Different genes, different mechanisms

Both DBE and KIT influence melanocytes — the specialised pigment-producing cells responsible for skin, coat and eye pigmentation, as well as for normal function of the inner ear. However, they affect these cells at different stages of development.

PAX3-associated DBE variants

Current evidence suggests that PAX3-associated DBE variants primarily influence the formation and migration of melanocyte precursor cells during embryonic development.¹ ³ In simple terms, fewer melanocytes may develop than normal.

Importantly, in DBE variants not associated with deafness, the melanocytes that do develop appear capable of functioning normally.¹ ⁴ The exact biological effect depends on the individual DBE variant — which is why each variant should always be evaluated independently rather than grouped together.

KIT-associated white

KIT functions differently. Rather than controlling the formation of melanocytes, KIT provides signals that allow these cells to survive, proliferate and remain functional after they have developed.

When KIT signalling is disrupted, melanocytes may fail to survive in affected tissues, including:

• the skin;

• the iris;

• the inner ear.

Loss of melanocytes within the cochlea is the recognised mechanism responsible for the congenital sensorineural deafness associated with KIT dominant-white cats.⁵ ⁶

Different mechanisms — the same cell population

Although DBE and KIT act through different molecular pathways, both ultimately affect melanocytes. In simplified terms:

• DBE may reduce the number of melanocytes that develop;

• KIT may reduce the survival of those melanocytes after they have formed.

These are different biological mechanisms, but they affect the same cell population.

Why combining DBE with KIT is not recommended

As a precaution, current guidance advises avoiding intentional matings between DBE variants and KIT-associated white or white spotting. This is because combining two different pigmentation mechanisms may:

• increase the biological complexity affecting melanocytes;

• increase the potential risk of congenital deafness;

• make interpretation of phenotype significantly more difficult;

• reduce the scientific value of breeding records;

• complicate long-term health monitoring.

For these reasons, responsible breeders are encouraged to select genetically compatible breeding pairs and to avoid combining these two mechanisms unless future scientific evidence demonstrates otherwise.

Phenotype cannot distinguish DBE from KIT

The currently described DBE variants are associated with some degree of white spotting.⁴ This may range from a very small area of white — such as between the toes, on the tail tip or another inconspicuous location — through to extensive white expression. KIT-associated white may produce a very similar phenotype.⁵

As a result:

• blue eyes,

• odd eyes,

• white spotting,

• bicolour,

• harlequin,

• van,

• or almost completely white cats

cannot be reliably classified as DBE or KIT based on appearance alone. Phenotype may suggest a possible genotype, but it cannot confirm one.

Why pedigree is not enough

Pedigrees record ancestry, not molecular genotype. In most registries, DBE variants are not recorded within the pedigree itself. Furthermore, where DBE and KIT have both been introduced into breeding lines, pedigree analysis alone cannot reliably determine which genetic mechanism is responsible for an individual cat’s phenotype. Only genetic testing can objectively confirm the presence or absence of a known DBE variant.

Every DBE variant should be evaluated individually

The term DBE refers to multiple genetically distinct variants. Current scientific evidence demonstrates that these variants differ in:

• molecular mechanism;

• biological effect;

• phenotype;

• and currently reported health outcomes.

To date, four PAX3 variants have been characterised — DBE-CEL, DBE-ALT, DBE-RE and DBE-AGO.¹ ² ³ ⁴ Reported outcomes are not uniform: the DBE-CEL variant has not been associated with deafness¹ ⁴, whereas the DBE-RE variant has been directly linked to congenital hearing loss, although its penetrance appears to vary between studies.³ ⁴ These variants should therefore never be treated as a single homogeneous condition, and scientific evaluation should always be based on the specific variant involved rather than assuming that all DBE variants carry identical biological or clinical significance.

Responsible breeding depends on evidence

The objective of responsible breeding is not simply to produce blue-eyed or odd-eyed cats. It is to preserve healthy, genetically well-characterised breeding lines through:

• individual genetic testing;

• routine BAER hearing assessment;

• transparent documentation;

• continuous monitoring;

• and breeding decisions based on current scientific evidence.

As our understanding of DBE continues to evolve, breeding recommendations should evolve alongside it.

DBE and KIT may produce similar phenotypes, but they represent different biological mechanisms affecting the same cell population.

Phenotype may suggest a genotype, but only genetic testing can confirm which genetic variant is present.

