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DCBLD2 has been implicated in relapsing polychondritis (RP) through two independent case‑control exome‑wide studies. In these studies, a significantly higher burden of ultra‑rare damaging variants in DCBLD2 was observed in RP patients compared to healthy controls (PMID:37292664, PMID:37918895). One recurrent variant, c.1303del (p.Gln435AsnfsTer8), was identified in multiple RP cases, underscoring its potential role as a genetic risk factor. Although the studies were based on unrelated individuals without formal segregation analysis, the magnitude of the association is supported by the stark difference in variant burden (7.6% in cases vs 0.1% in controls (PMID:37292664)).
The genetic evidence is bolstered by strong statistical associations derived from a collapsing analysis approach, and the recurrence of the frameshift variant across cohorts adds weight to the findings. Despite the absence of classical familial segregation data, the replicated case‑control evidence contributes to a moderate level of gene‑disease validity. In addition, experimental observations of elevated plasma DCBLD2 protein levels in RP patients further lend preliminary functional support, although detailed mechanistic studies are currently limited (PMID:37292664).
The combined genetic and functional data suggest that DCBLD2 may be involved in the pathogenesis of RP, potentially implicating dysregulated receptor signaling and inflammatory pathways. While more detailed functional work is needed to fully elucidate the molecular mechanism, the current data provide valuable insights for diagnostic decision‑making and may guide future research and therapeutic development. An integrated assessment of these data supports the clinical utility of screening for DCBLD2 variants in the context of RP risk.
The evidence reporting and validation of the DCBLD2 association with RP exceed the minimal ClinGen scoring threshold, confirming its relevance in both research and future clinical applications. Key take‑home: DCBLD2 represents a promising genetic risk factor in relapsing polychondritis, with replicated association findings that can directly inform patient stratification and further exploration of targeted interventions.
Gene–Disease AssociationModerateTwo independent exome‑wide association studies comprising 66 unrelated RP cases demonstrated a significant enrichment of ultra‑rare damaging variants in DCBLD2, including the recurrent c.1303del (p.Gln435AsnfsTer8) (PMID:37292664, PMID:37918895). Genetic EvidenceModerateThe case‑control collapsing analyses identified a robust signal for DCBLD2 with a markedly elevated variant burden in RP patients compared to controls, despite the absence of familial segregation data. Functional EvidenceLimitedElevated plasma levels of DCBLD2 in RP patients offer preliminary functional support for its role in disease pathogenesis, although detailed mechanistic studies remain to be performed. |