Clinical Tools to Diagnose Hereditary Disorders
World Small Animal Veterinary Association World Congress Proceedings, 2009
Urs Giger, Prof. Dr. med. vet., MS, FVH, DACVIM, DECVIM (Internal Medicine), ECVCP (Clinical Pathology)
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

While clinical and routine laboratory and imaging techniques are helpful, specific biochemical and DNA tests have become available for >80 disorders through various laboratories. Simple test sample requirements and result interpretations are presented with cases. As it is difficult to keep track of all the diseases, tests and treatments, a WSAVA web site for clinicians is being introduced.

It is difficult for a clinician to keep up with the rapidly accumulating information on clinical genetics and the large spectrum of disorders and genetic predispositions. Thus, comprehensive update resources are needed. There are several web sites that provide some information on many different diseases in companion animals such as "Inherited Diseases in Dogs"(; Mendelian Inheritance in Animals (; Canine Inherited Disease Database (; and the FAB list of feline hereditary disorders ( The WSAVA Committee on Hereditary Diseases is setting up a data base with the Veterinary Information Network ( and with pertinent practical information on clinical features, genetic diagnostics, and management specifically for the clinician.

Beyond physical examination and imaging tools, genetic, metabolic, and other laboratory techniques are used to diagnose hereditary disorders in companion animals. Most genetic defects cause clinical signs early in life. The term congenital only implies that the disease is present at birth, however, and does not necessarily mean it is inherited. A common presentation is failure to thrive; they are poor doers, often fade (hence the term fading puppy or kitten syndrome), and finally die. Failure-to-thrive should not be confused with growth retardation. In addition to these relatively unspecific clinical signs, some defects may cause specific clinical manifestations. Easy to recognize are malformations that involve any part of the skeleton and lead to disproportionate dwarfism, gait abnormalities, and/or facial dysmorphia. A large number of hereditary eye diseases have been described in dogs, some of which are not recognized until adulthood. Neuromuscular signs may vary from exercise intolerance to ataxia and seizures. Defects of many other internal organs are associated with unspecific clinical signs.

Diagnostic tests are generally required to further support a genetic disorder in a diseased animal. Radiology and other imaging techniques may reveal skeletal malformations or cardiac anomalies, and an ophthalmologic examination may further define an inherited eye disease, although some are not recognized until several years of age. Routine tests such as complete blood cell count, chemistry screen, and urinalysis may suggest some specific hematological or metabolic disorders or rule out many acquired disorders. Furthermore, clinical function studies may more clearly define a gastrointestinal, liver, kidney, or endocrine problem. Histopathology and/or electron microscopy of a tissue biopsy from an affected animal or from the necropsy of a littermate or relative may give the first clue to a genetic defect.

A few laboratories provide special diagnostic tests that allow a specific diagnosis of an inborn error of metabolism. Inborn errors of metabolism include all biochemical disorders due to a genetically determined, specific defect in the structure and/or function of a protein molecule. Disorders of intermediary metabolism typically produce a metabolic block in a biochemical pathway leading to product deficiency, accumulation of substrates, and production of substances via alternative pathways. The most useful specimen to detect biochemical derangements is urine because abnormal metabolites in the blood will be filtered through the glomeruli, but fail to be reabsorbed, as no specific renal transport system exist for most abnormal metabolites. Once the failing system has been identified, the defect can be determined at the protein level. For recessive traits, homozygously affected animals have very low protein activity and/or quantities (0-10%). These tests may also be used to detect carriers (heterozygotes), who typically have intermediate quantities at the protein level (30-70%), but no clinical signs. Unfortunately, protein assays usually require submission of appropriate tissue or fluid under special conditions to specialized laboratories along with a control sample, and are labor intensive.

The molecular defect has been identified for ~60 canine and ~20 feline hereditary diseases, and thus DNA screening tests have been developed. These tests are mutation or DNA marker specific and can therefore only be used in animals suspected to have the exact same gene defect. Small animals within the same or a closely related breed will likely have the same disease-causing mutation for a particular disease. However, dogs and cats as well as unrelated breeds of a species with the same disorder will likely have different mutations. On the other hand a few mutations have been found in a couple of breeds or may be widespread within the canine population. For many inherited disorders, the defective gene remains unknown; however, for a few, a polymorphic DNA marker that is linked to the mutant allele has been discovered. At present, mutation-specific and linkage tests are available only for single gene defects in small animals; however, complex genetic traits may also soon be approached by these methods as they are for humans. Many predispositions such as inflammatory, immune-mediated, malignant disorders have a genetic basis. While many more single gene defects are being studied from clinical signs to the molecular defect, current investigations are shifting toward complex genetic traits. The many breed predispositions for various complex genetic traits are particularly attractive to further define their molecular bases.

DNA tests have several advantages over other biochemical tests. The test results are independent of the age of the animals, thus, the tests can be performed at birth or at least long before an animal is placed in a new home as well as before clinical signs become apparent. DNA is very stable and only the smallest quantities are needed; hence, there are no special shipping requirements as long as one follows the specific mailing instructions for biological products. DNA can be extracted from any nucleated cells, e.g., blood, buccal mucosa (using cheek swabs), hair follicle, semen, and even formalinized tissue. For instance, blood can be sent in an EDTA tube or a drop of blood can be applied to a special filter paper; buccal swabs can be obtained with special cytobrushes--the cheek cells and not the saliva is needed and swabs need to be completely dried. The DNA segment of interest, which is surrounding the mutation, is amplified with appropriate DNA primers utilizing the polymerase chain reaction (PCR). The mutant and/or normal alleles are identified by DNA fragment size or base pair differences. These tests are generally simple, robust, and accurate as long as appropriate techniques and controls are used. Furthermore, they can be used not only for the detection of affected animals, but also for carriers from birth on.

Although some hereditary diseases can be successfully treated, of much greater importance is the screening of animals prior to breeding to assure that they are free of known hereditary diseases. Through various genetic screening programs, genetic counseling by veterinarians and with responsible breeders many hereditary disorders can be prevented from future generations. This should not be done without careful consideration of the severity of the disease, the treatment options and efficacy, prevalence of the mutant allele in the breed, and the overall gene pool in the breed.

Speaker Information
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Urs Giger, Prof. Dr. med. vet., MS FVH, DACVIM & DECVIM (Internal Medicine), ECVCP (Clinical Pathology)
School of Veterinary Medicine
University of Pennsylvania
Philadelphia, PA, USA

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