Genetic testing is a key component to state-of-the-art healthcare. Since the 1960s, direct DNA mutation testing has been performed on newborn humans for rapid detection of inborn errors of metabolism. Each state in the USA and various countries world-wide tailor their now more extensive newborn DNA screening programs to detect the common mutations found in their regions most predominant ethnic groups. The same high standard of healthcare is available for companion animals, even cats, their breeds being analogous to human ethnic groups and races. Dozens of DNA mutations have been identified in cats that are pertinent to specific breeds. Because controlled breeding is routine and the norm in pedigreed cats, the potential for a higher standard of healthcare is even higher than humans, since genetic testing can be used to prevent the mating of individuals that produce unhealthy, undesired offspring. This presents the pertinent genetic mutations that should be monitored for their healthcare.

Simple Mutations for Simple Traits and Diseases

To date, over 40 genes conferring approximately 70 mutations have been documented to cause phenotypic, disease, or blood type variations in the domestic cat.^44,45 Since the presentation in this volume series in 2010,⁴⁶ twelve new genes causing cat phenotypes and health issues have been identified, implying 3–4 mutations are now being identified each year for cats. The genetically characterized diseases and health concerns for specific breeds is presented in Table 1. An additional mutation for retinal atrophy in the Abyssinian cat has been discovered,⁴¹ as well as genes conferring fur types, including hairless⁴⁷ and tabby patterns⁴⁸. The discovery of the hypokalemia mutation for Burmese cats reveals that a gene influencing overall potassium levels in cats can also influence blood pressure in humans.³⁸ By considering the breed relationships, genetic health concerns across cat populations can be inferred. Additional DNA mutations have been identified in domestic cats that are not of significant consequence to breeds. These additional mutations are presented in Table 2. These breed specific diseases should be monitored with populations and are available as commercial tests from a wealth of companies and veterinary programs around the world (Table 3). If similar conditions are suspected in cats, the publishing authors will generally consider testing for the known mutation as a non-commercial service and may continue analysis of the entire gene to determine if new mutations can be identified and causative for the conditions.

Many mutations that have been identified in domestic cats and their breeds control the phenotypes that often demarcate a breed and control the aesthetic value of our pets. Knowledge and understanding of the mode of inheritance and the effect of the phenotypic alleles can support cat health in an indirect manner, by population management. If breeders can be counselled on breeding schemes that will produce more of the color and fur type varieties and less that are undesired, less unwanted cats are produced. Less unwanted cats reduces cat overpopulation and the likelihood that individuals representing breeds will be relegated to animal shelters. In addition, if a breeder has more desired cats and less excess cats, more time, energy, and precious funds can be designated to the healthcare. Importantly, the reduction of cattery size inherently reduces stress and stress-associated health issues, such as upper respiratory diseases, urinary tract diseases, and feline infectious peritonitis. Thus, the correct genetic management of a simple coat color trait may indirectly improve the health of the entire cattery.

Several desired genetic mutations are associated with health concerns and are now documented. The mutations for taillessness have been identified.⁴⁹ Continued studies of the breed and other background genetics may now elucidate why some Manx have lameness, constipation, or incontinence as a secondary impact of improper vertebral development. The discovery of the tailless mutation has also revealed that Japanese Bobtail cats do not have mutations in the same gene and that the Pixie-Bob breed has Manx and Japanese Bobtail genetic contributions. Similarly, the genetic mutation for Scottish Fold has been identified but is yet to be published. Once this mutation is revealed, studies to understand the development of osteochondroplasia can be initiated.^50-53 In the future, the association of deafness and white should have similar revelations of the importance of genetic background and modifying genes.^51-53

Genetic testing can provide definitive answers for many health concerns and can predict risk for certain diseases. Personalized medicine is improving human healthcare and is becoming available for the domestic cat. Technology and competition will reduce the costs of genetic testing in cats, making it feasible to perform large batteries of genetic tests and eventually whole genome sequencing. Veterinarians will have more predictive powers for health concerns and will be able to implement proper interventions. As the genetic data becomes more readily available, veterinarians will be providing larger roles in healthcare management of individual cats and their populations. Genetic counselling is becoming a norm in veterinary medicine, bringing together the tests of the individual into consideration with the genetic diversity and health of the entire breed population. As humans continue to live longer and higher quality lives, so too will our furry companion felines.

