BAG5 – Dilated Cardiomyopathy

The association between BAG5 and dilated cardiomyopathy is supported by robust clinical and genetic evidence. A novel truncating variant, c.444_445delGA (p.Lys149AsnfsTer6), was identified in a consanguineous family where affected siblings presented with severe dilated cardiomyopathy and arrhythmia (PMID:38796549). This report highlights the importance of BAG5 loss‑of‑function in the pathogenesis of this cardiac condition.

Detailed familial studies revealed autosomal recessive inheritance, with the homozygous variant segregating with disease among affected individuals while heterozygous or wild‑type alleles were found in unaffected relatives. In addition, multi‑patient studies have identified other loss‑of‑function variants in BAG5 across four unrelated families, further supporting the gene‑disease relationship (PMID:35044787).

Genetic evidence is bolstered by the discovery of multiple truncating mutations, including the frameshift variant c.444_445delGA (p.Lys149AsnfsTer6), which collectively reinforce the causal role of BAG5 in dilated cardiomyopathy. These findings are supported by segregation analyses demonstrating complete penetrance in affected families.

Functional studies using mouse models further validated the clinical observations. Under stress conditions, BAG5‑deficient mice exhibited reduced left ventricular contractility and increased cardiac apoptosis, closely recapitulating the human phenotype. This functional concordance underscores impaired ER stress response as a key pathogenic mechanism in BAG5‑related dilated cardiomyopathy (PMID:38796549).

Taken together, the combined genetic and experimental findings decisively establish a strong association between BAG5 and dilated cardiomyopathy. These data provide a compelling rationale for the incorporation of BAG5 into diagnostic genetic testing panels for dilated cardiomyopathy.

Key take‑home message: BAG5 loss‑of‑function variants represent a significant diagnostic marker for dilated cardiomyopathy and are supported by robust clinical, segregation, and functional evidence.

References

• Scientific Reports • 2024 • A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia PMID:38796549
• Science Translational Medicine • 2022 • Loss‑of‑function mutations in the co‑chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation PMID:35044787

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