We evaluated genome sequencing (GS) as an alternative to multigene panel sequencing (PS) for genetic testing in dilated cardiomyopathy (DCM).


Forty-two patients with familial DCM underwent PS and GS, and detection rates of rare single-nucleotide variants and small insertions/deletions in panel genes were compared. Loss-of-function variants in 406 cardiac-enriched genes were evaluated, and an assessment of structural variation was performed.


GS provided broader and more uniform coverage than PS, with high concordance for rare variant detection in panel genes. GS identified all PS-identified pathogenic or likely pathogenic variants as well as two additional likely pathogenic variants: one was missed by PS due to low coverage, the other was a known disease-causing variant in a gene not included on the panel. No loss-of-function variants in the extended gene set met clinical criteria for pathogenicity. One BAG3 structural variant was classified as pathogenic.


Our data support the use of GS for genetic testing in DCM, with high variant detection accuracy and a capacity to identify structural variants. GS provides an opportunity to go beyond suites of established disease genes, but the incremental yield of clinically actionable variants is limited by a paucity of genetic and functional evidence for DCM association.

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Additional information

A. Minoche and C. Horvat are joint first authors.

M. Dinger, M. Cowley, and D. Fatkin are joint senior authors.


  1. 1.

    Fatkin D, Seidman CE, Seidman JG. Genetics and disease of ventricular muscle. Cold Spring Harb Perspect Med. 2014;1:a021063.

  2. 2.

    Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Europace. 2011;13:1077–1109.

  3. 3.

    Fatkin D, Johnson R, McGaughran J, et al. Position statement on the diagnosis and management of familial dilated cardiomyopathy. Heart Lung Circ. 2017;26:1127–1132.

  4. 4.

    Sikkema-Raddatz B, Johansson LF, de Boer EN, et al. Targeted next-generation sequencing can replace Sanger sequencing in clinical diagnostics. Hum Mutat. 2013;34:1035–1042.

  5. 5.

    Pugh TJ, Kelly MA, Gowrisankar S, et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014;16:601–608.

  6. 6.

    Pua CJ, Bhalshankar J, Miao K, et al. Development of a comprehensive sequencing assay for inherited cardiac condition genes. J Cardiovasc Transl Res. 2016;9:3–11.

  7. 7.

    Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12:745–755.

  8. 8.

    Weischenfeldt J, Symmons O, Spitz F, Korbel JO. Phenotypic impact of genomic structural variation: insights from and for human disease. Nat Rev Genet. 2013;14:125–138.

  9. 9.

    Li X, Montgomery SB. Detection and impact of rare regulatory variants in human disease. Front Genet. 2013;4:67.

  10. 10.

    Dewey FE, Grove ME, Pan C, et al. Clinical interpretation and implications of whole-genome sequencing. JAMA. 2014;311:1035–1045.

  11. 11.

    Golbus JR, Puckelwartz MJ, Dellefave-Castillo L, et al. Targeted analysis of whole genome sequence data to diagnose genetic cardiomyopathy. Circ Cardiovasc Genet. 2014;7:751–759.

  12. 12.

    Roberts AM, Ware JS, Herman DS, et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015;7:270ra6.

  13. 13.

    Shi L, Zhang Y, Feng L, et al. Multi-omics study revealing the complexity and spatial heterogeneity of tumor-infiltrating lymphocytes in primary liver carcinoma. Oncotarget. 2017;8:34844–34857.

  14. 14.

    McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–1303.

  15. 15.

    Gayevskiy V, Roscioli T, Dinger ME, Cowley MJ Seave: a comprehensive web platform for storing and interrogating human genomic variation. BioRxiv (unpublished data in text).

  16. 16.

    Rehm HL, Bale SJ, Bayrak-Toydemir P, et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013;15:733–747.

  17. 17.

    Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.

  18. 18.

    Uhlén M, Fagerberg L, Hallström BM, et al. Tissue-based map of the human proteome. Science. 2015;347:1260419.

  19. 19.

    Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565–574.

  20. 20.

    Viguera E, Canceill D, Ehrlich SD. In vitro replication slippage by DNA polymerases from thermophilic organisms. J Mol Biol. 2001;312:323–333.

  21. 21.

    Kircher M, Stenzel U, Kelso J. Improved base calling for the Illumina Genome Analyzer using machine learning strategies. Genome Biol. 2009;10:R83.

  22. 22.

    Costa MW, Guo G, Wolstein O, et al. Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and dilated cardiomyopathy. Circ Cardiovasc Genet. 2013;6:238–247.

  23. 23.

    Begay RL, Tharp CA, Martin A, et al. FLNC gene splice mutations cause dilated cardiomyopathy. JACC: Basic Transl Sci. 2016;1:344–359.

  24. 24.

    Dalkilic I, Schienda J, Thompson TG, et al. Loss of filamin C (FLNC) results in severe defects in myogenesis and myotube structure. Mol Cell Biol. 2006;26:6522–6534.

  25. 25.

    Chevessier F, Schuld J, Orfanos Z, et al. Myofibrillar instability exacerbated by acute exercise in filaminopathy. Hum Mol Genet. 2015;24:7207–7220.

  26. 26.

    Bolduc V, Marlow G, Boycott KM, et al. Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. Am J Hum Genet. 2010;86:213–221.