Why Genetic Confirmation Is an Ethical Requirement

The overlap between PAX3-associated DBE and KIT-associated white phenotypes is not merely a scientific classification problem. It also creates a significant issue of transparency for buyers, breeders, judges and registries.

A white, white-spotted, bicolour, harlequin or van kitten with two blue eyes or odd eyes may carry:

• a known PAX3-associated DBE variant;

• KIT dominant white;

• KIT-associated white spotting;

• both a PAX3-associated DBE variant and a KIT allele;

• or another genetic cause that has not yet been identified.

These possibilities cannot be distinguished reliably by appearance, photographs, eye colour, pedigree or breeder opinion alone.

This creates two opposing risks.

A kitten whose blue or odd eyes are associated with KIT may be advertised and sold at a premium as “DBE” without evidence that it carries a known DBE variant.

Conversely, a cat carrying a DBE variant together with KIT-associated white may be presented simply as white, bicolour, harlequin or van. The KIT-associated phenotype may obscure the presence of DBE and make the cat appear eligible under classifications or rules that would otherwise restrict DBE cats.

The combination of DBE and KIT therefore creates a potential route for misclassification in both breeding and showing. This does not prove intent in any individual case, but it makes transparent genetic documentation essential.

Advertising a Kitten as DBE Requires Individual Proof

Blue eyes, odd eyes and white markings are phenotypes. They are not proof of a PAX3-associated DBE genotype.

When a kitten is advertised, priced or sold specifically as DBE, the breeder should provide a traceable, individual genetic result confirming the DBE variant detected in that kitten.

Testing only the parents is not sufficient. A heterozygous DBE parent does not transmit the variant to every kitten, and appearance alone cannot establish which kittens inherited it.

Each kitten advertised as carrying a known DBE variant should therefore have documentation showing:

• the identity of the kitten tested;

• the specific DBE variant detected;

• the testing laboratory;

• the individual sample or report reference;

• the zygosity result, where available;

• and the other DBE variants included in the testing panel.

Without an individual positive result, a kitten may accurately be described as blue-eyed, odd-eyed, white-spotted or originating from a DBE breeding line. It should not be represented as genetically confirmed DBE.

Where the genetic cause of a blue-eye lineage remains unresolved, this must also be stated clearly. A negative result for the currently known variants does not prove that a cat is free from every possible DBE cause, but it does mean that the breeder cannot claim that the cat carries a specific known variant.

A higher price, pedigree claim, parental result or visual resemblance does not replace individual genetic confirmation.

References

1. Abitbol M, Couronné A, Dufaure de Citres C, Gache V. A PAX3 insertion in the Celestial breed and certain feline breeding lines with dominant blue eyes. Animal Genetics. 2024;55(4):670–675. doi:10.1111/age.13433

2. Abitbol M, Dufaure de Citres C, Rudd Garces G, Lühken G, Lyons LA, Gache V. Different Founding Effects Underlie Dominant Blue Eyes (DBE) in the Domestic Cat. Animals. 2024;14(13):1845. doi:10.3390/ani14131845

3. Rudd Garces G, Farke D, Schmidt MJ, Letko A, Schirl K, Abitbol M, Leeb T, Lyons LA, Lühken G. PAX3 haploinsufficiency in Maine Coon cats with dominant blue eyes and hearing loss resembling the human Waardenburg syndrome. G3 Genes|Genomes|Genetics. 2024;14(9):jkae131. doi:10.1093/g3journal/jkae131

4. Abitbol M, Cloquell A, Kaczmarska A, Holmes K, Lühken G, Macaulay K. Dominant blue eyes in Maine Coon cats: New PAX3 variant and updated phenotypic data. Animal Genetics. 2025;56(3):e70020. doi:10.1111/age.70020

5. David VA, Menotti-Raymond M, Wallace AC, Roelke M, Kehler J, Leighty R, et al. Endogenous retrovirus insertion in the KIT oncogene determines white and white spotting in domestic cats. G3: Genes|Genomes|Genetics. 2014;4(10):1881–1891. doi:10.1534/g3.114.013425

6. Mari L, Freeman J, Van Dijk J, De Risio L. Prevalence of congenital sensorineural deafness in a population of client-owned purebred kittens in the United Kingdom. Journal of Veterinary Internal Medicine. 2019;33(4):1707–1713. doi:10.1111/jvim.15515