Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
The genomes of hundreds of dogs and cats have been sequenced, for cats as part of the 99 Lives Cat Genome Sequencing Initiative. Most veterinary colleges teach genetics in their core curriculum. But why should a feline practitioner care about genetics?
Advertisements for direct-to-consumer genetic testing, such as 23andMe, are commonplace and the lay public now understands genetics at a higher level than ever before. The same genetic information can be had for cats and dogs. DNA is the basis of life and the foundation of organismal biology. If you accept comparative anatomy, you must accept comparative genetics as a majority of genes are the same in all mammals.
Hundreds of thousands of humans have had their whole genome sequenced to improve their own health or to help identify health-related DNA variants in their children as part of Precision Medicine. Precision Medicine can be defined as using an individual’s DNA profile to use specific drugs and treatments that will have a more predictable and positive response in that individual. Many veterinary health care centers, especially veterinary teaching hospitals, have diagnostic capabilities comparable to human medicine, such as 3T MRI and 64-splice CT. The genetic and genomic resources for cats and dogs have vastly improved within the past 3 years, including more accurate genome assemblies. The vastly improved assemblies have enabled the development of resources needed for Precision Medicine, such as whole exome sequence (WES) and whole genome sequencing (WGS). The costs of Genomic Medicine have also radically reduced. WGS can be accomplished for ∼$1200 USD and WES for ∼$350 USD. These costs are well within the costs of current diagnostics used in veterinary medicine. Whether treatments are required for an allusive disease or to determine biomarkers for chemotherapy targets, Precision/Genomic Medicine can be applied to companion animals.
Hundreds of DNA variants causing diseases, morphologies and phenotypes are now documented in cats and dogs. The clinical descriptions and phenotypes of each of these diseases and traits have been curated at the Online Mendelian Inheritance in Animals (OMIA) website (http://omia.angis.org.au/home/), which is an invaluable resource comparison of the phenotypes across 2216 animal species.
Most of the identified disease tests in pets are very specific to breeds and populations are available as commercial genetic tests offered by university-associated and private laboratories. Many DNA alterations identified in random bred pets and disease conferring variants that have not propagated within a breed. These genetic variants should not be part of routine screening by breeders and registries, but clinicians should know that genetic tests are available for diagnostic purposes, especially from research groups with specialized expertise. If similar conditions are suspected in cats or dogs, researchers will generally consider testing for the known variant as a non-commercial service and may continue analysis of the entire gene to determine if new DNA alterations can be identified and causative for this particular condition. Other biomarkers are also available at these specialized laboratories to help decipher between specific conditions, such as the lysosomal storage diseases and metabolism orders.
Genetic Counseling in Veterinary Medicine
Veterinarians are expected to obtain, understand, and interpret DNA results and provide “genetic counseling.” Unlike dogs, because a majority of the cat population does not represent pedigreed cats, breeders are not generally the largest portion of clientele in a standard veterinary practice. Genetic testing in random bred cats is currently rather minimal and occurs primarily for rare and orphan diseases, such as mucopolysaccharidoses or porphyrias. With regard to genetic testing, what pertains to cats likely pertains to other domestic animals, including dogs, cattle, and horses. Genetics courses are a standard prerequisite for veterinary school admission; and for the past 10 to 15 years, many U.S. veterinary schools have formally added genetics into their curriculum. At a minimum, different modes of inheritance are reviewed and graduate veterinarians should be able to provide minimal genetic counseling as a result. The mode of inheritance (i.e., autosomal, sex-linked, recessive, dominant), incomplete penetrance, variable expression, age of onset, and risk are terms the modern veterinarian should come to know, understand, and hopefully embrace.
Genetic counseling can be structured into three distinct processes. The initial process is the procedure conducted by the veterinarian to obtain a diagnosis for a clinical presentation. Collection of the patient’s signalment and history should include considerations of the pet’s breed and the general health of its lineage, including parents, siblings, and offspring. Thus, the veterinarian may be looking for clues to a possible genetic cause for a condition by asking if this clinical presentation has been documented in the breed or noticed in any close relatives.
Any early presentation of a disease that normally affects older pets, such as mediastinal lymphoma, may indicate a potential genetic influence. Bilateral presentation, such as vessel attenuation in both eyes in normotensive cats or dogs, is a hallmark for heritable disease, such as retinal degeneration. At this time, the veterinarian and client will need to discuss if a DNA-based diagnostic test, such as DNA test for PKD, is more warranted, perhaps in lieu of or prior to additional more costly diagnostics, such as ultrasound examinations. Considerations such as what happens if the DNA test is positive or negative need to be considered and discussed.
Once a DNA test is obtained, test interpretation and prognosis need to be considered, which is a major secondary step in genetic counseling. The client and the veterinarian need to recognize that the current DNA tests do not predict severity of disease. In the case of PKD, many mildly affected cats will never develop renal failure and will die of causes not related to PKD, whereas others develop end-stage renal disease within a few years and have an early death attributed to the disease. Thus, ultrasound imaging is an important diagnostic in the cat’s healthcare management for PKD. Another important example is HCM in Maine Coon cats. The presence of the genetic mutation clearly confers risk, but the extent of the risk is nebulous. Thus, genetic tests should be used as a tool for the veterinarian and the owner, supporting the overall picture of a given cat’s healthcare plan. In the case of PKD, ultrasound and/or serum creatinine levels should be used to monitor disease progression in PKD-positive cats. Echocardiographic monitoring remains the standard for HCM patients, although early detection cardiac biomarkers are being explored. Genetic testing should be used to enhance (not replace) interactions among the patient, client, and veterinarian.
The third step in genetic counseling is communication with the client, which hopefully is a long-lasting interaction over the healthcare management of the pet. Directed (active) versus non-directed (passive) counseling is a concept that should be considered. Most veterinarians want to provide “directed” counseling. For example, “Your cat has PKD. You should never breed the cat again and should spay or neuter the cat.” Directed counseling is unacceptable in human medicine, and if the “big picture” is considered, directed counseling should also be nonstandard in veterinary medicine. The “big picture” pertains to not only the cat itself but also the breed population and the livelihood of the breeder. Thus, a more passive, non-directed approach where all the information regarding the patient’s health and likely information regarding the owner’s breeding program will need to be considered.
As noted with the gangliosidoses in the Korat breed, a passive approach led to a slow eradication of the disease variant in the population, without the production of unhealthy cats, but with maintenance of high genetic diversity in the breed population—the “big picture.” In individual cases, the veterinarian caused no harm to the patient or the breed, likely kept the breeder as a client, the client developed a healthier breeding program, and the veterinarian and breeder improved the overall health of the breed.
Genetics is not going to solve every health problem, even the ones with highly heritable influences. Interpretations and the determination of risk may be difficult for many conditions. As determined by sequencing of thousands of humans, each individual (human or pet) has several severe mutations in their genome that should render them unfit—we should all have some major health problem! It is important for veterinarians and pet owners to recognize that we do not yet understand how all the approximately 21,000 genes of the body interact and therefore cannot predict the overall health of an individual based on the presence or absence of a single mutation. Thus, in genetic counseling, one should consider all the good things as well as the bad things that a cat has to determine future breeding and population management strategies. The present health condition of the pet should be the primary concern, but temperament, reproductive success, resistance to other health problems, and aesthetic qualities should also be considered. By understanding the mode of inheritance, diseases and undesirable traits can be slowly removed from the feline population. Veterinarians play a vital role in human public health. So too with pets, the health of the individual and the health of the population both need to be considered in health management plans.