  27. 27.

    Xu J, El Refaey M, Xu L, et al. Genetic disruption of Ano5 in mice does not recapitulate human Ano5-deficient muscular dystrophy. Skelet Muscle. 2015;5:43.

  28. 28.

    Hoffmann L, Haussmann U, Mueller M, et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012;35:269–277.

  29. 29.

    Erdmann J, Daehmlow S, Wischke S, et al. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet. 2003;64:339–349.

  30. 30.

    Chen SN, Czernusczewicz G, Tan Y, et al. Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy. Circ Res. 2012;111:907–919.

  31. 31.

    Uys GM, Ramburan A, Loos B, et al. Myomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C. BMC Cell Biol. 2011;12:18.

  32. 32.

    Norton N, Li D, Rieder MJ, et al. Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am J Hum Genet. 2011;88:273–282.

  33. 33.

    Rice AM, McLysaght A. Dosage sensitivity is a major determinant of human copy number variant pathogenicity. Nat Commun. 2017;8:14366.

  34. 34.

    Barefield DY, Puckelwartz MJ, Kim EY, et al. Experimental modelling supports a role for MyBP-HL as a novel myofilament component in arrhythmia and dilated cardiomyopathy. Circulation. 2017;136:1477–1491.

  35. 35.

    Froissart R, Guffon N, Vanier MT, et al. Fabry disease: D313Y is an α-galactosidase A sequence variant that causes pesudodeficient activity in plasma. Mol Genet Metab. 2003;80:307–314.

  36. 36.

    Cirino AL, Lakdawala NK, McDonough B, et al. A comparison of whole genome sequencing to multigene panel testing in hypertrophic cardiomyopathy patients. Circ Cardiovasc Genet. 2017;10:e001768.

  37. 37.

    Bodi K, Perera AG, Adams PS, et al. Comparison of commercially available target enrichment methods for next-generation sequencing. J Biomol Tech. 2013;24:73–86.

  38. 38.

    Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10:531–547.

  39. 39.

    Haas J, Frese KS, Peil B, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J. 2015;36:1123–1135.

  40. 40.

    Stark Z, Lunke S, Brett GR, et al. Meeting the challenges of implementing rapid genomic testing in acute pediatric care [published online ahead of print March 15, 2018]. Genet Med 2018.

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We thank the Kinghorn Centre for Clinical Genomics for assistance with production and processing of genome sequencing data. We acknowledge Robert Graham, Matthew Grounds, John Mattick, and John Schubert, as founders of the Cardiogenomics Project. This research was undertaken with the assistance of resources and services from the National Computational Infrastructure, which is supported by the Australian Government.

This work was undertaken as part of the Cardiogenomics Project, and would not have been possible without the support of John Schubert, the Kinghorn Foundation, Garvan Foundation, and the Victor Chang Cardiac Research Institute. Funding support was also received from the NSW Office of Health and Medical Research Collaborative Grants Program, National Health and Medical Research Council (D.F., C.S.), Estate of the Late RT Hall (D.F.), Simon Lee Foundation (D.F.), Howard Hughes Medical Institute (C.E.S.), National Institutes of Health (J.G.S.), Leducq Foundation (J.G.S., C.E.S.), Cancer Institute NSW (M.J.C.), and NSW Department of Health (M.J.C). J.I. is the recipient of a National Heart Foundation of Australia Future Leader Fellowship.

Author information


  1. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    • Andre E. Minoche PhD
    • , Velimir Gayevskiy PhD
    • , Alexander P. Drew PhD
    • , Marcel E. Dinger PhD
    •  & Mark J. Cowley PhD
  2. Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute Sydney, Sydney, New South Wales, Australia

    • Claire Horvat PhD
    • , Renee Johnson PhD, MGC
    •  & Diane Fatkin MD
  3. Boston Children’s Hospital, Boston, Massachusetts, USA

    • Sarah U. Morton MD, PhD
  4. Genome.One, Sydney, New South Wales, Australia

    • Kerhan Woo BTech
    • , Aaron L. Statham BSc
    • , Ben Lundie BSc
    •  & Marcel E. Dinger PhD
  5. Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia

    • Richard D. Bagnall PhD
    • , Jodie Ingles MPH, PhD
    •  & Christopher Semsarian MBBS, PhD
  6. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia

    • Richard D. Bagnall PhD
    • , Jodie Ingles MPH, PhD
    •  & Christopher Semsarian MBBS, PhD
  7. Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

    • Jodie Ingles MPH, PhD
    •  & Christopher Semsarian MBBS, PhD
  8. Howard Hughes Medical Institute, Boston, Massachusetts, USA

    • J. G. Seidman PhD
  9. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    • J. G. Seidman PhD
    •  & Christine E. Seidman MD
  10. Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA

    • Christine E. Seidman MD
  11. St Vincent’s Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia

    • Marcel E. Dinger PhD
    • , Mark J. Cowley PhD
    •  & Diane Fatkin MD
  12. Cardiology Department, St Vincent’s Hospital, Sydney, New South Wales, Australia

    • Diane Fatkin MD


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M.E.D., K.W., A.L.S., and B.L. are employed by Genome.One, a clinically accredited genetic testing provider that uses genome sequencing. The other authors declare no conflict of interest.

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Correspondence to Diane Fatkin MD.

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