Table 1. Common commercialized DNA tests for diseases in domestic cats and breeds

‡ Mode of inheritance of the non-wild type variant
§ Long fur variants are more or less common depending on the breed.
Not all transcripts for a given gene may have been discovered or well documented in the cat, mutations presented as interpreted from original publication.

Table 2. Uncommon mutations for inherited domestic cat diseases†

† The presented conditions are not prevalent in breeds or populations but may have been established into research colonies.
‡ Not all transcripts for a given gene may have been discovered or well documented in the cat, mutations presented as interpreted from original publication.
*A variety of mutations have been identified, yet unpublished for porphyrias in domestic cats. Contact PennGen at the University of Pennsylvania for additional information.

Table 3. Domestic cat DNA testing laboratories

† Tests reference to those listed in Table 1. If a laboratory offers only one or two test, those tests are listed. PKD and the HCMs are the most popular cat tests offerings.
‡ PennGen also offers tests for diseases in Table 2 that are not of concern to the cat breeds or cat population in general.

References

1.  Vigne JD. The origins of animal domestication and husbandry: a major change in the history of humanity and the biosphere. C R Biol. 2011;334(3):171–181.

2.  Vigne JD, Briois F, Zazzo A, et al. First wave of cultivators spread to Cyprus at least 10,600 y ago. Proc Nat Acad Sci USA. 2012;109(22):8445–8449.

3.  Vigne JD, Guilaine J, Debue K, Haye L, Gerard P. Early taming of the cat in Cyprus. Science. 2004;304(5668):259.

4.  Malek J. In: The Cat in Ancient Egypt. Philadelphia, PA: University of Pennsylvania; 1993.

5.  Hu Y, Hu S, Wang W, et al. Earliest evidence for commensal processes of cat domestication. Proc Nat Acad Sci USA. 2014;111(1):116–120.

6.  Clutton-Brock J. In: A Natural History of Domesticated Mammals. London, UK: Cambridge University Press, British Museum; 1987.

7.  Driscoll CA, Clutton-Brock J, Kitchener AC, O'Brien SJ. The taming of the cat. Genetic and archaeological findings hint that wildcats became housecats earlier - and in a different place - than previously thought. Sci Am. 2009;300(6):68–75.

8.  Tresset A, Vigne JD. Last hunter-gatherers and first farmers of Europe. C R Biol. 2011;334(3):182–189.

9.  Todd NB. Cats and commerce. Sci Am. 1977;237:100–107.

10. Todd NB. An ecological, behavioral genetic model for the domestication of the cat. Carnivore. 1978;1:52–60.

11. Lipinski MJ, Froenicke L, Baysac KC, et al. The ascent of cat breeds: genetic evaluations of breeds and worldwide random-bred populations. Genomics. 2008;91(1):12–21.

12. Nowell K, Jackson P. Wild Cats Status Survey and Conservation Action Plan. Gland, Switzerland: IUCN; 1996.

13. Driscoll CA, Menotti-Raymond M, Roca AL, et al. The Near Eastern origin of cat domestication. Science. 2007;317(5837):519–523.

14. Grahn RA, Kurushima JD, Billings NC, et al. Feline non-repetitive mitochondrial DNA control region database for forensic evidence. Forensic Sci Int Genet. 2011;5(1):33–42.

15. Menotti-Raymond M, David VA, Pflueger SM, et al. Patterns of molecular genetic variation among cat breeds. Genomics. 2008;91(1):1–11.

16. Kurushima JD, Lipinski MJ, Gandolfi B, et al. Variation of cats under domestication: genetic assignment of domestic cats to breeds and worldwide random-bred populations. Animal Genet. 2013;44(3):311–324.

17. Driscoll CA, Menotti-Raymond M, Nelson G, Goldstein D, O'Brien SJ. Genomic microsatellites as evolutionary chronometers: a test in wild cats. Genome Res. 2002;12(3):414–423.

