In other species: domestic cat

Categories: Pigmentation phene , Hearing / vestibular / ear phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 193500 (trait) , 148820 (trait) , 606597 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2012

Cross-species summary: The name of this phene was changed from "Coat colour, white spotting, PAX3-related" to "Auditory-pigmentary syndrome, PAX3-related" on 01-Mar-2024.
The phene includes altered pigmentation of the eyes and/or skin together with a predisposition for unilateral or bilateral sensineural deafness. Affected animals often have blue eyes or eyes with different colors (heterochromia iridis). Skin pigmentation may include variable degrees of white spotting ranging from tiny white spots up to completely white animals. The absence of pigment is caused by the absence of melanocytes ("leucism"), not by a failure in the biochemical reactions required for pigment synthesis. The increased risk for deafness is the consequence of lacking melanocytes in the stria vascularis of the inner ear.

Species-specific name: splashed white

Species-specific description: Currently (in 2016), the horse is among domesticated animals the species with the highest number of known genetic variants that lead to white spotting phenotypes. Related coat colour phenotypes are caused by variants in the EDNRB, KIT, MITF, PAX3 and TRPM1 genes. Combinations of multiple variants in these gene can lead to more pronounced coat colour phenotypes. The splashed white phenotype may be caused by variants in the PAX3 gene as outlined below. However, by far the most common causative varaint for the splashed white phenotype is a non-coding regulatory promoter variant in the MITF gene.

History: Hauswirth et al. (2012) reported the first functional variant in the equine PAX3 gene.

Inheritance: The mode of inheritance depends on the specific variant and there are interactions with other genes. Animals with the typical splashed white phenotype normally have only one copy of the mutant allele(s). Homozygosity for the mutant alleles results in either embryonic lethality or more pronounced depigmentation phenotypes. There is incomplete penetrance for the auditory phenotype. The risk for deafness further increases in horses that carry combinations of mutant PAX3 alleles with additional white-spotting alleles at other genes.

Molecular basis: Hauswirth et al. (2012) reported three independent variants causing the splashed white phenotype, two of them in the MITF gene and one in the PAX3 gene: A missense variant in the PAX3 gene [omia.variant:791] (c.209G>A; p.C70Y; "SW2") was identified in Quarter Horses and American Paint Horses. Druml et al. (2018) demonstrated that the PAX3^C70Y allele also segregates in Noriker and Lippizan horses.
Hauswirth et al. (2013) reported a second missense variant in the PAX3 gene [omia.variant:978] in an Appaloosa family segregating for a splashed white phenotype (c.95C>G; p:Pro32Arg). Table S1 of Dürig et al. (2017) provides details of all PAX3 alleles (plus alleles at EDNRB, KIT, MITF) known in July 2016. McFadden et al. (2023) "report two novel mutations, a stop-gain mutation in PAX3 [omia.variant:1605] (XM_005610643.3:c.927C>T, ECA6:11,196,181, EquCab3.0) and a missense mutation in a binding domain of MITF [omia.variant:1606] (NM_001163874.1:c.993A>T, ECA16:21,559,940, EquCab3.0), each with a strong association with increased depigmentation in Pura Raza Española horses ... ."

Clinical features: Magdesian et al. 2009 demonstrated an increased risk for deafness in horses with the splashed white and/or frame overo spotting phenotype. Hauswirth et al. 2012 reported that "Some, but not all, splashed white horses are deaf."

Prevalence: Druml et al. (2018) reported that "besides Quarter Horses, the PAX3^C70Y [SW2] allele is also present in Noriker (seven out of 189) and Lipizzan (three out of 329) horses" and that of "10 heterozygous PAX3^C70Y-carrier horses, two had nearly a splashed white phenotype".

Breeds: American Paint (Horse) (VBO_0000897), Appaloosa (Horse) (VBO_0000904), Lipizzan horse (Horse) (VBO_0001014), Noric (Horse) (VBO_0001030), Purebred Spanish (Horse) (VBO_0001056), Quarter Horse (Horse) (VBO_0001057).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: