Pathways to Discovering the Cause of Disease: Could it be Genetic?
Tufts' Canine and Feline Breeding and Genetics Conference, 2011
Cynthia O'Connor, DVM, DACT
Slade Veterinary Hospital, Framingham, MA, USA

With the recent advances in molecular genetics and the availability of genetic maps, we have witnessed the emergence of genomics into clinical veterinary practice. Currently, there are over 400 hereditary diseases in dogs and approximately half of that in cats that have been documented with a growing number of new diseases reported every year.1 This has led to the development and growing need for incorporation of clinical genetics into veterinary practice with the small animal practitioner playing an ever growing and vital role in both genetic counseling and in the detection of potentially new genetic diseases.

Hereditary disease is any disease that is caused by a DNA mutation that can be passed from parent to offspring, where a congenital disease is a disease present at birth. With this distinction, congenital diseases can be genetic, but not all congenital diseases are genetic.2 For example, an autosomal recessive gene mutation in Portuguese water dogs results in early age dilated cardiomyopathy and sudden death (Portuguese water dog juvenile dilated cardiomyopathy or JDCM); however, perinatal infection with parvovirus can result in a myocarditis with resultant myocardial damage, heart failure, and sudden death in young puppies as well.3,4 The onset of clinical signs can vary for hereditary diseases. Some hereditary diseases may be seen at early ages where the most common presentation is embryonic/fetal death, stillbirth, or fading puppies/kittens. Unfortunately, many of these animals may remain undiagnosed as breeders and veterinarians may not pursue additional diagnostics in these prenatal and neonatal cases. Traditionally, clinical signs of a hereditary disorder may not be recognized until after weaning since musculoskeletal, ocular, digestive, and other anomalies may not be as readily identified during the neonatal phase of development. Some diseases may have a much later onset. One example is prcd-PRA where affected animals suffer from retinal atrophy that leads to eventual blindness with clinical signs rarely seen before 3–5 years of age.5

The number and variety of genetic diseases is extremely large and many of them are very rare, with new diseases recognized at an exponential rate.6 As such, it is important for a practicing veterinarian to consult reference sources to obtain knowledge about a known genetic disorder, breed distributions, and the distinguishing characteristics regarding diagnosis, treatment, and control (Table 1). When encountering a disorder whose cause has not been previously defined, there are several types of evidence that may suggest a genetic etiology:7

 Does the disorder occur in a greater frequency within a line or breed than in the general population?

 Is the disease seen more often in animals with a higher degree of inbreeding? (Remembering that you need to search beyond a typical 3–5 generation pedigree to reveal a more accurate degree of inbreeding.)

 Does the disease have a characteristic age of onset and clinical course, especially when seen in young animals?

 Is the same syndrome found in another species and is it known to be genetic?

 Is there a specific phenotypic defect or syndrome that is associated with a specific chromosomal abnormality?

 Can the disease process be related to a molecular defect such as a defect in an enzyme pathway, structural protein, or molecular receptor?

It is also important to keep in mind that genetic diseases are not limited to purebred dogs and cats. While many mixed breed dogs have a significantly lower degree of inbreeding, many populations such as local stray cat populations may actually have a higher than expected degree of inbreeding. In general, autosomal recessive diseases are more likely to be expressed when there is a higher degree of inbreeding. However, dominant disease and polygenetic diseases may be just as likely to be seen in mixed breed populations as they are in more inbred populations depending upon the disease and the population.2

The clinical approach to identifying genetic disease begins with a thorough history and physical exam of the patient. Additional queries regarding littermates and relatives as well as in some cases, a population medicine approach when dealing with kennels and catteries will assist with the collection of infectious disease, toxin, nutritional, and other important data to be considered in the investigation of new disease presentations. Diagnostic tests generally are required to further support a genetic disorder in a diseased animal.8 For example, radiology and other imaging techniques may reveal skeletal malformations, echocardiogram may reveal cardiac anomalies, and ophthalmologic examination may further define an inherited eye disease. Routine tests such as a complete blood cell count, chemistry screen, and urinalysis may suggest specific hematologic or metabolic disorders, and they may help rule out many acquired disorders. Based on these findings, additional clinical function testing may more clearly define a gastrointestinal, liver, kidney, or endocrine problem.10,11 Histopathology of a tissue biopsy or in some cases a necropsy evaluation from an affected animal are often required for a complete evaluation and definitive diagnosis for animals with a genetic defect. The latter is particularly important when faced with a fading neonatal puppy or kitten as this may give information vital to surviving littermates as well as future planned matings; however, this important diagnostic tool is often underutilized for these neonatal patients.

