Margret L. Casal, Dr med vet, PhD, DECAR
Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania
Philadelphia, PA, USA
IS IT A GENETIC DISEASE?
This is probably the most common question posed to the veterinarian by the conscientious breeder when confronted with a puppy or kitten with an unusual illness. What are the chances of it happening again? What can be done about it? First, it is most important to make an accurate diagnosis. Second, one needs to know if the same disease has been seen in related animals, in the same breed or is known to be a genetic disease in other species. If any of these statements are true, then one is most likely dealing with a genetic disease. Or, to quote the "father" of small animal genetics, Dr. Donald Patterson, "Everything is inherited until proven otherwise!" Alternatively, if the same disease has never been seen in the breed and is not known to be inherited in other species, then one may be dealing with a developmental disorder that may have occurred during pregnancy as a result from toxins, malnutrition, medications, and such. Occasionally, illnesses are not what they seem to be. For example, we see a puppy in practice that has demodicosis, kennel cough, and diarrhea caused by Giardia and campylobacter. It seems like simple infectious diseases. However, it is worthwhile checking for immune deficiencies, hypothyroidism or diabetes mellitus as an underlying cause. All of these diseases are known to be inherited.
The knowledge of known genetic disorders, their breed distributions, and their distinguishing characteristics is basic to their recognition and control. As discussed during this conference, the number and variety of genetic diseases are extremely large. Many of them are rare, and new entities are discovered at frequent intervals. Because of this, it is often necessary for the veterinarian in practice to consult a reference source for information.
The Section of Medical Genetics at the University of Pennsylvania is currently working on a computerized information system that will catalog the clinical, pathologic, laboratory and genetic features of all of the genetic diseases of dogs and indicate the breeds in which they occur, recommended methods of control, and key references. The project has been partially supported by the American Kennel Club. This computerized system has the advantage that it can be searched in a variety of ways. One way of particular use to the practicing veterinarian is by breed. If a client/breeder presents a young dog for examination to exclude the presence of inherited defects, the veterinarian can obtain a check list of all of the genetic disorders known to occur in that breed.
Being a mixed breed dog does not exclude from being born with a genetic disease, although it is less likely because of the "dilution" of autosomal recessive traits. However, dominant traits are just as common in mixed breed dogs as they are in pure bred dogs. Dominant traits are generally new mutations; just one allele needs to acquire a mutation for the trait or disease to be expressed. Also, as a rule of thumb, dominant mutations generally lead to structural defects, such as Ehlers-Danlos, osteogenesis imperfecta, congenital lymphedema, to name a few examples. Dominant traits are simple to eliminate by not breeding the affected animal. In mixed breed cats, we see more autosomal recessive diseases than in mixed breed dogs because many cats that live outdoors are not neutered and inbreeding is a frequent occurrence. Thus, the chance of recessive alleles pairing up in the offspring is greater than in mixed breed dogs which are generally neutered at a young age.
If a disease has been seen in the breed before or occurs as a genetic disease in another species, it is likely to be genetic in the animal presented to the veterinarian. If one needs to make an educated guess as to the mode of inheritance, then it is helps to have an idea of the biochemical cause of disease. Most enzyme deficiencies are autosomal recessive and most structural defects are dominant. These are just rules of thumb, there are exceptions!
In summary, here are the key points for evidence that a disease has a genetic cause:
Greater frequency of the specific disorder within a group of related individuals than in the general population (e.g., within a family group, strain or breed).
Increase in the frequency of the disorder with inbreeding (in simple recessive or polygenic disorders).
Increased frequency of defects involving the same anatomic site or functional system in a group of related individuals as compared to the general population.
Characteristic age of onset and clinical course.
A specific phenotypic defect or syndrome is consistently associated with a specific chromosomal anomaly.
The disease process can be related to a molecular defect in a single polypeptide (e.g., enzyme or structural protein, receptor).
If, as is the case with many genetic disorders, there is no available laboratory test for the carrier state, the only method by which carriers can be detected is test mating. The principle behind this approach is as follows. The animal to be tested is hypothesized to be a carrier and is usually mated to an animal known to be homozygous or heterozygous for the gene in question. If any affected offspring are produced, we know that the tested animal is a carrier and the hypothesis is shown to be correct. If, however enough normal offspring and no affecteds are produced, we can reject the carrier hypothesis with some degree of statistical assurance.
For some genetic diseases, carriers are identifiable by biochemical testing (e.g., enzyme defects, clotting factor defects). These assays can be very useful and have been all that has been available for a number of years. However, compared with the possibility of DNA-based tests (see below), they have a number of disadvantages, including:
Normal and carrier levels of the enzyme/substrate often overlap.
A biochemical test may not be possible for a specific disease because the in vitro assay (laboratory test) results do not reflect the in vivo (real-life) conditions.
A test may be possible but is not available because of expense.
The enzyme or substrate may be unstable and would not survive shipment.
Age-matched controls are necessary.
There may be lab to lab variation in the assay.
The tissue needed for the assay may be difficult to obtain.
Molecular Genetic (DNA-Based) Tests for Affected and Carrier Animals
DNA-based genetic tests identify differences in DNA sequences and are of two different varieties. One type of test, referred to as a mutation-based test, recognizes disease-causing mutations while a second type of test, the linked-polymorphism test, recognizes DNA differences that are near the disease-causing gene and are used to track normal and mutant alleles of that gene through pedigrees. While there are significant differences between how these two types of tests are developed and how they are used, they both involve the same basic techniques.
Essentially all DNA-based genetic tests are based on the polymerase chain reaction, and consequently can be performed using a very small amount of DNA from the animal of interest. DNA-based genetic tests have the advantage (over biochemical assays) that DNA is very easy to obtain by fairly non-invasive techniques and is very stable. Common sources of DNA include: blood, hair follicles, cheek swabs, semen, and skin biopsies.
USES OF GENETIC TESTING
The more accurate the test, the quicker a disease can be eliminated from the breeding stock. The parents and relatives can be tested and their use as a breeder established if they are not carriers for the disease. Alternatively, if we know that a champion dog is a carrier of a specific disease but the dog has all the best qualities for its breed, then we are able to not only test the bitch he is to be bred to ensuring that she is not a carrier, but we can also test the offspring and retain only those for future breeding that are not carriers. Thus, we do not have to loose the desired traits in the champion dog.
The practicality of a genetic screening program depends on the following requisites:
The disease must occur in a defined population (family, herd, breed) with sufficient frequency to be of economic or social importance.
The test for the heterozygote is accurate and affordable.
Culling of heterozygotes does not deplete key genetic resources.
Test and control program should be acceptable to breeders (precede by educational and public relations programs).
Genetic counseling is available to breeders.
Breed society must have rules to insure that control is based on test results (registries).