18. Hasegawa D, Yamato O, Kobayashi M, et al. Clinical and molecular analysis of GM2 gangliosidosis in two apparent littermate kittens of the Japanese domestic cat. J Feline Med Surg. 2007;9(3):232–237.

19. Uddin MM, Hossain MA, Rahman MM, et al. Identification of Bangladeshi domestic cats with GM1 gangliosidosis caused by the c.1448G>C mutation of the feline GLB1 gene: case study. J Vet Med Sci/Japan Soc Vet Sci. 2013;75(3):395–397.

20. Yamato O, Matsunaga S, Takata K, et al. GM2-gangliosidosis variant 0 (Sandhoff-like disease) in a family of Japanese domestic cats. Vet Rec. 2004;155(23):739–744.

21. Martin-Burriel I, Rodellar C, Canon J, et al. Genetic diversity, structure, and breed relationships in Iberian cattle. J Anim Sci. 2011;89(4):893–906.

22. Filler S, Alhaddad H, Gandolfi B, et al. Selkirk Rex: morphological and genetic characterization of a new cat breed. J Hered. 2012;103(5):727–733.

23. 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(6):555–566.

24. Gandolfi B, Alhaddad H, Joslin SE, et al. A splice variant in KRT71 is associated with curly coat phenotype of Selkirk Rex cats. Sci Rep. 2013;3:2000.

25. Barthez PY, Rivier P, Begon D. Prevalence of polycystic kidney disease in Persian and Persian related cats in France. J Feline Med Surg. 2003;5(6):345–347.

26. Beck C, Lavelle RB. Feline polycystic kidney disease in Persian and other cats: a prospective study using ultrasonography. Aust Vet J. 2001;79(3):181–184.

27. Biller DS, Chew DJ, DiBartola SP. Polycystic kidney disease in a family of Persian cats. J Am Vet Med Assoc. 1990;196(8):1288–1290.

28. Biller DS, DiBartola SP, Eaton KA, Pflueger S, Wellman ML, Radin MJ. Inheritance of polycystic kidney disease in Persian cats. J Hered. 1996;87(1):1–5.

29. Bogdanova N, Dworniczak B, Dragova D, et al. Genetic heterogeneity of polycystic kidney disease in Bulgaria. Hum Genet. 1995;95(6):645–650.

30. Bonazzi M, Volta A, Gnudi G, Bottarelli E, Gazzola M, Bertoni G. Prevalence of the polycystic kidney disease and renal and urinary bladder ultrasonographic abnormalities in Persian and Exotic Shorthair cats in Italy. J Feline Med Surg. 2007;9(5):387–391.

31. Domanjko-Petric A, Cernec D, Cotman M. Polycystic kidney disease: a review and occurrence in Slovenia with comparison between ultrasound and genetic testing. J Feline Med Surg. 2008;10(2):115–119.

32. Eaton KA, Biller DS, DiBartola SP, Radin MJ, Wellman ML. Autosomal dominant polycystic kidney disease in Persian and Persian-cross cats. Vet Pathol. 1997;34(2):117–126.

33. Lyons L, Biller D, Erdman C, et al. Feline polycystic kidney disease mutation identified in PKD1. J Am Soc Nephrol. 2004;15(10):2548–2555.

34. Zook BC. Encephalocele and other congenital craniofacial anomalies in Burmese cats. Vet Med/Small Anim Clin. 1983;78:695–701.

35. Noden DM, Evans HE. Inherited homeotic midfacial malformations in Burmese cats. J Craniofac Genet Dev Biol Suppl. 1986;2:249–266.

36. Rusbridge C, Heath S, Gunn-Moore DA, Knowler SP, Johnston N, McFadyen AK. Feline orofacial pain syndrome (FOPS): a retrospective study of 113 cases. J Feline Med Surg. 2010;12(6):498–508.

37. Heath S, Rusbridge C, Johnson N, Gunn-Moore D. Orofacial pain syndrome in cats. Vet Rec. 2001;149(21):660.

38. Gandolfi B, Gruffydd-Jones TJ, Malik R, et al. First WNK4-hypokalemia animal model identified by genome-wide association in Burmese cats. PloS One. 2012;7(12):e53173.

39. Rand JS, Bobbermien LM, Hendrikz JK, Copland M. Over representation of Burmese cats with diabetes mellitus. Aust Vet J. 1997;75(6):402–405.

40. O'Leary CA, Duffy DL, Gething MA, McGuckin C, Rand JS. Investigation of diabetes mellitus in Burmese cats as an inherited trait: a preliminary study. New Zeal Vet J. 2013;61(6):354–358.

41. Menotti-Raymond M, Deckman K, David V, Myrkalo J, O'Brien S, Narfström K. Mutation discovered in a feline model of human congenital retinal blinding disease. Invest Ophthalmol Vis Sci. 2010;51(6):2852–2859.

42. Menotti-Raymond M, David VA, Schaffer AA, et al. Mutation in CEP290 discovered for cat model of human retinal degeneration. J Hered. 2007;98(3):211–220.

43. Grahn RA, Grahn JC, Penedo MC, Helps CR, Lyons LA. Erythrocyte pyruvate kinase deficiency mutation identified in multiple breeds of domestic cats. BMC Vet Res. 2012;8(1):207.

44. Lyons LA. Feline genetics: clinical applications and genetic testing. Top Companion Anim Med. 2010;25(4):203–212.

45. Lyons LA. Genetic testing in domestic cats. Mol Cell Probes. 2012;26(6):224–230.

46. Lyons LA. Genetic testing in domestic cats. In: August JR, ed. Consultations in Feline Medicine. Vol 6. St. Louis, MO: Saunders Elsevier; 2010.

47. Gandolfi B, Outerbridge C, Beresford L, et al. The naked truth: Sphynx and Devon Rex cat breed mutations in KRT71. Mamm Genome. 2010;21(9–10):509–15.

48. Kaelin CB, Xu X, Hong LZ, et al. Specifying and sustaining pigmentation patterns in domestic and wild cats. Science. 2012;337(6101):1536–1541.

49. Buckingham KJ, McMillin MJ, Brassil MM, et al. Multiple mutant T alleles cause haploinsufficiency of Brachyury and short tails in Manx cats. Mamm Genome. 2013;24(9–10):400–408.

50. Malik R, Allan G, Howlett C, et al. Osteochondrodysplasia in Scottish fold cats. Aust Vet J. 1999;77(2):85–92.

51. Bamber RC. Correlation between white coat colour, blue eyes, and deafness in cats. J Genet. 1933;27:407–413.

52. Wilson TG, Kane F. Congenital deafness in white cats. Acta Otolaryngol. 1959;50(3–4):269–275; discussion 275–267.

53. Bergsma DR, Brown KS. White fur, blue eyes, and deafness in the domestic cat. J Hered. 1971;62(3):171–185.

54. Brosco JP, Paul DB. The political history of PKU: reflections on 50 years of newborn screening. Pediatrics. 2013;132(6):987–989.

55. Hoffmann GF, Lindner M, Loeber JG. 50 years of newborn screening. J Inherit Met Dis. 2014;37(2):163–164.

56. Stadler ZK, Schrader KA, Vijai J, Robson ME, Offit K. Cancer genomics and inherited risk. J Clin Oncol. 2014;32(7):687–698.

57. Roach JC, Glusman G, Smit AF, et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science. 2010;328(5978):636–639.

58. Torjesen I. Genomes of 100,000 people will be sequenced to create an open access research resource. Brit Med J. 2013;347:f6690.

59. Rabbani B, Tekin M, Mahdieh N. The promise of whole-exome sequencing in medical genetics. J Hum Genet. 2014;59(1):5–15.

60. Meurs KM, Sanchez X, David RM, et al. A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. Hum Mol Genet. 2005;14(23):3587–3593.

61. Longeri M, Ferrari P, Knafelz P, et al. Myosin-binding protein C DNA variants in domestic cats (A31P, A74T, R820W) and their association with hypertrophic cardiomyopathy. J Vet Intern Med. 2013;27(2):275–285.

