In other species: dog , domestic cat , llama , taurine cattle , domestic guinea pig , water buffalo

Categories: Pigmentation phene , Hearing / vestibular / ear phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 193510 (trait) , 103500 (trait) , 156845 (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: 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, leucistic"), not by failure in the biochemical reactions required for pigment synthesis.

Species-specific name: Splashed white, macchiato

Species-specific description: Currently (in 2016), among domesticated animals the horse is 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 TPRM1 genes. Combinations of multiple variants in these gene can lead to more pronounced coat colour phenotypes. Variants in MITF can lead to a variable degree of white spotting. The splashed white phenotype in horses is most frequently due to variants in the MITF gene, but may also be caused by variants in the PAX3 gene. As described by Hauswirth et al. (2012), "The “splashed white” pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf." For variants in the KIT gene that result in a white spotting phenotype see OMIA:000209-9796 : Coat colour, dominant white in Equus caballus.

Inheritance: 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 a non-coding regulatory 10 bp insertion into the melanocyte-specific promoter of the MITF gene (ECA16:g.20,117,302Tdelins11; "SW1"), which disrupts a PAX3 binding site. This allele is apparently several hundred years old and can be found in many different breeds segregating for the splashed white phenotype, such as e.g. American Paint Horses, Icelandic Horses, Miniature Horses, Quarter Horses, Shetland Ponies, Thoroughbreds, and Trakehner. Horses heterozygous for the SW1 allele exhibit the splashed white phenotype. Horses homozygous for SW1 are viable and often show very pronounced spotting patterns, which also involve depigmentation of parts of the trunk. Hauswirth et al. (2012) reported a frameshift mutation in exon 5 of the MITF gene (c.837_841delGTGTC; p.C280fs*20; "SW3"), which also causes a splashed white phenotype. This variant appears to be very young and was exclusively encountered in a Quarter Horse mare and her American Paint Horse registered foal. It is assumed that the "SW3" allele leads to embryonic lethality in the homozygous state (Hauswirth et al. 2012). Hauswirth et al. (2012) furthermore reported a reported "a de novo missense mutation in exon 6 of the MITF gene . . . (c.929A>G; )" in a Franches-Montagnes stallion as causing the newly-described macchiato phenotype. If the melanocyte-specific transcript MITF-M is considered (XM_005600318.1), this variant should be termed c.629G>A or p.Asn210Ser. The amino acid exchange affects the conserved bHLH DNA binding domain and leads to weaker binding of the mutant MITF protein to target DNA. This variant thus has a more pronounced phenotypic effect than the SW1 and SW3 variants, probably due to a dominant-negative interaction of mutant MITF with the wildtype protein. Haase et al. (2013) provided evidence that additional non-coding regulatory variants at the KIT and MITF loci contribute to the genetic control of white markings in horses. However, the exact variants and their quantitative effect sizes could not be resolved as they act together in functional haplotypes. Dürig et al. (2017) identified another de novo missense mutation in the MITF gene in an American Standardbred foal (XM_005600318.1:c.731G>A; p.Gly244Glu). This variant also affected the conserved bHLH DNA binding domain of the MITF transcription factor. The foal with this variant had an almost completely white skin and blue irsises with irregular borders. Table S1 of Dürig et al. (2017) provides details of all MITF alleles (plus alleles at EDNRB, KIT, PAX3) known in July 2016. Negro et al. (2017): "The g.20147039C>T intronic variant located 29.9 kb downstream from the transcription start site of the MITF gene was associated with less white markings on forelimbs (P < 0.05) in PRMe horses, with a relative contribution of 63.9%, whereas in PRE horses this variant was associated with white facial markings (P < 0.05), with a relative contribution of 63.9%." Durward-Akhurst et al. (2024) report that this "variant [omia.variant:806] is the major allele or present in greater than 50% of horses in all 12 target breeds and the other breed group in these 605 horses [investigated in their study] ... . Interestingly, the C > A variant was homozygous in all 17 Icelandic horses, a breed in which white markings are accepted. It is unclear if this intronic variant causes white face and leg markings, or if it is only tagging another variant in the MITF transcription factor that is known to be a major regulator of pigmentation."
Henkel et al. (2019) "investigated an American Paint Horse family segregating a phenotype involving white spotting and blue eyes . . . [in which] Six of eight horses with the white-spotting phenotype were deaf." Sequencing of functional candidate genes in one affected horse "revealed a heterozygous ~63-kb deletion spanning exons 6-9 of the MITF gene (chr16:21 503 211-21 566 617). We confirmed the breakpoints of the deletion by PCR and Sanger sequencing. PCR-based genotyping revealed that all eight available affected horses from the family carried the deletion." Magdesian et al. (2020) reported "an 8.7 kb deletion in MITF on ECA16 (NC_009159.3:g.21551060-21559770del)", named SW6, as the likely causal variant of splashed white in a family of American Paint Horse. Patterson Rosa et al. (2022) "investigated a small family of dual registered American Quarter Horse/American Paint Horse individuals segregating for a SW similar phenotype that could not be explained by individual genotypes at previously published white variants ... . ... This colt was also diagnosed with complete deafness... . ... Exon sequencing identified a novel three-base pair deletion (NM_001163874.1; c.949_951delTCT; p.R317del; “SW7”) in MITF, present in the foal ... . ...We propose to designate this polymorphism as SW7 ... ." 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 ... ." Bellone et al. (2023): "A splashed white Thoroughbred stallion, whose sire and dam were not patterned, was hypothesized to have a de novo variant leading to his white coat pattern." The authors identified a de novo deletion in MITF (NC_009159.3:g.21555811_21558139delinsAAAT, SW8) as likely causal variant. "Genotyping three of this stallion's offspring identified SW8 only in the nearly all-white foal that was confirmed deaf by brainstem auditory evoked response testing. This foal was also a compound heterozygote for dominant white variants (W20/W22), but to date, W variants alone have not been connected to deafness."

Clinical features: Magdesian et al. 2009 demonstrated an increased risk for deafness in horses with the splashed white and/or frame overo spotting phenotype. Horses with the SW1 allele have an increased risk for unilateral and bilateral deafness, but the exact risk is unknown. The risk for deafness and the extent of depigmentation increase, if multiple "white increasing" alleles occur simultaneously in the same horse (Hauswirth et al. 2012). The macchiato Franches-Montagnes horse carrying the p.Asn210Ser variant was deaf and had low sperm quality (Blatter et al. 2013).

Breeds: American Miniature Horse (Horse) (VBO_0000896), American Paint (Horse) (VBO_0000897), American Trotter (Horse) (VBO_0000899), Appaloosa (Horse) (VBO_0000904), Cavall Menorquí, Spain (Horse) (VBO_0011409), Freiberger (Horse) (VBO_0000965), Icelandic Horse (Horse) (VBO_0000991), Morgan (Horse) (VBO_0001022), Purebred Spanish (Horse) (VBO_0001056), Quarter Horse (Horse) (VBO_0001057), Shetland Pony (Horse) (VBO_0001066), Tori hobune, Estonia (Horse) (VBO_0011097), Trakehner (Horse) (VBO_0001087).
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: