Whole exome sequencing identified 1 base pair novel deletion in BCL2‐associated athanogene 3 (BAG3) gene associated with severe dilated cardiomyopathy (DCM) requiring heart transplant in multiple family members

Abstract

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. © 2017 Wiley Periodicals, Inc.

Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion

“…The crucial role for Bag3 in cardiac homeostasis is best understood for loss of function mutations in the human BAG3 gene [36, 37] and inactivation of Bag3 in mice [24], both resulting in DCM. However, the protein has also been implicated in skeletal muscle disease (myofibrillar myopathy, [38]) and desmin-related cardiomyopathy, e.g.…”

Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies

“…Among the 33 frame‐shift truncating variants recorded in ClinVar, 28 (84.85%) variants are classified as P/LP 29 , 62 , 85 and 5 (15.15%) are classified as VUS. The first frame‐shift variant is p.Ser14fs and the last is p.Ala474fs.…”

Molecular Epidemiology of Mitochondrial Cardiomyopathy: A Search Among Mitochondrial and Nuclear Genes

“…The colored square indicates the gene function as showed in Figure 1 . Data from References [ 7 , 16 , 19 , 48 , 151 , 152 , 154 , 155 , 174 , 175 , 176 ]. The Transcript ID refers to RefSeq with NM number (from Ensembl: Genome browser for vertebrate genomes.…”

“…The use of next generation sequencing technology has revolutionized the MDs diagnosis, leading to the discovery of about half of the overall three hundred currently known genes. Thus, by searching publications regarding the most recent advances in understanding the molecular genetic basis of mitochondrial cardiomyopathy during the last ten years [7,16,19,48,151,152,154,155,[174][175][176] and investigating the above mentioned databases, we identified the main nuclear and mitochondrial genes reported in association with mitochondrial cardiomyopathy and MDs showing cardiac manifestations or conduction defects. 3 shows the 130 genes (mtDNA and nDNA genes) collected according to their function showed by colored squares, as reported in Figure 1.…”