Few laboratories provide special diagnostic tests that allow for investigation into a possible inborn error of metabolism (Table 1). Inborn errors of metabolism include biochemical disorders due to a genetic defect in the structure and/or function of a protein or receptor. For example, a deficiency in the enzyme β-glucuronidase results in the lysosomal storage disorder mucopolysaccharidosis VII that has been reported in German shepherd dogs as well as a mixed breed dog.10 The most useful specimen to detect biochemical derangements is urine because abnormal metabolites are filtered but not resorbed by the kidneys. Once identified, the defect can be further investigated with more specific protein assays. The Section of Medical Genetics at the School of Veterinary Medicine of the University of Pennsylvania is one of the few places that perform such tests to diagnose as well as to discover novel hereditary disorders (VIN editor note: link updated11/13/15).9

In addition, few laboratories offer cytogenetic studies to evaluate for potential abnormalities in chromosomes (Table 1). Any cell capable of dividing can be used for this purpose; however, most commonly blood lymphocytes or skin fibroblasts are used. For lymphocyte culture, blood is collected into sodium heparin where it is then cultured in media and stimulated to divide. The cells are then arrested in mitosis during metaphase where chromosomes are compacted. The chromosomes can then be stained to result in a typical banding pattern of the chromosomes used in traditional karyotyping, or fluorescent probes can be utilized in a technique known as fluorescence in situ hybridization (FISH).

A thorough investigation into the family history of a patient with a suspected genetic disease is also important to determine a potential mode of inheritance. Knowing how a disease is passed from generation to generation is the most important aspect of planning a breeding program to manage genetic diseases as well as starting the investigation into a genetic cause of a new disease presentation. The inheritance patterns reported in veterinary medicine include autosomal recessive, autosomal dominant, X-linked recessive, X-linked dominant, and complex (polygenetic) diseases.2 Recessive diseases account for a majority of the diseases for which there is a known inheritance pattern and for which a genetic defect has been identified.12 However, with continued advances in molecular biology and technology, this will soon be true for complex (polygenetic) disorders as well.

Autosomal recessive diseases are identified most commonly as the presentation of affected animals with both sexes equally represented born to clinically normal parents. Typically, the clinically normal parents have a common ancestor. These animals that are phenotypically normal are referred to as carriers (heterozygous for the disease causing allele).2 Common theories for the increased prevalence of the expression of autosomal diseases in purebred dog and cat populations include the higher degree of inbreeding related to popular sire effects, selective inbreeding, and bottlenecks in their populations.

Autosomal dominant diseases are often seen with an affected individual produced from at least one affected parent since carrying one (heterozygous) or both (homozygous) copies of the mutant allele will result in disease. However, not uncommonly, new mutations can occur which results in an affected animal that is produced by two clinically normal parents.2 In some cases, diseases are referred to as being incompletely dominant. Traditionally, incomplete dominance occurs when the expression of disease with a heterozygous genotype (one copy of the mutant allele) is an intermediate or has variable expression of the disease. In these cases, the parents with the disease causing allele may not exhibit any clinical signs and appear normal, yet they may pass that disease causing allele on to their offspring. Some theorize that interactions with other modifying genes and in some cases, the environment, affect the expression and severity of the disease making some believe that a proportion of these incompletely dominant diseases may have inheritance patterns more similar to complex modes of inheritance.

X-linked recessive diseases are distinguished mainly by males being predominantly affected. Females are far less likely to be affected based on the presence of two X chromosomes and the requirement for an affected male to survive long enough to reproduce with a carrier female in order to produce an affected female offspring.8 The first canine mutation discovered was the X-linked recessive disease, hemophilia B.13 X-linked dominant diseases are extremely rare with the only reported example in veterinary medicine being X-linked Alport syndrome in Samoyed dogs.14

Y-linked disorders are caused by mutations on the Y chromosome. Since males inherit a Y chromosome from their fathers, every son of an affected father will be affected. However, since females only inherit an X chromosome from their fathers, female offspring of affected fathers are always normal with Y-linked disorders. Since the Y chromosome is relatively small and contains very few genes, there are relatively few Y-linked disorders and none have been reported to date in small animals. Another rare mode of inheritance in veterinary medicine is mitochondrial inheritance. This type of inheritance, also known as maternal inheritance, applies to mutations of the genes in the mitochondrial DNA of a cell. Since only egg cells (oocytes) contribute mitochondria to the developing embryo, only mothers can pass on mitochondrial conditions to their offspring.8

Complex disorders are more difficult to identify as they are a combination of the effects of multiple genes (polygenetic) as well as environmental influences that result in an expressed phenotype. Although complex disorders often cluster in breed or family lines, they do not have a clear-cut pattern of inheritance as seen with single gene disorders.2 This non-Mendelian inheritance pattern, as is often used to describe complex disorders, makes it difficult to determine an animal's risk of inheriting or passing on these diseases. Complex disorders are also more difficult to study and identify all the factors leading to expression of disease. However, common veterinary diseases are increasingly recognized as having a genetic component. In fact, some of the most common diseases recognized in veterinary medicine such as hip dysplasia, hypothyroidism, cancer, and atopy (allergies) are recognized to occur more frequently in certain breeds or family lines.15 As more information is obtained as to the gene involvement in disease, clinical veterinary genetics becomes increasingly important in the diagnosis, management, and prevention of disease in our veterinary patients.

Veterinarians are part of an important team involved in identification and control of genetic diseases. Breeders, pet owners, primary care veterinarians, veterinary specialists, veterinary researchers, genetic databases, and research funding institutions make up some of the vital pieces of this team. When a new genetic disease is suspected, all players of this team need to work together to compile the information and resources needed to determine the gene defect(s) involved. Sometimes this is not always as straightforward and as easy as it may seem. In general, researchers often modify and combine multiple techniques in the process of uncovering a genetic mutation, the most common being the genome-wide association study and the candidate gene approach.

Genome-wide association studies compare the DNA of two groups of participants: affected animals and similar animals without disease (normal controls). DNA is collected from these individuals and gene chips along with computer technology are utilized in order to read millions of DNA sequences. However, rather than reading the entire DNA sequence, single nucleotide polymorphisms (SNPs) which are variations in a single nucleotide of a DNA sequence are utilized as markers for evidence of DNA variation. Different variations are then identified and their association with different traits, in this case the disease in question, is further examined. If genetic variations are more frequent in the diseased animals as compared to normal controls, the variations are considered to be associated with the disease. The associated genetic variations are then considered as linked-markers to the region of the genome where the disease-causing problem is likely to reside. Most of the SNP variations associated with disease are not in the region of DNA that codes for a protein. Instead, they are usually in the large non-coding regions on the chromosome between genes that are edited out of the DNA sequence when proteins are processed. However, once these markers are linked to a disease, further molecular techniques can be utilized to narrow down the region and sequence potential genes thus identifying mutations.16

Another method that is utilized in the investigation of a genetic mutation is the candidate gene approach. This approach requires researchers to investigate the validity of an educated guess about the genetic basis of a disorder as opposed to genome-wide association studies which are predicated on the unbiased search of the entire genome without any preconceptions about the role of a certain gene. Similar to genome-wide association studies, the candidate gene approach involves the comparison of the affected individuals with normal controls; however, since one gene is the focus, large populations are not required with this technique for an association with the disease to be detected. The major difficulty with this approach is that in order to choose a potential candidate gene, researchers must already have an understanding of the disease pathophysiology and the potential genes that may influence the mechanism of that specific disease, such as a gene mutation known to cause the same disease in another species.17,18

