Key result
Whole exome sequencing identified a novel 1-bp heterozygous deletion in the BAG3 gene (Chr10:121435979delC) as the causal mutation in three related males with severe dilated cardiomyopathy.
Case Report (n=3)
Whole exome sequencing identified a novel BAG3 mutation as the cause of severe familial dilated cardiomyopathy, suggesting BAG3 should be included in routine cardiomyopathy gene panels.
This case expands known BAG3 variants in familial dilated cardiomyopathy; hypothesis-generating for panel inclusion pending larger studies.
Dilated cardiomyopathy (DCM) is characterized by dilation and impaired contraction of the left ventricle or both ventricles. Among hereditary DCM, the genetic causes are heterogeneous, and include mutations encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. We report three severely affected males, in a four-generation pedigree, with DCM phenotype who underwent cardiac transplant. Cardiomegaly with marked biventricular dilation and fibrosis were noticeable histopathological findings. The affected males had tested negative on a 46-gene pancardiomyopathy panel. Whole Exome Sequencing (WES) was performed to reveal mutation in the gene responsible in generation of DCM phenotypes. The 1-bp (Chr10:121435979delC; c.913delC) novel heterozygous deletion in exon 4 of BAG3, was identified in three affected males, resulted in frame-shift and a premature termination codon (p.Met306-Stop) producing a truncated BAG3 protein lacking functionally important PXXP and BAG domains. WES data were further utilized to map 10 SNP markers around the discovered mutation to generate shared disease haplotype in all affected individuals encompassing 11 Mb on 10q25.3-26.2 harboring BAG3. Finally genotypes were inferred for the unavailable/deceased individuals in the pedigrees. Here we propose that Chr10:121435979delC in BAG3 is a causal mutation in these subjects. Our and earlier studies indicate that BAG3 mutations are associated with DCM phenotypes. BAG3 should be added to cardiomyopathy gene panels for screening of DCM patients, and patients previously considered gene elusive should undergo sequencing of the BAG3 gene.
No takes yet. Share an insight, caveat, or question.
Rafiq et al. (2017) conducted a case report in Dilated cardiomyopathy (DCM) (n=3). Whole Exome Sequencing (WES) was evaluated on Identification of causal mutation. Whole exome sequencing identified a novel 1-bp heterozygous deletion in the BAG3 gene (Chr10:121435979delC) as the causal mutation in three related males with severe dilated cardiomyopathy.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: