Categories: Pigmentation phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 193500 (trait) , 148820 (trait) , 606597 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2012

Cross-species summary: Variable degree of white spotting ranging from tiny white spots up to completely white animals. The absence of pigment is caused by the absence of skin melanocytes ("leucism"), not by failure in the biochemical reactions required for pigment synthesis.

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.

Molecular basis: Hauswirth et al. (2012) reported three independent mutations causing the splashed white phenotype, two of them in the MITF gene and one in the PAX3 gene: A missense mutation in the PAX3 gene (c.209G>A; p.C70Y; "SW2"), which arose in the year 1987 in a Quarter Horse mare. It has only been encountered in Quarter Horses and American Paint Horses, which descend from this founder mare.

Hauswirth et al. (2013) reported a second missense variant in the PAX3 gene 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.

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".

Genetic testing: Genetic testing is offered by the Veterinary Genetics Laboratory of UC Davis.

Breeds: American Paint (Horse) (VBO_0000897), Appaloosa (Horse) (VBO_0000904), Quarter Horse (Horse) (VBO_0001057).

Associated gene: