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This summary evaluates the association between VAMP5 (HGNC:12646) and Hirschsprung disease (MONDO_0018309) as reported in multiple studies. The combined evidence supports a strong gene–disease association. Two independent case–control studies, one from Neurogastroenterology and Motility (PMID:26970437) and a second from Aging (PMID:29695640), have demonstrated significant associations of VAMP5 polymorphisms with distinct Hirschsprung disease subtypes. In particular, SNPs such as rs10206961 and rs1254900 have been repeatedly implicated in increasing the risk for total colonic aganglionosis and long‐segment aganglionosis, respectively, with p‑values reaching as low as 9.69 × 10⁻⁵ (PMID:26970437).
The genetic evidence is bolstered by large sample sizes. One study involved 187 patients with Hirschsprung disease versus 283 controls, while another replicated the association in a Southern Chinese cohort of 1473 cases and 1469 controls (PMID:26970437; PMID:29695640). Although the studies do not report traditional familial segregation, the robust case–control findings across independent populations have established credibility for VAMP5 as a susceptibility locus.
In terms of variant analysis, the reported evidence focuses on common single nucleotide polymorphisms rather than classical coding variants described in HGVS notation. As a result, no qualifying c. variant meeting the specified criteria is available from the supplied data.
The functional evaluation, while more limited, provides a plausible mechanistic link. VAMP5 is a component of the VAMP/synaptobrevin complex, playing a key role in neurotransmitter vesicular fusion. This functional insight supports the biological plausibility of its involvement in the development of the enteric nervous system. However, further experimental studies are needed to consolidate the mechanistic understanding (PMID:26970437).
No significant conflicting evidence has been noted, although additional replications and extended functional evaluations are warranted to fully elucidate the genetic architecture of Hirschsprung disease. The integration of robust genetic findings across diverse populations with emerging functional insights suggests that VAMP5 genetic markers could serve as a valuable tool in diagnostic decision‑making and clinical management for Hirschsprung disease.
Key take‑home: VAMP5 polymorphisms represent a clinically useful risk factor for Hirschsprung disease, underscoring their potential role in both diagnostic workup and future therapeutic stratification.
Gene–Disease AssociationStrongTwo independent case–control studies with large cohorts demonstrated significant associations of VAMP5 SNPs (e.g., rs10206961, rs1254900) with Hirschsprung disease subtypes (PMID:26970437, PMID:29695640). Genetic EvidenceStrongRobust replication across studies evaluating multiple VAMP5 polymorphisms in case–control designs confirms the genetic contribution to Hirschsprung disease. Functional EvidenceLimitedPreliminary functional data indicates that VAMP5’s role in vesicular fusion is biologically plausible in the context of enteric nervous system development, although experimental evidence remains sparse. |