Abstract 15073: Exome Sequencing Identifies Bag3 Gene Mutation in Dilated Cardiomyopathy
Background: A mutation called BAG3 has been recently identified as a cause of genetic forms of dilated cardiomyopathy, but the consequences of BAG3 mutations on cardiac pathology and the role of BAG3 in heart failure are not known.
Methods: Whole exome DNA analysis was performed on a multi-generational family affected with dilated cardiomyopathy. Prior studies including linkage analysis, candidate gene analysis, and SNP array analysis had failed to locate the pathogenic mutation. Exome capture was achieved using the Agilent SureSelect Exome capture system and sequencing was completed on an Illumina HiSeq2000. Analysis of an explanted human heart tissue from one affected mutations carrier was performed and BAG3 levels in control and failing hearts were assayed utilizing Western blot analysis.
Results and Conclusions: In exon 4 a 10-nucleotide deletion of the BAG3 gene was found using exome sequencing from family members distantly related. The mutation was present in seven affected family members and absent in eight healthy close and distant relatives. Standard histology of a BAG3 mutation carrier’s explanted heart revealed mild to moderate myocyte hypertrophy and patchy mild to moderate interstitial fibrosis. Also changes were more prominent in the left ventricle and septum than the right ventricle. Electron microscopy suggested increased glycogen deposition, possibly related to the role of BAG3 protein in autophagy and cellular trafficking. BAG3 levels were markedly depressed without evidence of truncated BAG3 protein in the explanted heart specimen, consistent with haploinsufficiency. Conclusions: Exome sequencing has been shown to be very useful in identifying pathogenic mutations in cardiomyopathy families where distant relatives are available for segregation analysis. The microscopic evaluation identified notable features of BAG3 heart biopsy due to apparent haploinsufficiency of BAG3, suggesting that modulation of BAG3 levels could show a novel avenue for therapeutic exploration.
- © 2013 by American Heart Association, Inc.