Recent Advances in Hereditary Diseases and Genetic Predispositions for the Clinician
Urs Giger, DACVIM, DECVIM-CA (Internal Medicine), DECVCP (Clinical Pathology)
The unique traits of canine and feline breeds and many hereditary disorders and genetic predispositions to disease have been and are being characterized from the clinical signs to the gene defect. With the recent completion of the canine and feline genome sequences genetic tests are now becoming available for many hereditary diseases. Moreover, with DNA tests it is now possible to determine the ancestry of mixed breed and purebred dogs, a first example of a complex trait. The recent advances in canine clinical genetics will be covered and illustrated with clinical case examples.
The topic of clinical genetics in small animals has often been overlooked by veterinarians, presumably because hereditary disorders were thought to occur rarely in clinical practice, to offer relatively little for a clinician to do, or to represent an area where clinicians defer to breeders or academic institutions. However, many of the characteristic breed traits and common and rare genetic diseases and predispositions seen in veterinary practice are now recognized to have a heritable basis and have taken on an increasingly important role in veterinary medicine as many infectious diseases, nutritional deficiencies, and intoxications have been controlled. Today, many hereditary diseases are well characterized from clinical signs to the gene defect, precise diagnostic tools have been developed to detect affecteds but also carriers, specific treatments can be offered for a few, and genetic counseling with breeder clients can improve the health of small animals in future generations.
Because of the increased awareness of breeders, pet owners, and veterinarians of genetic defects and the improved diagnostic abilities in clinical practice, the number of reported hereditary diseases in small animals is rapidly growing. At present, > 900 and > 220 hereditary diseases in dogs and cats, respectively, have been adequately documented, and every year over a dozen new defects are being reported. For the small animal practitioner, it can be a daunting, nearly impossible task to remember all these diseases and be aware of the many novel tests and their appropriate management and control. The recent advances in canine clinical genetics will be covered and illustrated with clinical case examples.
Many of the characteristic breed traits and common and rare diseases seen in veterinary practice have a heritable basis. Recent exciting advances in our current knowledge of the completed dog and feline genome sequences offer the opportunity to clinicians to use these emerging tools in clinical practice and have a positive impact on the health of dogs as well as cats and in particular the diagnosis, management, and control of hereditary diseases. Many specific breed traits such as size, chondrodysplasia, brachycephaly and many skin and coat color characteristics have been defined.
Genetic screening tests permit the identification of animals at risk for many of the single-gene hereditary diseases prior to the development of clinical signs, mitigating the suffering of dogs and cats carrying 2 mutant alleles for autosomal recessive traits. This advancement has far-reaching benefits for promoting canine and feline health permitting the elimination of deleterious gene defects, while preserving desirable traits in a breed. Identification of complex trait markers, such as those responsible for temperament and trainability, will likely prove extremely valuable to guide- and service-dog organizations, but also the common pet dog and cats. For the first time, the investigation and identification of polygenic diseases is a realistic proposition. Lastly, collaborative comparative veterinary-human studies will serve to accelerate the rate of discovery and the extent to which both human and veterinary medicine accrues benefits from gene-based research.
Genetic diseases are caused by chromosomal alterations or gene mutations. Disease-causing mutations are heritable changes in the sequence of genomic DNA that alter the expression, structure, and function of the coded protein. The genotype refers to the animal's genetic makeup, reflected by its DNA sequence, whereas the phenotype relates to the clinical manifestation of specific gene(s) and environment, or both. The molecular genetic defect is now known for > 60 hereditary disorders in dogs and > 20 in cats. These molecular genetic changes include point mutations, deletions, and insertions in the DNA sequence that result in a missense or nonsense sequence with an altered codon sequence. For approximately half of the disorders suspected to be of a genetic nature the mode of inheritance remains however unknown. Both the canine and feline genomes (7.5x) have been sequenced during the past years, which have and will continue to greatly facilitate the characterization of molecular bases of simple and complex hereditary diseases in dogs and cats. The high quality canine DNA genome sequence of a Boxer and Abyssinian make each up a total of ~ 20,000 genes. Based upon the vast variety of polymorphic markers (microsatellites and Single Nucleotide Polymorphisms [SNPs]) spread throughout the genome new genes can be discovered and associated with disease traits. Moreover, certain SNP panels can be used to group breeds of dogs and cats. Recently this technology has been applied to develop a mixed breed test (Veterinary-based Mars Veterinary Wisdom Panel Mx mixed breed analysis based upon > 160 AKC breeds). Knowing the breed contributions of a mixed breed puppy may predict the size, temperament and other traits as well as possibly some hereditary disease predilections.
