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A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death

  • Kathryn M. MeursEmail author
  • Steven G. Friedenberg
  • Justin Kolb
  • Chandra Saripalli
  • Paola Tonino
  • Kathleen Woodruff
  • Natasha J. Olby
  • Bruce W. Keene
  • Darcy B. Adin
  • Oriana L. Yost
  • Teresa C. DeFrancesco
  • Sunshine Lahmers
  • Sandra Tou
  • G. Diane Shelton
  • Henk Granzier
Original Investigation
Part of the following topical collections:
  1. Canine Genetics

Abstract

The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. A pathologic missense variant in the titin gene located in an immunoglobulin-like domain in the I-band spanning region of the molecule was identified and was highly associated with the disease (p < 0.0001). We demonstrate here the identification of a variant in the titin gene highly associated with the disease in this spontaneous canine model of dilated cardiomyopathy. This large animal model of familial dilated cardiomyopathy shares many similarities with the human disease including mode of inheritance, clinical presentation, genetic heterogeneity and a pathologic variant in the titin gene. The dog is an excellent model to improve our understanding of the genotypic phenotypic relationships, penetrance, expression and the pathophysiology of variants in the titin gene.

Notes

Funding

Research reported in this publication was supported by the Heart Lung and Blood Institute of the National Institutes of Health under award number R35HL144998.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest. North Carolina State University offers the canine titin variant test as a risk assement tool for dogs.

Supplementary material

439_2019_1973_MOESM1_ESM.xlsx (15 kb)
Supplementary material 1 (XLSX 15 KB)
439_2019_1973_MOESM2_ESM.xlsx (17 kb)
Supplementary material 2 (XLSX 16 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Kathryn M. Meurs
    • 1
    Email author
  • Steven G. Friedenberg
    • 2
  • Justin Kolb
    • 5
  • Chandra Saripalli
    • 5
  • Paola Tonino
    • 5
  • Kathleen Woodruff
    • 1
  • Natasha J. Olby
    • 1
  • Bruce W. Keene
    • 1
  • Darcy B. Adin
    • 1
  • Oriana L. Yost
    • 1
  • Teresa C. DeFrancesco
    • 1
  • Sunshine Lahmers
    • 3
  • Sandra Tou
    • 1
  • G. Diane Shelton
    • 4
  • Henk Granzier
    • 5
  1. 1.Department of Veterinary Clinical SciencesNorth Carolina State UniversityRaleighUSA
  2. 2.Department of Veterinary Clinical SciencesUniversity of MinnesotaSaint PaulUSA
  3. 3.Department of Small Animal Clinical SciencesVA-MD College of Veterinary MedicineBlacksburgUSA
  4. 4.Department of PathologyUniversity of California San DiegoLa JollaUSA
  5. 5.Department of PhysiologyUniversity of ArizonaTucsonUSA

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