title: Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy.
abstract: Dilated cardiomyopathy commonly causes heart failure and is the most frequent precipitating cause of heart transplantation. Familial dilated cardiomyopathy has been shown to be caused by rare variant mutations in more than 30 genes but only ~35% of its genetic cause has been identified, principally by using linkage-based or candidate gene discovery approaches. In a multigenerational family with autosomal dominant transmission, we employed whole-exome sequencing in a proband and three of his affected family members, and genome-wide copy number variation in the proband and his affected father and unaffected mother. Exome sequencing identified 428 single point variants resulting in missense, nonsense, or splice site changes. Genome-wide copy number analysis identified 51 insertion deletions and 440 copy number variants > 1 kb. Of these, a 8733 bp deletion, encompassing exon 4 of the heat shock protein cochaperone BCL2-associated athanogene 3 (BAG3), was found in seven affected family members and was absent in 355 controls. To establish the relevance of variants in this protein class in genetic DCM, we sequenced the coding exons in BAG3 in 311 other unrelated DCM probands and identified one frameshift, two nonsense, and four missense rare variants absent in 355 control DNAs, four of which were familial and segregated with disease. Knockdown of bag3 in a zebrafish model recapitulated DCM and heart failure. We conclude that new comprehensive genomic approaches have identified rare variants in BAG3 as causative of DCM.
authors.affiliation: Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136-1015, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Norton
authors.forename: Duanxiang
authors.initials: D
authors.lastname: Li
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Jill D
authors.initials: JD
authors.lastname: Siegfried
authors.forename: Evadnie
authors.initials: E
authors.lastname: Rampersaud
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Steve
authors.initials: S
authors.lastname: Mangos
authors.forename: Jorge
authors.initials: J
authors.lastname: Gonzalez-Quintana
authors.forename: Libin
authors.initials: L
authors.lastname: Wang
authors.forename: Sean
authors.initials: S
authors.lastname: McGee
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.forename: Eden
authors.initials: E
authors.lastname: Martin
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Ray E
authors.initials: RE
authors.lastname: Hershberger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D006824:Hybridization, Genetic; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D011786:Quality Control; D055815:Young Adult; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D029961:Zebrafish Proteins