62. Eizirik E, Yuhki N, Johnson WE, Menotti-Raymond M, Hannah SS, O'Brien SJ. Molecular genetics and evolution of melanism in the cat family. Curr Biol. 2003;13(5):448–453.

63. Lyons LA, Foe IT, Rah HC, Grahn RA. Chocolate coated cats: TYRP1 mutations for brown color in domestic cats. Mamm Genome. 2005;16(5):356–366.

64. Schmidt-Kuntzel A, Eizirik E, O'Brien SJ, Menotti-Raymond M. Tyrosinase and tyrosinase related protein 1 alleles specify domestic cat coat color phenotypes of the albino and brown loci. J Hered. 2005;96(4):289–301.

65. Imes DL, Geary LA, Grahn RA, Lyons LA. Albinism in the domestic cat (Felis catus) is associated with a tyrosinase (TYR) mutation. Anim Genet. 2006;37(2):175–178.

66. Lyons LA, Imes DL, Rah HC, Grahn RA. Tyrosinase mutations associated with Siamese and Burmese patterns in the domestic cat (Felis catus). Anim Genet. 2005;36(2):119–126.

67. Ishida Y, David VA, Eizirik E, et al. A homozygous single-base deletion in MLPH causes the dilute coat color phenotype in the domestic cat. Genomics. 2006;88(6):698–705.

68. Peterschmitt M, Grain F, Arnaud B, Deleage G, Lambert V. Mutation in the melanocortin 1 receptor is associated with amber colour in the Norwegian Forest Cat. Anim Genet. 2009;40(4):547–552.

69. Drogemuller C, Rufenacht S, Wichert B, Leeb T. Mutations within the FGF5 gene are associated with hair length in cats. Anim Genet. 2007;38(3):218–221.

70. Gandolfi B, Alhaddad H, Affolter VK, et al. To the root of the curl: a signature of a recent selective sweep identifies a mutation that defines the Cornish Rex cat breed. PloS One. 2013;8(6):e67105.

71. Bighignoli B, Niini T, Grahn RA, et al. Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) mutations associated with the domestic cat AB blood group. BMC Genet. 2007;8:27.

72. De Maria R, Divari S, Bo S, et al. Beta-galactosidase deficiency in a Korat cat: a new form of feline GM1-gangliosidosis. Acta Neuropathol. 1998;96:307–314.

73. Bradbury AM, Morrison NE, Hwang M, Cox NR, Baker HJ, Martin DR. Neurodegenerative lysosomal storage disease in European Burmese cats with hexosaminidase beta-subunit deficiency. Mol Genet Metab. 2009;97(1):53–59.

74. Muldoon LL, Neuwelt EA, Pagel MA, Weiss DL. Characterization of the molecular defect in a feline model for type II GM2-gangliosidosis (Sandhoff disease). Am J Pathol. 1994;144(5):1109–1118.

75. Martin DR, Cox NR, Morrison NE, et al. Mutation of the GM2 activator protein in a feline model of GM2 gangliosidosis. Acta Neuropathol. 2005;110(5):443–450.

76. Meurs KM, Norgard MM, Ederer MM, Hendrix KP, Kittleson MD. A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy. Genomics. 2007;90(2):261–264.

77. Lettice LA, Hill AE, Devenney PS, Hill RE. Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly. Hum Mol Genet. 2008;17(7):978–985.

78. Lyons LA, Biller DS, Erdman CA, et al. Feline polycystic kidney disease mutation identified in PKD1. J Am Soc Nephrol. 2004;15(10):2548–2555.

79. Fyfe JC, Menotti-Raymond M, David VA, et al. An approximately 140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival. Genome Res. 2006;16(9):1084–1090.

80. Owens SL, Downey ME, Pressler BM, Birkenheuer AJ, Chandler DW, Scott-Moncrieff JC. Congenital adrenal hyperplasia associated with mutation in an 11beta-hydroxylase-like gene in a cat. J Vet Intern Med. 2012;26(5):1221–1226.

