Subjects

Abstract

Purpose

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

Methods

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.

Results

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.

Conclusion

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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Acknowledgements

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

Affiliations

  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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Disclosure

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.

Corresponding author

Correspondence to Diane Fatkin MD.

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DOI

https://doi.org/10.1038/s41436-018-0084-7

Article notes

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

Article notes

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

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