1. Overview

Inherited/genetic skin diseases are very common in dogs and common in cats. Some genetic traits/diseases are considered part of the breed standard (alopecia in Chinese crested dogs or in Sphinx cats, hair ridge in Rhodesian ridgebacks) and some others are always considered pathologic, as the ichthyoses or the lethal acrodermatitis in bull terriers.

The common hallmarks for inherited diseases include 1) early age of onset (congenital, juvenile); 2) presence in a closed or small population (family, breed); 3) indications of inbreeding; 4) uniformity in presentation.¹ In humans, advanced parental age at birth is also a hallmark (for instance, older mothers have a higher frequency of having children with trisomy 21), but this has not been demonstrated in dogs and cats.

The recent development of high efficiency techniques to investigate the genetic background of traits and diseases (genome-wide association analysis, genome sequencing) has allowed the investigation of many diseases of suspected genetic origin, especially in the dog. The most successful approach has been the GWAS (genotyping adequately selected cases and controls) followed by fine sequencing of the genome region associated with the trait. In cats, most genetic defects have been detected using the candidate gene approach, based on knowledge coming from other species. Many inherited skin diseases caused by mutations in one gene (simple genetic traits, monogenic diseases) have been investigated and unraveled in the last years following these approaches. Due to time restriction, only a few selected examples will be reviewed (see Section 2).

In addition to this first group of diseases, there is a larger group of diseases in dogs and cats that have a complex background (complex genetic diseases and genetic risk factors). A few examples will be discussed in Section 3.

2. Simple Genetic Diseases of the Skin (Simple Genetic Traits)

Canine inherited dermatologic conditions (examples)

Feline inherited dermatologic conditions (examples)

3. Complex Genetic Skin Diseases (Genetic Risk Factors and Complex Traits)

To date, most genetic tests have been for traits that have nearly complete penetrance, have little variability in expression, and are early in onset. There are, however, numerous diseases where the genetic background plays a role, but in a more complex way than the monogenic diseases of high penetrance. In these diseases, the clinical signs only manifest under certain conditions, for instance when other non-genetic factors (environmental) occur or when multiple genetic changes concur in the same patient (multiple genes involved, quantitative traits).

Some diseases included in this group are very prevalent and important and although currently they are not fully understood, it is worth to discuss a few examples.

3.1. Canine Juvenile Generalized Demodicosis (CJGD)

Canine juvenile generalized demodicosis is a severe dermatitis caused by the proliferation of Demodex mites. It is not a contagious disease because the mites are normal inhabitants of the skin of all dogs. Some individuals, however, are unable to control their Demodex populations and an overgrowth of the mites occurs, leading to alopecia and severe cutaneous inflammation.¹²

Canine juvenile generalized demodicosis is considered to have a hereditary basis, although there is very little published evidence supporting this hypothesis. The presentation of the disease at an early age (3–6 months), in siblings and related dogs, and the increased prevalence in certain breeds, all support a hereditary basis. The observed reduction of the frequency of the disease by withholding affected and carrier dogs from breeding programs would also argue in favor of a genetic background for the development of disease. However, none of these observations per se can be considered conclusive of a genetic origin of the disease. To the best of our knowledge, only one genetic study has been published.¹³ The authors, reporting on Argentinian mastiffs and boxers (56 affected dogs and 60 breed-matched control animals), offer a statistically significant association between the phenotype 'generalized juvenile demodicosis' and certain microsatellite markers or DLA haplotypes (FH2202,FH2975, and FH2054). This is probably the most convincing published evidence of a genetic background for juvenile generalized canine demodicosis. Additional genetic studies are clearly needed to advance the understanding of the primary causes of canine demodicosis and to develop an effective prevention strategy. A large-scale genome-wide association study focused on some of the breeds with high prevalence of the disease, followed by the sequencing of genome candidate regions, could be a fruitful approach. In the meantime, it is recommended neutering dogs affected by juvenile generalized demodicosis. As mentioned previously, withholding affected and carrier dogs from breeding programs has led to a decrease in the prevalence of the disease.

3.2. Canine Atopic Dermatitis (CAD)

Canine atopic dermatitis is defined as an inflammatory and pruritic allergic skin disease caused by an interaction between genetic and environmental factors. The characteristic clinical features are most commonly associated with IgE antibodies directed towards environmental allergens.

As in the case of demodicosis, there are some evidences suggesting an inherited basis for canine atopic dermatitis, the most prevalent canine allergic disease in the dog:

1.  Very strong breed predisposition, with prevalence in some breeds and lines over 20%: West Highland white terrier, French bulldogs, Shar peis, Labrador, setter, German shepherd, Dalmatian

2.  Early age of onset (6 months to 3 years).

3.  Development of colonies of atopic dogs by inbreeding

4.  Demonstration of genetic background in human atopic dermatitis, a disease which is very similar to CAD

For years, atopic dermatitis (AD) has been considered an allergic disease, with uncertain genetic background. The identification in 2006¹⁴ that mutation in the gene coding for epidermal protein filaggrin was a major predisposing factor for atopic dermatitis changed completely the paradigm of this very common disease. Nevertheless, numerous investigations demonstrated that the pathogenesis of AD in humans is more complex than expected and that loss-of-function variants of filaggrin are only part of the conundrum. In fact, only 42% of the patients with AD have mutations in the filaggrin gene (10% in the general European population) and over 60% of the people with mutations in filaggrin gene do not develop AD. Several large GWAS have suggested a role for epidermal barrier functions, innate-adaptive immunity, interleukin-1 family signaling, regulatory T cells, the vitamin D pathway, and the nerve growth factor pathway in the pathogenesis of AD. Combinations of these genetic factors may influence a wide range of phenotypes of AD among individuals.¹⁵

In the dog, the investigations on the genetics of AD have led to contradictory results. A study performed in British guide dogs (mostly Labrador and golden retriever cross-bred dogs) detected a heritability of 0.47 (range 0.13–0.81), suggesting that the genetic background accounts for almost 50% of the risk of developing AD.¹⁶ The first GWAS in canine AD evaluated DNA from 242 atopic and 417 control dogs of eight breeds from the UK, US, and Japan.¹⁷ Although some SNPs seemed to be associated with the disease phenotype, the implicated SNPs were different in different breeds, making difficult the identification of the main genetic background of CAD. A second GWAS performed in West Highland white terriers was unable to detect any association between the phenotype "AD" and a specific genome region.¹⁸ However, a more recent GWAS in German shepherds was able to identify a string association between the phenotype and one region of chromosome 27. Specifically, they consider that in this region, the gene encoding the plakophilin 2, a central component of desmosomes, is an excellent candidate for CAD.¹⁹

Atopic dermatitis involves a complex network of many genes, with multiple variants affecting gene function and expression. The effect of any one polymorphism is likely to be relatively small, and the final phenotype will depend on their interactions across the genome. These findings also suggest that the genetic background to canine AD varies between breeds and geographical gene pools. This could explain variations in clinical phenotype and response to treatment between individuals and breeds. This complexity and the high prevalence of canine AD mean that at this time, a screening and breeding program to eliminate the condition is unlikely to succeed. It is clearly necessary to have more information about the interaction between genotype and environment in CAD, before initiating any program to reduce the prevalence of the disease. In any case, breeders of predisposed breeds (West Highland white terrier, French bulldogs, Shar peis, Labrador, setter, German shepherd, Dalmatian) or with data suggesting high incidence of the disease in their descendants should monitor the prevalence of the disease and consider asking advice from a veterinary dermatologist to select sires and dams without any clinical signs suggesting AD.

A better understanding of the genotype will enable not only the development of preventative programs but also better targeting of treatment options; for example, some dogs may respond well to skin barrier therapy, whereas others would benefit more from allergen-specific immunotherapy. We should also be able to identify dogs that may have a poor response or have an increased risk of adverse effects to certain anti-inflammatory drugs. Finally, it may be possible to discover atopic genotypes in young dogs and manage environmental and other factors to minimize their risk of developing clinical AD.²⁰

3.3. Feline Atopic Dermatitis (FAD)

Feline AD is characterized by seasonal or non-seasonal pruritus, and affected cats are reported commonly to exhibit one or more lesional patterns, including symmetrical alopecia, miliary dermatitis, focused head and neck pruritus, and eosinophilic granuloma complex (EGC) lesions. Young cats are reported to be predisposed, with clinical signs often developing before 3 years of age, although a wide age range is noted. No sex or breed predilections have been identified, and evidence of inheritance is restricted to a single report of AD occurring in three domestic shorthair littermates. Clinical signs consistent with pruritus (i.e., hair pulling, hair loss, excessive grooming, and face rubbing) were first noted when the cats were 6 months of age.²¹ The cats were treated for a possible ear mite and/or flea infestation; there was no response to treatment and clinical signs progressed.

