Researchers identify gene associated with deadly heart disease in golden retrievers

Researchers have discovered the first genetic mutation associated with hypertrophic cardiomyopathy (HCM) and sudden death in golden retrievers. The work could lead to increased early detection and disease prevention for the breed while further shaping our understanding of the disease in humans.

HCM is a cardiac disease that most commonly affects humans and cats but was previously considered rare in dogs. In HCM, the left ventricular muscle thickens, affecting the heart’s ability to deliver oxygenated blood to the body. The disease can lead to abnormal blood clotting, irregular heart rhythms and heart failure, although in up to 50% of cases individuals with the disorder show no clinical signs. HCM affects approximately one in 500 humans and one in seven cats, representing one of the top causes of sudden death in both populations.

In the study, the research team looked at the whole genome sequences for three related golden retriever puppies less than two years of age who all suffered sudden cardiac deaths. Genetic sequences were compared to other dogs within the puppies’ family tree, sequences from over 2,500 unrelated dogs of various breeds, and sequences from wolves and coyotes.

Bioinformatic analysis and sequential filter steps led the team to identify a single genetic variant located in a gene called Cardiac Troponin-I, or TNNI3.

“In humans, TNNI3 mutations are associated with juvenile HCM and sudden death,” says Victor Rivas, DVM student and Ph.D. graduate at North Carolina State University. “This is the first genetic variant to explain HCM outside of humans and cats. And while it is specific to golden retrievers, it’s the first variant to be described in any dog breed.” Rivas is first author of the study.

The researchers also found that the mutation is autosomal recessive, which means that two copies of the gene – one from each parent – must be present for the disease to occur. In the case of the affected puppies, both parents were cardiovascularly normal, but each carried a copy of the mutation.

The researchers hope that this information can be used to prevent the spread of the TNNI3 variant – and thereby HCM – through the breed. Golden retriever owners who may be interested in breeding can have genotype testing performed for this mutation to determine whether their animal is a carrier.

“The positive news is that by collaborating with the golden retriever community we may be able to ensure that HCM remains a very rare disease in dogs,” Rivas says. “Additionally, the case similarities in humans and golden retrievers with these TNNI3 variants is remarkable and could lead to translational health studies that can shape our understanding of the disease mechanisms and ultimately benefit humans with similar mutations.”

The study appears in Circulation: Genomic and Precision Medicine. Other NC State contributors were Michael Vandewege, Ronald Li, Sandra Losa, Meghan Leber, Panchan Sitthicharoenchai, and Joshua Stern. Dayna Goldsmith, Jennifer Davies and Carolyn Legge of the University of Calgary; Kim Hawkes of Pulse Veterinary Cardiology and Sarah Revell of Highview Animal Clinic also contributed to the work.

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Note to editors: An abstract follows.

“Novel Cardiac Troponin-I Missense Variant (c.593C>T) Is Associated With Familial Hypertrophic Cardiomyopathy in Golden Retrievers”

DOI: 10.1161/CIRCGEN.125.005096

Authors: Victor Rivas, Michael Vandewege, Ronald Li, Sandra Losa, Meghan Leber, Panchan Sitthicharoenchai, Joshua Stern, North Carolina State University; Dayna Goldsmith, Jennifer Davies, Carolyn Legge, University of Calgary; Kim Hawkes, Pulse Veterinary Cardiology; Sarah Revell, Highview Animal Clinic
Published: Aug. 22, 2025 in Circulation: Genomic and Precision Medicine

Abstract:
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a naturally occurring cardiac disorder afflicting humans, cats, rhesus macaques, pigs, and rarely dogs. The disease is characterized by maladaptive left ventricular wall thickening. Over 1500 sarcomere-coding mutations explain HCM in humans, whereas only 3 have been reported in cat breeds. To date, no mutations have been described in dogs. HCM in a nuclear family of Golden Retrievers was identified following the sudden cardiac death of 3 related puppies <2 years of age from 2 dam-offspring repeat matings. METHODS: Whole-genome sequencing on the 3 affected puppies, along with nuclear family members (ie, sire, dam, 4 unaffected littermates, 4 unaffected half-siblings), and 1 distantly related, geriatric, cardiovascularly normal Golden Retriever was performed (n=14). Candidate variant genotyping was performed in an unphenotyped cohort of dogs (n=2771) and an expanded population of phenotyped, unrelated Golden Retrievers (n=45). Left ventricular tissue immunofluorescence staining was subsequently performed to investigate incorporation and expression of mutant protein within the cardiac sarcomere of HCM-affected cases. RESULTS: Gross and histopathologic evaluations of the HCM-affected puppies revealed hallmark features of the disease, including cardiomyocyte hypertrophy, interstitial fibrosis, and left-sided congestive heart failure. Segregation analysis of called variants, performed under assumptions of an autosomal-recessive mode of inheritance, identified a single segregating c.593C>T missense variant in TNNI3 (Cardiac Troponin-I). This variant was not observed in the unphenotyped (n=2771) nor in the phenotyped, unrelated cohort of dogs (n=45). Immunofluorescence staining of left ventricular tissues did not reveal obvious aberrant protein localization and expression at the sarcomeric level, suggesting the molecular pathogenesis of the TNNI3 variant is not related to abnormal protein incorporation within the sarcomere.
CONCLUSIONS: This variant represents the first-ever reported HCM-associated variant in any canine species, and its identification holds promise for establishing translational models, genetic screening, and early disease prevention within the breed.