Often, linkage to a disease is known before the mutation is identified. Linked marker testing can then be utilized to assist breeders in mating choices before a mutation based test is established. It is important for veterinarians and breeders to understand the advantages and limitations with a particular genetic test in order to achieve their goals of controlling genetic diseases while maintaining genetic diversity in the population as a whole. Several types of inherited disease screening and genetic tests have been described in veterinary medicine including phenotypic testing, linked-marker testing, and mutation based tests. In short, not all genetic tests are created equally and understanding the different types of tests along with mode of inheritance of a disease is vital to proper utilization of these tests. For example, linked marker testing may have two potentials for errors. The first error can occur from a recombination event where the marker is no longer linked to the mutant allele resulting in either a false positive or false negative result.2 In general, the closer the marker is to the mutant allele, the more likely they will remain together, or linked, and the less likely recombination will result in their separation. Another error occurs if the marker is not linked to the mutant allele, but is present in a high enough frequency in the population that it may initially appear linked resulting in a false positive test.2 While caution must be utilized when interpreting test results, it is also important to recognize that a linked marker test is extremely useful when dealing with a disease for which the mutation is not yet known.

Once a gene mutation is identified, it is important to note that these mutations are very specific. Small animals within the same or a closely related breed may likely have the same disease-causing mutation for a particular disease. However, small animals of other breeds, particularly unrelated breeds, with the same disorder may also have different mutations that may not be detected with a mutation based test.8 There may also be more than one genetic mutation within a breed that may result in similar clinical signs, and in these cases, both mutations need to be evaluated.

DNA tests have several advantages. The test can be performed at any age and long before clinical signs become apparent, detecting affected, normal, and carrier animals. DNA can be extracted from any nucleated cell, such as white blood cells, cheek cells, hair follicles, semen, and even formalinized tissue. Cheek swabs should be used very cautiously or avoided in nursing animals due to the potential contamination of the oral cavity with maternal nucleated cells.8 Since DNA is very stable and small quantities are required, it can be banked for long term storage and utilized in future genetic studies. Several veterinary DNA storage facilities have been developed for this purpose. The key factor in the usefulness of DNA for these future studies is determined by the complete and thorough records kept on that animal. An animal suffering from an inherited disease needs to have an accurate diagnosis of the cause of that disease in order to prevent false associations when utilizing that animal's DNA for a potential gene mutation study. For example, a cat with suspected liver disease due to amyloidosis needs to have histopathological confirmation of that disorder or there is a risk that an animal with hepatic adenocarcinoma may confuse and invalidate future genetic studies.

With the growing advancements in molecular genetics and the availability of genetic tests which are being developed at an exponential rate, it is important for veterinarians and breeders to have a basic understanding of how to utilize these techniques in order to control genetic diseases while maintaining the genetic diversity of the population as a whole. We have witnessed the emergence of genomics into clinical veterinary practice which has led to the development and growing need for a team based approach to control and identification of genetic disorders in small animals.8 With the hard work and cooperation between breeders, pet owners, primary care veterinarians, veterinary specialists, veterinary researchers, genetic databases, and funding institutions, we have seen the development of close to 100 genetic tests.6 This research has not only benefited the lives of our small animal patients and their families, but has also furthered our understanding of genetic diseases in other species, including humans. As we look to the future, we all need to continue our vital roles in this process so that we can further unlock the mysteries behind some of the most common diseases we see in veterinary medicine.

Table 1. Some Useful Websites Relating to Canine and Feline Genetic Diseases.

Listing of available tests and testing center information (VIN editor note: unable to access link as of 11/13/15) (VIN editor note: unable to access link as of 11/13/15) (VIN editor note: unable to access link as of 11/13/15)

Databases and recommendations for health screening (VIN editor note: unable to access link as of 11/13/15)

Metabolic screening laboratory

Karyotyping/Cytogenetic services (VIN editor note: unable to access link as of 11/13/15) (VIN editor note: unable to access link as of 11/13/15)

Selected parentage testing services


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Speaker Information
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Cynthia O'Connor, DVM, DACT
Slade Veterinary Hospital
Framingham, MA, USA

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