A recent paper describes a series of cases with a sound diagnosis of FAD and suggests a breed predisposition for Abyssinian and mixed-breed cats, and possibly Devon rex cats.²²

At this time, there is not enough knowledge on the genetics of this entity in cats to make breeding recommendations.

References

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2.  Grall A, Guaguère E, Planchais S, et al. PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet. 2012;44:140–147.

3.  Jagannathan V, Bannoehr J, Plattet P, et al. A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation. PLoS Genet. 2013;9(10):e1003848.

4.  Plassais J, Guaguère E, Lagoutte L, et al. A spontaneous KRT16 mutation in a dog breed: a model for human focal non-epidermolytic palmoplantar keratoderma (FEPPK). J Invest Dermatol. 2015;135:1187–1190.

5.  Olsson M, Meadows J, Truve K, et al. A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. PLoS Genet. 2011;7:e1001332.

6.  Droegemuller C, Karlsson EK, Hytonen MK, et al. A mutation in hairless dogs implicates FOXI3 in ectodermal development. Science. 2008;321:1462.

7.  Paradis M, de Jaham C, Page N, et al. Acral mutilation and analgesia in 13 French spaniels. Vet Dermatol. 2005;16:87–93.

8.  Schmidt-Küntzel A, Eizirik E, O'Brien SJ, et al. Tyrosinase and tyrosinase related protein 1 alleles specify domestic cat coat color phenotypes of the albino and brown loci. J Hered. 2005;96:289–301.

9.  Drogemuller C, Rufenacht S, Wichert B, et al. Mutations within the FGF5 gene are associated with hair length in cats. Anim Genet. 2007;38:218–221.

10. Kehler JS, David VA, Schaffer AA, et al. Four independent mutations in the feline fibroblast growth factor 5 gene determine the long-haired phenotype in domestic cats. J Hered. 2007;98:555–566.

11. Gandolfi B, Outerbridge CA, Beresford LG, et al. The naked truth: Sphynx and Devon Rex cat breed mutations in KRT71. Mamm Genome. 2010;21:509–515.

12. Ferrer L, Ravera I, Silbermayr K. immunology and pathogenesis of canine demodicosis. Vet Dermatol. 2014;25:427-e65.

13. It V, Barrientos L, Lopez Gappa, et al. Association of canine juvenile generalized demodicosis with the dog leukocyte antigen system. Tissue Antigens. 2010;76:67–70.

14. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38:441–446.

15. Tamari M, Hirota T. Genome-wide association studies of atopic dermatitis. J Dermatol. 2014;41:213–220.

16. Shaw SC, Wood JLN, Freeman J, et al. Estimation of heritability of atopic dermatitis in Labrador and Golden Retrievers. Am J Vet Res. 2004;65:1014–1020.

17. Wood SH, Ke XY, Nuttall T, et al. Genome-wide association analysis of canine atopic dermatitis and identification of disease related SNPs. Immunogenetics. 2009;61:765–772.

18. Barros Roque J, O'Leary CA, Kyaw-Tanner M, et al. Haplotype sharing excludes canine orthologous Filaggrin locus in atopy in West Highland White Terriers. Anim Genet. 2009;40:793–794.

19. Tengvall K, Kierczak M, Begvall K, et al. Genome-wide analysis in German shepherd dogs reveals association of a locus on CFA 27 with atopic dermatitis. PLoS Genet. 2013;9(5):e1003475.

20. Nuttall T. The genomics revolution: will canine atopic dermatitis be predictable and preventable? Vet Dermatol. 2013;24:10-8.e3-4.

21. Moriello K. Feline atopy in three littermates. Vet Dermatol. 2001;12:177–181.

22. Ravens PA, Xu BJ, Vogelnest LJ. Feline atopic dermatitis: a retrospective study of 45 cases (2011–2012). Vet Dermatol. 2014;25:95–102.