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

Kathryn M. Meurs, 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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)515-524
Number of pages10
JournalHuman Genetics
Volume138
Issue number5
DOIs
StatePublished - May 1 2019

Fingerprint

Connectin
Sudden Cardiac Death
Dogs
Dilated Cardiomyopathy
Genetic Heterogeneity
Genes
Canidae
Animal Models
Penetrance
Cardiovascular Diseases
Familial dilated cardiomyopathy
Genome
pyruvate dehydrogenase kinase 4

PubMed: MeSH publication types

  • Journal Article

Cite this

A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death. / Meurs, Kathryn M.; Friedenberg, Steven G; Kolb, Justin; Saripalli, Chandra; Tonino, Paola; Woodruff, Kathleen; Olby, Natasha J.; Keene, Bruce W.; Adin, Darcy B.; Yost, Oriana L.; DeFrancesco, Teresa C.; Lahmers, Sunshine; Tou, Sandra; Shelton, G. Diane; Granzier, Henk.

In: Human Genetics, Vol. 138, No. 5, 01.05.2019, p. 515-524.

Research output: Contribution to journalArticle

Meurs, KM, Friedenberg, SG, Kolb, J, Saripalli, C, Tonino, P, Woodruff, K, Olby, NJ, Keene, BW, Adin, DB, Yost, OL, DeFrancesco, TC, Lahmers, S, Tou, S, Shelton, GD & Granzier, H 2019, 'A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death', Human Genetics, vol. 138, no. 5, pp. 515-524. https://doi.org/10.1007/s00439-019-01973-2
Meurs, Kathryn M. ; Friedenberg, Steven G ; Kolb, Justin ; Saripalli, Chandra ; Tonino, Paola ; Woodruff, Kathleen ; Olby, Natasha J. ; Keene, Bruce W. ; Adin, Darcy B. ; Yost, Oriana L. ; DeFrancesco, Teresa C. ; Lahmers, Sunshine ; Tou, Sandra ; Shelton, G. Diane ; Granzier, Henk. / A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death. In: Human Genetics. 2019 ; Vol. 138, No. 5. pp. 515-524.
@article{f6ded023c5a44a289a8952c2e64f4c38,
title = "A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death",
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.",
author = "Meurs, {Kathryn M.} and Friedenberg, {Steven G} and Justin Kolb and Chandra Saripalli and Paola Tonino and Kathleen Woodruff and Olby, {Natasha J.} and Keene, {Bruce W.} and Adin, {Darcy B.} and Yost, {Oriana L.} and DeFrancesco, {Teresa C.} and Sunshine Lahmers and Sandra Tou and Shelton, {G. Diane} and Henk Granzier",
year = "2019",
month = "5",
day = "1",
doi = "10.1007/s00439-019-01973-2",
language = "English (US)",
volume = "138",
pages = "515--524",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "5",

}

TY - JOUR

T1 - A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death

AU - Meurs, Kathryn M.

AU - Friedenberg, Steven G

AU - Kolb, Justin

AU - Saripalli, Chandra

AU - Tonino, Paola

AU - Woodruff, Kathleen

AU - Olby, Natasha J.

AU - Keene, Bruce W.

AU - Adin, Darcy B.

AU - Yost, Oriana L.

AU - DeFrancesco, Teresa C.

AU - Lahmers, Sunshine

AU - Tou, Sandra

AU - Shelton, G. Diane

AU - Granzier, Henk

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85061045913&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061045913&partnerID=8YFLogxK

U2 - 10.1007/s00439-019-01973-2

DO - 10.1007/s00439-019-01973-2

M3 - Article

VL - 138

SP - 515

EP - 524

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 5

ER -