Common inherited diseases of cats (Proceedings)
The human genome is composed of about 3 billion base pairs, of which only about 2% forms coding DNA (genes); the rest is non-coding and serves various functions, such as gene regulation. Humans have about 20-25,000 genes, although the function of 50% of them is unknown. A 99% complete map of the human genome was announced in 2003. The cost was approximately $2.7 billion, and the project required a consortium of 20 groups and took 13 years. A light coverage map of the feline genome (2-fold; capturing about 80% of the genome), representing the DNA of an Abyssinian cat named "Cinnamon", was announced by the National Human Genome Research Institute (NHGRI) in 2005. In 2009, NHGRI funded an effort to improve the genome coverage from 2-fold to 10-fold. The feline genome also has about 3 billion base pairs. Improving the detail of the map and filling in gaps will require the collective resources of sequencing facilities, genetic mappers, geneticists, veterinarians, and others over the coming years.
About 250 genetic diseases are known in the cat, many of them having close parallels to human diseases. In fact, the cat serves as animal model for about 200 human diseases. Genetic research focuses not only on inherited diseases, but also on infectious diseases such as feline immunodeficiency virus (FIV; a model for human immunodeficiency virus, HIV). Even genes responsible for coat colors in cats are being identified and may have medical implications. As the feline genome project progresses, more single gene trait diseases will be identified, as well as diseases with a complex genetic component (e.g., feline infectious peritonitis, diabetes, asthma). Currently, more than one dozen genetic tests are available for the cat, including tests for blood type and some coat colors. Veterinarians and veterinary technicians must understand the proper use and interpretation of genetic tests as more become available. Resources for feline genetic diseases include the University of Pennsylvania, Section of Medical Genetics (http://w3.vet.upenn.edu/research/centers/penngen/) and the University of California Veterinary Genetics Lab ( http://www.vgl.ucdavis.edu/).
Hypertrophic cardiomyopathyHypertrophic cardiomyopathy (HCM) is a primary disease of the left ventricular myocardium characterized by mild to severe concentric hypertrophy. It is the most common cardiac disease of the cat1 and may cause congestive heart failure, sudden death, or arterial thromboembolism in some affected cats. The average age at diagnosis is 5 to 7 years. Diagnosis of HCM requires a combination of tools, such as physical examination, thoracic radiography, and echocardiography.
HCM occurs in 1 in 500 people, and is inherited in at least 60% of cases, usually as an autosomal dominant genetic trait. The mutations causing human HCM are found in several genes, including the β-myosin heavy-chain, α-tropomyosin, cardiac troponin T and I, and myosin-binding protein C (MYBPC). Approximately 35-40% of human mutations are found in the β-myosin heavy-chain gene, with over 50 point mutations identified to date. Some mutations causing HCM produce malignant disease with short survival time; others produce more benign disease with little effect on survival.
Familial HCM was identified in cats 35 years after the first identification of a human family with HCM. To date, two genetic mutations have been identified in cats, one each in the Maine Coon and Ragdoll breeds. Maine Coon cats are the best studied example of feline HCM. The disease is inherited as an autosomal dominant trait in this breed. One causative mutation has been identified in a long-term research colony of Maine Coons. The colony cats were originally obtained from Maine Coon breeders. The mutation is in the myosin-binding protein C3 (MYBPC3) gene changes a conserved amino acid, which alters protein structure and changes the function of the sarcomere, the basic contractile unit in heart muscle. The mutation (referred to as A31P) changes an alanine to a proline in codon 31 of the gene. Cats homozygous for the mutation tend to develop moderate to severe disease, and in one study, most homozygotes died of their disease before 4 years of age. Cats heterozygous for the mutation may live into late middle or old age with moderate disease. The A31P mutation is present in about 34% of all Maine Coon cats worldwide.
Not all Maine Coons with the A31P mutation will be diagnosed with HCM as this is an example of a mutation that has variable expression and age-related penetrance. Genetic heterogeneity – more than one mutation in a gene or mutations in related genes may cause the same disease – also plays a role. At least one other mutation causing HCM is likely present in the breed, but further causative mutations have not yet been definitely identified. Another potential causative mutation, A74T, is not well documented but is offered by some commercial laboratories despite lack of evidence. Other factors that may cause discordance between genetic testing and echocardiographic diagnosis include inaccuracy in methods used to detect the mutation and inaccurate clinical diagnosis.
The form of HCM found in Ragdoll cats seems to cause severe disease, often with an early age of onset. A causative mutation has been identified in the Ragdoll MYBPC3 gene, but it is not the same mutation responsible for HCM in the Maine Coon. The Ragdoll mutation (referred to as R820W) changes an arginine to a tryptophan in codon 820. Other breeds with familial HCM are known (e.g., Persian, British Shorthair, American Shorthair, Sphynx, Norwegian Forest Cat, Bengal, etc.) but further research is required to determine the respective causative mutations. Some cat breeds appear to be at low risk for HCM, such as Siamese and Abyssinians.
Genetic testing for HCM in Maine Coon cats and Ragdoll cats can be performed by some diagnostic laboratories, usually with a simple buccal (cheek) swab. The results are typically reported as "negative", "positive homozygote", or "positive heterozygote." A negative test result means the cat does not have the specific HCM mutation being tested. However, the cat could have another HCM mutation and still develop disease. A positive homozygote has two abnormal copies of the gene and may develop moderate to severe HCM. These cats should be evaluated regularly, including an echocardiogram. A positive heterozygote has one abnormal copy of the gene, and one normal copy. These cats might develop mild to moderate HCM and also should be evaluated regularly. The prevalence of the R820W mutation in the Ragdoll breed is not known.
For more information on testing and research: Veterinary Cardiac Genetics Lab at Washington State University ( http://www.vetmed.wsu.edu/deptsVCGL/).