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The association between HSPB6 and dilated cardiomyopathy is supported by case‐level data that, while limited in number, offers important mechanistic insights. In a pivotal study, sequencing of the HSPB6 coding region in 1347 patients with dilated cardiomyopathy revealed a C59T substitution in one patient, resulting in a missense change from proline to leucine at residue 20 (c.59C>T (p.Pro20Leu)) (PMID:18790732). This variant, noted in a heterozygous state, implicates a potential pathogenic effect though segregation data is minimal. Additional case‐series evidence from a recent study in peripartum cardiomyopathy cohorts also identified HSPB6 variants, albeit with no significant enrichment in dilated cardiomyopathy, thereby contributing conflicting data to the genetic landscape (PMID:36918127). The paucity of unrelated probands and family segregation evidence tempers the overall confidence in the gene–disease relationship. Nonetheless, the identification of a candidate variant provides a stimulus for further investigation into its clinical relevance.
Functional studies provide strong evidence for a deleterious impact of the P20L variant. In vitro experiments using rat cardiomyocytes demonstrated that while wild‑type HSPB6 confers significant protection against apoptosis, the P20L variant completely abrogates this effect by markedly reducing phosphorylation at the critical Ser16 residue (PMID:18790732). This functional impairment is in line with the proposed loss‐of‐function mechanism and supports a biological link between HSPB6 dysfunction and cardiomyocyte vulnerability under stress conditions. However, the low prevalence of the variant and the absence of robust segregation data call for cautious interpretation of its pathogenicity. Further studies with larger cohorts and family‐based analyses are needed to definitively establish clinical utility. Key take‑home: Despite compelling in vitro data, the limited genetic evidence warrants additional research before HSPB6 variants can be reliably used in diagnostic decision-making for dilated cardiomyopathy.
Gene–Disease AssociationLimitedThe association is based on the identification of a single proband carrying the c.59C>T (p.Pro20Leu) variant (PMID:18790732), with minimal segregation and replication data. Genetic EvidenceLimitedOnly one coding variant has been reported in a dilated cardiomyopathy patient, and additional case‐series did not show significant enrichment, limiting the genetic evidence. Functional EvidenceStrongFunctional assays in rat cardiomyocytes demonstrated that the P20L variant abolishes HSPB6 cardioprotection through reduced phosphorylation at Ser16 (PMID:18790732), supporting a pathogenic mechanism. |