HYPERTROPHIC CARDIO MYOPATHY
Genetics & HCM An Article by Mark D. Kittleson, DVM, PhD, Diplomate ACVIM (Cardiology)

In human medicine it is becoming more and more clear that HCM is primarily, if not almost entirely, a genetic disease. Fortunately, many mutations that cause the disease have been identified in humans. Unfortunately, the number of mutations is large (over 400) and the mutations are spread across a number of different genes, which makes initial screening to identify the specific mutation in a family difficult and expensive. Most of these genes code for proteins that build sarcomeres, the small units in muscle that are responsible for contraction. Most of the sarcomeric gene mutations (around 80%) that have been identified are in the beta myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) genes. When looked at another way, anywhere from 20% to 40% of humans with HCM screened for a mutation have a MYBPC3 mutation. One exception to this is in the Netherlands where three MYBPC3 mutations predominate and so 70% of patients with HCM have a MYBPC3 mutation.

Although HCM is at least as prevalent in cats as it is in humans (where it is 1 in 500 people), to date only two mutations have been identified that cause HCM in cats. Not unexpectedly, both of them are in the cardiac myosin binding protein C gene. The first one (A31P) was discovered in 2005 in Maine Coon cats and the second one (C820T) in Ragdoll cats was discovered in 2007. It is expected that other mutations will be found in other cat breeds. It is also already apparent that at least one more HCM-causing mutation is present in Maine Coon cats since not all Maine Coon cats with HCM in the colony at the University of California, Davis (UCDavis) or in the real world have the A31P mutation.

In order to understand the heritable nature of HCM one must understand the difference between heterozygosity and homozygosity. Following is a simplified explanation. There are primarily two types of proteins in the body – structural proteins and enzymes. In general (although many exceptions exist), mutations in genes that code for enzymes cause autosomal recessive disease and mutations in genes that code for structural proteins cause autosomal dominant disease. Why is that? Mother Nature has many backup systems that she has constructed within the body and for a disease to be produced by an enzyme deficiency usually more than 90% of that enzyme must be absent or nonfunctional before an abnormality is seen. Consequently, both alleles (the gene from each parent) must be mutated to produce disease when a gene that codes for an enzyme is involved. In other words, an individual must be homozygous for a mutation in order for disease to be present. Heterozygous individuals (only one mutated allele from either the mother or the father) still have 50% of the normal enzyme present, which is sufficient to allow normal function. So, in autosomal recessive conditions, heterozygous individuals are called carriers because they never develop disease but have a mutation they can pass on to their offspring.

Mutations in genes that code for structural proteins, on the other hand, only have to be present on one allele (heterozygous) since a 50% reduction in the amount of a structural protein usually causes significant problems with the structure that protein helps build, which causes disease. Cardiac myosin binding protein C is a structural protein. Consequently, mutations in the gene that codes for this protein are said to be inherited in an autosomal dominant fashion. This means that if one parent has one mutated allele (and the other parent has no mutation) the affected parent can pass the mutation on its one allele to an offspring and that offspring can develop HCM. Each offspring would have a 50% chance of inheriting the genetic defect. In a litter, on average, approximately 50% of the offspring would have one mutated allele and one normal allele (heterozygote) while the other 50% should be free of the mutation.

Unlike in humans where inbreeding is frowned upon (except in certain populations), inbreeding in cats is often encouraged or at least tolerated. Consequently, it is extremely rare for two humans who are heterozygous for the same mutation to reproduce and produce offspring. In purebred cats the chance of this happening is much, much greater. As a result, not only are cats that are heterozygous for the mutation seen but cats that are homozygous for the mutation are also seen in both Maine Coon cats and Ragdoll cats. It was originally thought that homozygous individuals would not survive (would die in utero or be stillborn) but it is now well established that cats (and humans) that are homozygous for a mutation do survive. They add another level of complexity to the disease. When a cat that is homozygous for one of the mutations is bred to a cat without a mutation all of the kittens in a litter will be heterozygous for the mutation and so have the potential for developing HCM and, even if they don’t, can still pass the mutation on to descendants. When a cat that is homozygous for a mutation is bred to a cat that is heterozygous, on average, 50% of the kittens will be homozygous and 50% will be heterozygous. Obviously, if two homozygous parents are bred, all of the kittens will be homozygous. These determinations are made by using a simple relationship called a Punnett square. Here are several Punnett squares illustrating the outcome of possible mating combinations.

Hypertrophic cardiomyopathy is a disease that is not present at birth but instead is one that develops over time. The reason for this is unknown. In cats it would appear that the disease develops earlier in cats that are homozygous for a mutation. In humans it is well known that MYBPC3 mutations often produce a form of the disease that develops later in life in individuals that are heterozygous for a mutation. Consequently, patients with a MYBPC3 mutation often are normal until they are in their 50s and beyond. There is evidence that this can occur in Maine Coon cats as well.

There is also evidence in humans that some mutations cause a more malignant form of HCM while others cause a more benign form. MYBPC3 mutations are generally, but not always, on the more benign end of the spectrum.

Not all individuals with an autosomal dominant mutation actually develop demonstrable disease and that is certainly true for MYBPC3 mutations. This is called penetrance. For example, if 100 individuals with a mutation are examined and only 50 have the disease known to be caused by the mutation then the penetrance is said to be 50%. Since it is not 100% in this scenario penetrance is said to be incomplete. In a sense, penetrance is a reflection of our ability to detect or recognize clinical disease, and is often age-related. In humans, penetrance in patients with a MYBPC3 mutation borders on 100% if they are followed out to beyond 50 years of age. In Maine Coon cats it was originally reported that penetrance was 100% in the colony at UCDavis. However, observation in the general population has demonstrated penetrance varying from the initial report. Real world experience suggests that penetrance may be low for cats that are heterozygous for the A31P mutation. Penetrance for homozygous cats is still expected to be very high.

