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Distinguishing Hypertrophic Cardiomyopathy-Associated Mutations from Background Genetic Noise

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Abstract

Despite the significant progress that has been made in identifying disease-associated mutations, the utility of the hypertrophic cardiomyopathy (HCM) genetic test is limited by a lack of understanding of the background genetic variation inherent to these sarcomeric genes in seemingly healthy subjects. This study represents the first comprehensive analysis of genetic variation in 427 ostensibly healthy individuals for the HCM genetic test using the “gold standard” Sanger sequencing method validating the background rate identified in the publically available exomes. While mutations are clearly overrepresented in disease, a background rate as high as ∼5 % among healthy individuals prevents diagnostic certainty. To this end, we have identified a number of estimated predictive value-based associations including gene-specific, topology, and conservation methods generating an algorithm aiding in the probabilistic interpretation of an HCM genetic test.

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Abbreviations

1kG:

1000 Genomes Sequencing Project

ACTC:

Actin

ARVC:

Arrhythmogenic right ventricular cardiomyopathy

DHPLC:

Denaturing high-performance liquid chromatography heteroduplex analysis

EPV:

Estimated predictive value

ESP:

National Heart Lung and Blood Institute Exome Sequencing Project

HCM:

Hypertrophic cardiomyopathy

LQTS:

Long QT syndrome

MYH7:

Beta myosin heavy chain

MYL2:

Regulatory myosin light chain

MYL3:

Essential myosin light chain

MYPBC3:

Cardiac myosin binding protein C

PCR:

Polymerase chain reaction

SCD:

Sudden cardiac death

TNNC1:

Cardiac troponin C

TNNI3:

Cardiac troponin I

TNNT2:

Cardiac troponin T

TPM1:

Alpha-tropomyosin

rNSV:

Rare non-synonymous variant

VUS:

Variant of undetermined/uncertain significance

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Acknowledgments

J.D.K. is supported by the NIH grant GM72474-08 and thanks the Mayo Clinic MSTP for fostering an outstanding environment for physician-scientist training. This project was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (MJA).

Conflict of Interest

B.A.S is an employee of Knome, Inc. T.E.C. is an employee of Transgenomic Inc. MJA is a consultant for Boston Scientific, Medtronic, St. Jude Medical, Inc., and Transgenomic. Intellectual property derived from MJA’s research program resulted in license agreements in 2004 between Mayo Clinic Health Solutions (formerly Mayo Medical Ventures) and PGxHealth (formerly Genaissance Pharmaceuticals, now assigned to Transgenomic) with respect to their FAMILION-LQTS and FAMILION-CPVT genetic tests but not their FAMILION-HCM genetic test. The other authors have no conflicts of interest to disclose. None of the disclosures pertain to this study and none of the companies provided financial support for this study.

Author information

Author notes

  1. Andrew P. Landstrom

    Present address: Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

  2. Benjamin A. Salisbury

    Present address: Knome, Inc., Cambridge, MA, USA

Authors and Affiliations

  1. Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    Jamie D. Kapplinger, Andrew P. Landstrom, J. Martijn Bos & Michael J. Ackerman

  2. Mayo Medical School, Mayo Clinic, Rochester, MN, USA

    Jamie D. Kapplinger, Andrew P. Landstrom & Michael J. Ackerman

  3. Mayo Clinic Medical Scientist Training Program, Mayo Clinic, Rochester, MN, USA

    Jamie D. Kapplinger, Andrew P. Landstrom & Michael J. Ackerman

  4. Transgenomic Inc., New Haven, CT, USA

    Benjamin A. Salisbury & Thomas E. Callis

  5. Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA

    Michael J. Ackerman

  6. Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, USA

    Michael J. Ackerman

  7. Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN, 55905, USA

    Michael J. Ackerman

Authors
  1. Jamie D. Kapplinger
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Corresponding author

Correspondence to Michael J. Ackerman.

Additional information

Associate Editor Daniel P. Judge oversaw the review of this article

Jamie D. Kapplinger and Andrew P. Landstrom contributed equally and are co-equal first authors.

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Kapplinger, J.D., Landstrom, A.P., Bos, J.M. et al. Distinguishing Hypertrophic Cardiomyopathy-Associated Mutations from Background Genetic Noise. J. of Cardiovasc. Trans. Res. 7, 347–361 (2014). https://doi.org/10.1007/s12265-014-9542-z

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  • DOI: https://doi.org/10.1007/s12265-014-9542-z

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