Dilated Cardiomyopathy (LMNA related)

Gene: LMNA

Transmission : Autosomal recessive, possibly dominant with incomplete penetration

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease. Both parents of an affected animal must be carriers of at least one copy of the mutation. Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Deletion, LMNA gene; c.1726 del, p.(D576T fs STOP 124), chr.7.

Medical system: Cardiac

Breeds: Nova Scotia Duck Tolling

Age of onset of symptoms: 15 months for homozygotes, possibly 5 years for heterozygotes.

Dilated cardiomyopathy (DCM) is a common primary heart disease seen in several breeds of dog with both genetic and environmental causes. The genetics of DCM is complex, with several genes and mutations contributing to a juvenile or adult-onset disease that can display either dominant or recessive heredity. As a result of the genetic mutation, heart muscle cells function inefficiently which in turn results in compensatory ventricle dilatation, inefficient contraction, and heart arrhythmias. Clinical signs of DCM include sudden death due to the arrhythmias or prolonged congestive heart failure with exercise intolerance, fatigue, coughing, difficulty breathing, weight loss, fluid accumulation in the abdomen, and fainting. In terms of comparison, mutations in over 60 genes have been associated with a high risk of dilated cardiomyopathy in humans.

Two Nova Scotia Duck Tolling Retriever (NSDTR) littermates presented at about 10 months of age with tachycardia and DCM proceeding sudden death. Pathology revealed severe myocardial fibrosis. Whole genomic sequencing was performed for one of these animals as well as for one parent and one grandparent. When results were compared to 128 unrelated dog genomes, a mutation within the LMNA gene was identified. Mutations in the LMNA gene are a common cause of DCM and tachycardia in humans. The LMNA gene codes for the Lamin A intermediate filament protein which is important for structural support of the nuclear membrane and plays a role in regulating transcription and heterochromatin organization. A DNA survey of 300 unrelated NSDTR dogs revealed a carrier frequency for the identified mutation of 8.7%. A DNA test will now allow NSDTR breeders to identify carrier animals which will enable selective breeding to eliminate this disease and eventually this mutation from their breed.

Mutations in additional genes that can be risk factors or be responsible for DCM in the dog:

PLN gene, OMIA link: [2195-9615]

PDK4 gene, OMIA link: [0162-9615]

TTN gene, OMIA link: [0162-9615]

RBM20 gene, OMIA link: [2365-9615]

LMNA gene, OMIA link: [2796-9615]

ABCC9 gene, OMIA link: [2710-9615]

References:

OMIA link: [2796-9615]

Bannasch DL, Oertle DT, Vo J, et al. (2023). Naturally occurring canine laminopathy leading to a dilated and fibrosing cardiomyopathy in the Nova Scotia Duck Tolling Retriever. Sci Rep 13(1):19077. [pm/37925523]

Rivas VN, Stern JA, Ueda Y. (2023) The role of personalized medicine in companion animal cardiology. Vet Clin North Am Small Anim Pract. [pubmed/37423841]

Gaar-Humphreys KR, Spanjersberg TCF, Santarelli G, et al. (2022) Genetic Basis of Dilated Cardiomyopathy in Dogs and Its Potential as a Bidirectional Model. Animals (Basel) 12(13):1679. [pubmed/35804579]

Contributed by: Maëlle Laforce-Lemyre and Marie Dubois, Class of 2028, Faculty of Veterinary Medicine, University of Montreal. (Translation DWS).