Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy

Nadine Norton, Duanxiang Li, Mark J. Rieder, Jill D. Siegfried, Evadnie Rampersaud, Stephan L Zuchner, Steve Mangos, Jorge Gonzalez-Quintana, Libin Wang, Sean McGee, Jochen Reiser, Eden R Martin, Deborah A. Nickerson, Ray E. Hershberger

Research output: Contribution to journalArticle

188 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)273-282
Number of pages10
JournalAmerican Journal of Human Genetics
Volume88
Issue number3
DOIs
StatePublished - Mar 11 2011

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Exome
Dilated Cardiomyopathy
Genome
Exons
Heart Failure
Genetic Association Studies
Zebrafish
Heart Transplantation
Heat-Shock Proteins
Fathers
Mothers
Mutation
DNA
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. / Norton, Nadine; Li, Duanxiang; Rieder, Mark J.; Siegfried, Jill D.; Rampersaud, Evadnie; Zuchner, Stephan L; Mangos, Steve; Gonzalez-Quintana, Jorge; Wang, Libin; McGee, Sean; Reiser, Jochen; Martin, Eden R; Nickerson, Deborah A.; Hershberger, Ray E.

In: American Journal of Human Genetics, Vol. 88, No. 3, 11.03.2011, p. 273-282.

Research output: Contribution to journalArticle

Norton, N, Li, D, Rieder, MJ, Siegfried, JD, Rampersaud, E, Zuchner, SL, Mangos, S, Gonzalez-Quintana, J, Wang, L, McGee, S, Reiser, J, Martin, ER, Nickerson, DA & Hershberger, RE 2011, 'Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy', American Journal of Human Genetics, vol. 88, no. 3, pp. 273-282. https://doi.org/10.1016/j.ajhg.2011.01.016
Norton, Nadine ; Li, Duanxiang ; Rieder, Mark J. ; Siegfried, Jill D. ; Rampersaud, Evadnie ; Zuchner, Stephan L ; Mangos, Steve ; Gonzalez-Quintana, Jorge ; Wang, Libin ; McGee, Sean ; Reiser, Jochen ; Martin, Eden R ; Nickerson, Deborah A. ; Hershberger, Ray E. / Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. In: American Journal of Human Genetics. 2011 ; Vol. 88, No. 3. pp. 273-282.
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AU - Rampersaud, Evadnie

AU - Zuchner, Stephan L

AU - Mangos, Steve

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AU - McGee, Sean

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