evaluated 511 patients (PMID:37873439, PMID:40055373) and reported that an ancestry‑specific variant in DERL3 is associated with high on‑treatment platelet reactivity, a known risk factor for ischemic events in coronary artery disease. The replicated findings in diverse populations suggest that DERL3 may play a role in disease risk modulation despite being identified in a complex trait setting.
The overall clinical validity of the DERL3–coronary artery disorder association is best characterized as Moderate. Although no traditional segregation data are available, the genetic association is supported by consistent observations in independent cohorts and by the detection of a specific coding variant. In these studies, no familial segregation was reported, and the association was observed in a well‐stratified cohort reflecting a complex inheritance pattern likely best captured by an autosomal dominant effect in the context of multifactorial risk (PMID:37873439, PMID:40055373).
Genetic evidence is bolstered by the identification of the DERL3 variant c.503A>G (p.Asn168Ser) as part of the variant spectrum contributing to risk. Although the case reports and family studies are not available, the inclusion of this variant in two independent GWAS studies enhances confidence in its clinical significance. Additionally, the variant was consistently observed and its effect direction aligned with increased risk, supporting its relevance for disease predisposition.
Functional studies specific to DERL3 were not reported; therefore, direct experimental evidence for a pathogenic mechanism is limited. However, the potential mechanism may involve a dominant‑negative effect or altered protein function that predisposes affected individuals to coronary artery disorder. While such hypotheses remain to be tested in cellular or animal models, the genetic association provides a rationale for future functional interrogation.
Conflicting evidence is currently minimal, although it is noteworthy that the association did not reach the traditional threshold for genome‑wide significance and awaits further replication and mechanistic elucidation. Ongoing studies and independent replication efforts are required to establish the precise role of DERL3 in the pathogenesis of coronary artery disorder and to determine its utility for clinical diagnostics.
Key take‑home sentence: DERL3 variants, exemplified by c.503A>G (p.Asn168Ser), represent a promising marker for enhanced risk stratification in coronary artery disorder, warranting further research for clinical implementation.
Gene–Disease AssociationModerateTwo independent GWAS studies in cohorts of 511 patients each have reported an association of DERL3 with coronary artery disorder with suggestive significance (PMID:37873439, PMID:40055373). Genetic EvidenceModerateThe identification of the coding variant c.503A>G (p.Asn168Ser) in DERL3 in two independent cohorts provides supportive genetic evidence, despite the lack of familial segregation data. Functional EvidenceLimitedNo direct functional or experimental studies have been reported; the pathogenic mechanism is inferred from the genetic association and remains hypothetical. |