Cardiac genetics: testing and interpreting in clinical practice

Introduction

Many forms of congenital and acquired disease have a strong breed predisposition suggesting a familial/genetic etiology. The small animal practitioner may be asked to provide consultation on genetic issues in order to provide information to owners of breeding animals to aid them in breeding decisions and to provide pet owners information about etiologies of disease.

Breed-specific lists of known (also non-cardiac) and presumed inherited diseases in the dog and cat can be found at several websites. Some good examples:

• Cats: https://icatcare.org/advice/cat-breeds/inherited-disorders-cats
• Dogs: www.vet.cam.ac.uk/idid
• Cardiac health testing in dogs and cats: https://cvm.ncsu.edu/genetics/submit-dna-testing

Key points during this lecture:

• My focus will be on what we know about genetics and the utility of understanding the genetic/mutation status of animals presented for (screening of) heart disease.
• The result of a genetic test, whether positive, or negative, do not provide information about the presence or absence of cardiac disease or about cardiac function at the time of testing. Echocardiography and other diagnostics always remain required to determine cardiac function. A genetic test with a positive result increases the likelihood of disease development in the future, but because there are likely many other unknown mutations that are associated with disease, a genetic test with a negative result does not preclude the change of the disease.

Technique DNA testing can be performed on a variety of sample types including whole blood and a buccal mucosal (cheek) swab. The samples can be sent to several commercial labs for DNA analysis.

Hypertrophic cardiomyopathy (HCM) in cats

Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats and is characterized by concentric left ventricular muscle hypertrophy, impaired muscle relaxation and eventually may lead to congestive left-sided heart failure, aortic thromboembolism and sudden death in a subset of cats. This disease is also observed frequently in humans and is familial with over 1000 known mutations in many different human genes. Maine Coon and Ragdoll cats are observed to also possess a familial form of HCM that is inherited in an autosomal dominant pattern. Through genetic research in a colony of cats in the USA, a mutation in the myosin binding protein C 3 gene in Maine Coon cats was found. In Ragdoll cats, another mutation in myosin binding protein C 3 gene has been found. It is important to know that many Maine Coon cats and Ragdoll cats develop HCM while they screen negative on these mutations, suggesting (similar to humans) more (unknown) genetic defects are likely at play.

DILATED CARDIOMYOPATHY (DCM) IN DOGS

Dilated cardiomyopathy represents the most common form of heart disease in large-breed dogs. DCM is like HCM an adult onset disease and as such it represents a problem for the breeding population as many dogs that develop DCM will have already produced offspring. Dobermann Pinschers are significantly overrepresented in prevalence of this disease. Human beings with DCM have many genes that are involved and multiple mutations in the same genes that lead to development of DCM. Doberman Pinschers appear to be the same. A mutation in a pyruvate dehydrogenase kinase 4 (PDK4; also called DCM1), a gene involved in myocyte metabolism, is described in Dobermans with DCM. This genetic mutation is not the only cause of DCM in Dobermans. Recently another mutation has been published (missense variant in the titin gene; named DCM2). Although there are Dobermans with DCM that are mutation negative, there is increased relative risk conferred by possessing the mutations in either a heterozygous or homozygous fashion.

ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY (ARVC) IN BOXER DOGS

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle abnormality that leads to fatty infiltration and fibrous tissue accumulation within the right ventricular myocardium, resulting in the hallmark of the disease: ventricular arrhythmias.
The best test to diagnose this condition currently is the presence of right-sided VPCs on Holter monitor that exceed 100 in a 24-hour period. This disease is classically described in the Boxer. In 2010 a mutation was discovered in a protein called striatin, which was demonstrated to co-localize with the cardiac desmosome.

SUBVALVULAR AORTIC STENOSIS IN NEWFOUNDLAND DOGS

Subvalvular aortic stenosis (SAS) is a congenital heart defect that leads to restriction to left ventricular outflow and pressure overload on the left ventricle. Dogs severely affected with this condition on average live between 4 and 5 years of age with no interventional cardiology technique showing any survival benefit beyond the use of oral beta-blockers alone. The primary lesion is an abnormal fibrous tissue ridge below the aortic valve. Newfoundland dogs are overrepresented with a familial form of this disease. The pattern of inheritance is autosomal dominant with incomplete penetrance, much like the previously discussed conditions. Recently a mutation in phosphatidylinositol-binding clathrin assembly protein (PICALM) was identified that is associated with development of SAS in Newfoundlands.   […]