title: 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.
authors.affiliation: Physiology and Experimental Medicine, The Hospital for Sick Children and Research Institute, Toronto, Ontario, Canada.|Department of Bio-Sciences, COMSATS Institute of Information Technology (CIIT), Islamabad, Pakistan.
authors.forename: Muhammad Arshad
authors.initials: MA
authors.lastname: Rafiq
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ayeshah
authors.initials: A
authors.lastname: Chaudhry
authors.affiliation: Fred A. Litwin Family Center in Genetic Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Melanie
authors.initials: M
authors.lastname: Care
authors.affiliation: Division of Cardiology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Danna A
authors.initials: DA
authors.lastname: Spears
authors.affiliation: Fred A. Litwin Family Center in Genetic Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Chantal F
authors.initials: CF
authors.lastname: Morel
authors.affiliation: Physiology and Experimental Medicine, The Hospital for Sick Children and Research Institute, Toronto, Ontario, Canada.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hamilton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis* / Q000235:genetics* / Q000601:surgery; D004252:DNA Mutational Analysis; D059472:Exome; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006334:Heart Function Tests; D016027:Heart Transplantation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human
keywords: BAG3; DCM; dilated cardiomyopathy; exome sequencing; heart transplant