81. Berg T, Tollersrud OK, Walkley SU, Siegel D, Nilssen O. Purification of feline lysosomal alpha-mannosidase, determination of its cDNA sequence and identification of a mutation causing alpha-mannosidosis in Persian cats. Biochem J. 1997;328(Pt 3):863–870.

82. Mazrier H, Van Hoeven M, Wang P, et al. Inheritance, biochemical abnormalities, and clinical features of feline mucolipidosis II: the first animal model of human I-cell disease. J Hered. 2003;94(5):363–373.

83. He X, Li CM, Simonaro CM, et al. Identification and characterization of the molecular lesion causing mucopolysaccharidosis type I in cats. Mol Genet Metab. 1999;67(2):106–112.

84. Yogalingam G, Litjens T, Bielicki J, et al. Feline mucopolysaccharidosis type VI. Characterization of recombinant N-acetylgalactosamine 4-sulfatase and identification of a mutation causing the disease. J Biol Chem. 1996;271(44):27259–27265.

85. Martin DR, Krum BK, Varadarajan GS, Hathcock TL, Smith BF, Baker HJ. An inversion of 25 base pairs causes feline GM2 gangliosidosis variant. Exp Neurol. 2004;187(1):30–37.

86. Yogalingam G, Hopwood JJ, Crawley A, Anson DS. Mild feline mucopolysaccharidosis type VI. Identification of an N-acetylgalactosamine-4-sulfatase mutation causing instability and increased specific activity. J Biol Chem. 1998;273(22):13421–13429.

87. Crawley AC, Yogalingam G, Muller VJ, Hopwood JJ. Two mutations within a feline mucopolysaccharidosis type VI colony cause three different clinical phenotypes. J Clin Invest. 1998;101(1):109–119.

88. Kanae Y, Endoh D, Yamato O, et al. Nonsense mutation of feline beta-hexosaminidase beta-subunit (HEXB) gene causing Sandhoff disease in a family of Japanese domestic cats. Res Vet Sci. 2007;82(1):54–60.

89. Fyfe JC, Kurzhals RL, Lassaline ME, et al. Molecular basis of feline beta-glucuronidase deficiency: an animal model of mucopolysaccharidosis VII. Genomics. 1999;58(2):121–128.

90. Goree M, Catalfamo JL, Aber S, Boudreaux MK. Characterization of the mutations causing hemophilia B in 2 domestic cats. J Vet Intern Med. 2005;19(2):200–204.

91. Somers K, Royals M, Carstea E, Rafi M, Wenger D, Thrall M. Mutation analysis of feline Niemann-Pick C1 disease. Mol Genet Metab. 2003;79:99–103.

92. Clavero S, Bishop DF, Giger U, Haskins ME, Desnick RJ. Feline congenital erythropoietic porphyria: two homozygous UROS missense mutations cause the enzyme deficiency and porphyrin accumulation. Mol Med. 2010;16(9–10):381–388.

93. Goldstein R, Narala S, Sabet N, Goldstein O, McDonough S. Primary hyperoxaluria in cats caused by a mutation in the feline GRHPR gene. J Hered. 2009;100(Supplement 1):S2–S7.

94. Clavero S, Bishop DF, Haskins ME, Giger U, Kauppinen R, Desnick RJ. Feline acute intermittent porphyria: a phenocopy masquerading as an erythropoietic porphyria due to dominant and recessive hydroxymethylbilane synthase mutations. Hum Mol Genet. 2010;19(4):584–596.

95. Geisen V, Weber K, Hartmann K. Vitamin D-dependent hereditary rickets type I in a cat. J Vet Intern Med. 2009;23(1):196–199.

96. Ginzinger DG, Lewis ME, Ma Y, Jones BR, Liu G, Jones SD. A mutation in the lipoprotein lipase gene is the molecular basis of chylomicronemia in a colony of domestic cats. J Clin Invest. 1996;97(5):1257–1266.

97. Grahn RA, Ellis MR, Grahn JC, Lyons LA. A novel CYP27B1 mutation causes a feline vitamin D-dependent rickets type IA. J Feline Med Surg. 2012;14(8):587–590.