In addition, not all individuals express the disease (HCM) in the same way. Some have very mild disease while others develop more severe disease. This is termed variable expressivity. In humans it has been well established by looking at individual families that mutations that cause HCM have variable expressivity. In other words, in human families it is well known that different family members with the same mutation have varying disease severity, age of onset, or progression of disease – often some will have mild disease while others will have severe disease. This has also been seen in the Maine Coon cat colony at UCDavis. While expressivity is expected to be more uniform in cats homozygous for a mutation and usually is (i.e., all homozygous cats have severe disease) this has not always been the case in the colony at UCDavis. For example, the longest surviving homozygous cat in that colony died at 12 years of age, albeit with severe but somewhat unusual cardiac disease. However, most died at a young (<5 years) age.

Since penetrance is not 100% and because expressivity is variable, it is common to identify Maine Coon and Ragdoll cats with a causal mutation that do not have echocardiographic evidence of HCM. This is more common in young cats but can also be the case in older cats. Also, as already noted, not all Maine Coon cats with HCM have the A31P mutation. These facts inevitably raise questions regarding the validity of the research findings that identified the A31P and C820T mutations as causal in producing HCM. Unfortunately, this may also lead some breeders to rationalize breeding cats that have a mutation. In order to clarify this issue, several factors must be considered to understand how we know that these mutations actually cause HCM.

What is the proof? First, the mutations identified to date are located in regions of the gene that are highly conserved. That means when you look across species that the base pair change (i.e., the mutation) occurs in a position where the base pair is always the same, regardless of species. This means that it’s important that the particular base pair is always the same because if it’s not, bad things (i.e., disease) will happen. Second, when you enter the mutated sequence into a computer program to predict what the mutated protein will look like, that protein looks very abnormal. Third, when examined in two labs now, the amount of cardiac myosin binding protein C protein in cardiac cells is reduced in Maine Coon cats with the A31P mutation, especially those that are homozygous for the mutation.

So there is almost no doubt that the two mutations identified cause HCM in two breeds of cats. What then needs to be done to rid the Maine Coon and Ragdoll breeds of this disease-causing mutation? That is a scientifically, ethically and politically challenging question. It becomes scientifically challenging primarily because the incidence of the mutations is so high. In Maine Coon cats that have been screened for the A31P mutation, although not a random sample, the incidence is over 30%. The scientific argument then becomes, what would happen if all of those cats were removed from the breeding pool? At first blush it looks as if this would be detrimental to the gene pool. By saying that 30% of the cats couldn’t be bred and moving to the remaining 70% it would appear that you would run the risk of compounding other existing mutations in that gene pool and potentially causing more harm to the breed than good. However, this overlooks the fact that the gene pool is already selected by cat breeders. It is estimated that of the kittens produced by cat breeders less than 10% of those cats ever get bred. So cat breeders already remove 90% of the gene pool in their quest to have the best looking, and hopefully healthiest, cats. When that is taken into account one then realizes that 30% of 10% (or 3%) of the cats are really being affected by removing those with a causal mutation. And so the effect on the gene pool becomes much less onerous IF cat breeders are willing to breed cats selected first for good health.

What recommendation has been made to Maine Coon cat and Ragdoll cat breeders? The first recommendation is to have all breeding cats tested for the appropriate mutation. The second recommendation is to never breed a cat that is homozygous for a mutation. The third recommendation is less clear and addresses cats that are heterozygous. Ideally those cats should not be bred also. However, one loophole has been left in place. It states that if a cat has qualities that are deemed by the breeder to be exceptional and of great advantage to the breed, that cat can be bred once. The offspring from that cat then must be tested and the kittens that have the mutation must not be bred. The line is continued with kittens that do not have the mutation. The fourth recommendation is to never sell a kitten that has a mutation. Obviously it is better never to produce a kitten that has a mutation but it certainly is unethical to sell a kitten with a mutation to an unsuspecting (or even knowledgeable) owner. Full disclosure of the DNA status of a kitten or cat should be given to potential owners, prior to offer for placement, with an explanation of the possible complications in the health of a cat with the mutation.

What about purebred breeding cats that belong to breeds where a mutation has not been identified or in which another mutation is believed to be present (e.g., Maine Coon cats)? These cats need to be screened periodically using echocardiography (cardiac ultrasound) for the presence of HCM. However, echocardiographic screening has several shortcomings.

First, as noted previously, HCM usually does not show up in young cats and so a cat may be bred before there is echocardiographic evidence of the disease.

Second, penetrance is not 100% so some cats with a mutation may never have clinical evidence of HCM although they can pass a mutation on to their offspring and those offspring can develop HCM.

Third, cats can express a very mild form of the disease making it difficult to impossible to distinguish them from normal cats (i.e., equivocal diagnosis). Consequently, genetic testing is much preferred over echocardiographic screening when it is available and there is only one mutation in a breed. Unfortunately, this dream has yet to be realized for most breeds.

Still, careful attention to the health history of ancestors and closely related cats, plus intelligent and informed use of all the tests available to ascertain the health of a breeding cat can only benefit the breed when individuals who are found to be affected are removed from breeding programs.


Copyright © 1997-2009 Mark D. Kittleson, DVM, PhD, Diplomate ACVIM (Cardiology)