The dog has 76 autosomes (38 pairs) and 2 sex chromosomes (78XX or 78XY), and the cat's karyotype is 38XX or 38XY. The pattern of inheritance depends mainly on two factors: 1) whether the mutation is located on an autosome (autosomal) or on the X-chromosome (X-linked), and 2) whether the phenotype, the observable expression of a genotype as a disease trait, is dominant, i.e., expressed when only one chromosome of a pair carries the mutation, or recessive, i.e., expressed when both chromosomes of a pair carry the mutation. Thus, it is the phenotype rather than the mutant gene or protein that is dominant or recessive. Whereas in humans most diseases are dominantly inherited, recessive traits are favored by the common inbreeding practices in small animals. In addition, complex genetic traits where more than one gene alteration (polygenic) and environmental factors play are role in the expression and severity of a disease. Many susceptibilities to disease, such as inflammatory, immune-mediated, and neoplastic diseases as well as drug reactions, are considered to be transmitted by a complex trait. In contrast the MDR 1 mutation in Collies, Australian shepherds and other breeds is inherited as a simple autosomal recessive trait.
At present, the therapeutic options in the treatment of hereditary diseases are limited and ethical principles need to be carefully considered. Many hereditary diseases are progressive with currently only palliative therapy available, and thus lead to the early demise of a diseased animal or euthanasia. Surgical interventions may correct some malformations including some orthopedic and eye problems as well as hepatic shunts, but such animals should be altered to prevent them from being used for breeding. In a few cases a deficient protein, cofactor, substrate, or metabolite can be supplemented to correct the defect. For instance, vitamin B12 deficiency in cachectic and lethargic giant schnauzers and Border collies with an ileal receptor defect can be helped by monthly cobalamin injections. Pancreatic enzyme supplementation and daily insulin injections are used to manage animals with exocrine or endocrine pancreatic insufficiency, respectively. Fresh frozen plasma is administered in the treatment of hereditary coagulopathies and von Willebrand disease whenever animals excessively bleed. Other enzyme and protein replacements are also experimentally attempted. For instance, recombinant coagulation factors such as human recombinant factor VIIa has been successfully used for factor VII deficiency in Beagles and has also been tried as a bypassing agent in other coagulopathies and von Willebrand disease.
Although kidney transplants have been established in clinical practice for chronic renal failure in cats, they have not been applied in animals with hereditary (juvenile) renal disorders. Several hereditary disorders of hematopoietic cells have been experimentally corrected by bone marrow transplantation, e.g., pyruvate and phosphofructokinase deficiency, cyclic hematopoiesis, and interleukin-2 (IL-2) receptor defects. Furthermore, bone marrow transplantation is being attempted to deliver functional cells or active proteins to other tissues including liver, bone, and brain, e.g., in lysosomal storage disease. Finally, gene therapy, the integration of a functional gene into the patient's own defective cells, will likely be clinically feasible in this decade. Experiments in rodent models have provided encouraging results. However, effective gene therapy has proven more difficult in larger mammals, and the technology continues to be further improved to achieve persistent and regulated gene expression in larger mammals including humans, dogs and cats. One of the first and most promising canine gene therapy experiments has been the correction of mucopolysaccharidosis type VII in neonatal puppies with a retroviral vector carrying the beta-glucuronidase gene; these treated animals remain ambulatory, whereas affected become tetraparetic by a few months. Other examples include feline mannosidosis, hemophilia, and severe x-linked combined immunodeficiency. Such treatments are being developed for humans and once the technique is established, it may also be readily applied in companion animals in the near future. Much more important than the treatment of hereditary disorders is the control of these traits in breeding programs. This will be discussed in a separate presentation.
In conclusion, it is most exciting to learn about many recent advances for many hereditary disorders and genetic predispositions in small animal practice, be it for the diagnostic approach to a hereditary disease, the understanding of its pathophysiology, or its control. In addition to the clinician's responsibility to suspect a genetic disease and to appropriately diagnose it with modern specific techniques, clinicians must become involved in the control of these disorders in the breeders' kennels or catteries. Practitioners thus can make an important contribution toward controlling the further spread of mutant genes and reducing future suffering of animals.
Additional references are available from author.
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