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This summary details the association between ZBTB17 (HGNC:12936) and dilated cardiomyopathy (MONDO_0005021), a disease characterized by congestive heart failure, arrhythmia, and sudden cardiac death. The evidence spans case reports, multi‐patient genetic studies, and functional analyses, supporting its clinical relevance for diagnostic decision‑making and personalized management.
A seminal case report identified a heterozygous loss‑of‑function mutation in ZBTB17 that co‑segregated with dilated cardiomyopathy in a familial setting. In the study, the index patient and several affected relatives carried the mutation, and it was absent in unaffected members (PMID:29445930). This finding established an autosomal dominant inheritance pattern with complete penetrance.
Multi‑patient studies have reinforced this observation. A case‑control study in a Han Chinese population demonstrated an association of a ZBTB17 polymorphism (rs10927875) with dilated cardiomyopathy (PMID:23570452). Additional large‐scale exome‐wide studies have further underscored the contribution of ZBTB17 mutations to the genetic heterogeneity observed in dilated cardiomyopathy.
The genetic evidence is reinforced by the identification of a heterozygous nonsense mutation, represented as c.727G>T (p.Glu243Ter), in an affected individual. This variant, absent in control cohorts, underlines the pathogenicity of ZBTB17 loss‑of‑function alleles in contributing to the cardiomyopathy phenotype (PMID:29445930).
Functional studies have provided mechanistic insights into the association. Experiments demonstrated that the truncated ZBTB17 protein loses its normal transcriptional activity and fails to protect cardiac myocytes from stress‑induced apoptosis. Complementary in vivo models further confirmed that disruption of ZBTB17 compromises the cardiac stress response, aligning with the human phenotype (PMID:26175529).
Overall, both genetic and functional evidence converge to support a strong association between ZBTB17 mutations and dilated cardiomyopathy. This robust data, exceeding typical ClinGen scoring criteria, highlights the significant role of ZBTB17 in the disease mechanism. Key take‑home: ZBTB17 genetic testing can be a potent diagnostic and prognostic tool for risk stratification and personalized management in dilated cardiomyopathy.
Gene–Disease AssociationStrongA loss-of-function mutation in ZBTB17 co-segregates with dilated cardiomyopathy in a familial case (PMID:29445930) and is supported by replication in a Han Chinese case-control study (PMID:23570452) with functional data confirming impaired transcriptional activity (PMID:26175529). Genetic EvidenceStrongThe identification of the heterozygous c.727G>T (p.Glu243Ter) variant in an index patient and its co-segregation in multiple affected relatives provide robust genetic evidence, further corroborated by case-control association studies (PMID:29445930; PMID:23570452). Functional EvidenceModerateFunctional assays demonstrate that the truncated ZBTB17 protein lacks transcriptional activity, with in vivo models showing a compromised response to cardiac stress, aligning with the human disease phenotype (PMID:26175529). |