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Animal genetics2023; 54(6); 752-762; doi: 10.1111/age.13352

A de novo 2.3 kb structural variant in MITF explains a novel splashed white phenotype in a Thoroughbred family.

Abstract: Splashed white in horses is characterized by extensive white patterning on the legs, face and abdomen and may be accompanied by deafness. To date, seven variants in microphthalmia-associated transcription factor (MITF) and two variants in Paired Box 3 (PAX3) have been identified to explain this phenotype. 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. A whole-genome sequencing candidate gene approach identified two single nucleotide variants (SNVs) in SOX10, four SNVs in MITF and a 2.3 kb deletion in MITF with the alternative allele present in this stallion but absent in the other 18 horses analyzed. All six SNVs were annotated as modifiers and were not further considered. The deletion in MITF (NC_009159.3:g.21555811_21558139delinsAAAT) encompasses exon 9 encoding a part of the helix-loop-helix domain required for DNA binding. Sanger sequencing and parentage testing confirmed that this deletion was a de novo mutation of maternal origin. Consistent with the published nomenclature, we denote this likely causal variant as SW8. 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. SW8 marks the fourth de novo MITF variant in horses reported to cause white patterning. The link between deafness and all MITF variants with and without other variants impacting melanocyte development and function needs to be further explored.
© 2023 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.
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Publication Date: 2023-09-12 PubMed ID: 37697831DOI: 10.1111/age.13352Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The study investigates the cause of a uniquely extensive white coat pattern (‘splashed white’) in a Thoroughbred stallion that wasn’t inherited from its parents. The researchers identified a new genetic mutation (a 2.3kb deletion in the MITF gene) as the likely cause and linked it to not just the horse’s white patterning but to its deafness as well.

Objective of the Research

  • The primary objective of the study was to explore the genetic reason behind an unusually white coat pattern observed in a Thoroughbred stallion. As the foal’s parents didn’t exhibit these patterns, researchers speculated a de novo (new) genetic variant to be the cause of this unique phenotype. Another significant goal was to understand the connection between this genetic mutation and deafness in the horse.

Methodology

  • Researchers used a whole-genome sequencing candidate gene approach on the Thoroughbred stallion and found two single nucleotide variants (SNVs) in SOX10, four SNVs in MITF, and a 2.3kb deletion in MITF. The deletion was not present in other horses in the study.
  • Further study of the deletion in MITF, which encompasses exon 9, revealed a disruption in the DNA binding process. Parentage testing and Sanger sequencing validated this deletion as a de novo mutation from the female parent.

Findings and Conclusion

  • The study determined the MITF deletion (termed as SW8) as the primary cause for the unusual white patterning. The researchers found this variant upon genotyping three of the Thoroughbred stallion’s offspring — only the almost all-white, deaf foal had this variant.
  • Also notable was the fact that the all-white foal was also a compound heterozygote for dominant white variants (W20/W22). Nevertheless, these variants haven’t been linked to deafness so far.
  • This research presented the MITF deletion as the fourth de novo MITF variant in horses associated with white patterning. Additionally, it highlighted the necessity to further investigate the relationship between deafness and all MITF variants, with and without other variants impacting melanocyte development and function.

Cite This Article

APA
Bellone RR, Tanaka J, Esdaile E, Sutton RB, Payette F, Leduc L, Till BJ, Abdel-Ghaffar AK, Hammond M, Magdesian KG. (2023). A de novo 2.3 kb structural variant in MITF explains a novel splashed white phenotype in a Thoroughbred family. Anim Genet, 54(6), 752-762. https://doi.org/10.1111/age.13352

Publication

Animal genetics
ISSN: 1365-2052
NlmUniqueID: 8605704
Country: England
Language: English
Volume: 54
Issue: 6
Pages: 752-762

Researcher Affiliations

Bellone, R R
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, UC Davis, Davis, California, USA.
  • Department of Population Health and Reproduction, School of Veterinary Medicine, UC Davis, Davis, California, USA.
Tanaka, J
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, UC Davis, Davis, California, USA.
Esdaile, E
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, UC Davis, Davis, California, USA.
Sutton, R B
  • Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
Payette, F
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, University School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, USA.
Leduc, L
  • Department of Clinical Studies, New Bolton Center, University of Pennsylvania School of Veterinary Medicine, University School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, USA.
Till, B J
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, UC Davis, Davis, California, USA.
Abdel-Ghaffar, A K
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, UC Davis, Davis, California, USA.
Hammond, M
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, UC Davis, Davis, California, USA.
  • Department of Population Health and Reproduction, School of Veterinary Medicine, UC Davis, Davis, California, USA.
Magdesian, K G
  • Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.

MeSH Terms

  • Horses / genetics
  • Animals
  • Male
  • Microphthalmia-Associated Transcription Factor / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Phenotype
  • Alleles
  • Exons
  • Deafness / genetics
  • Mutation
  • Horse Diseases / genetics

Grant Funding

  • UC Davis Veterinary Genetics Laboratory

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Citations

This article has been cited 6 times.
  1. Esdaile E, Houston K, Till BJ, Sutton RB, Scurrell E, Ling M, Hartley C, Bellone RR. A de novo FBN1 variant likely causes congenital bilateral ectopia lentis in a crossbred horse. Sci Rep 2025 Oct 24;15(1):37238.
    doi: 10.1038/s41598-025-21139-7pubmed: 41136527google scholar: lookup
  2. Kassymbekova SN, Bimenova ZZ, Iskhan KZ, Sobiech P, Jastrzebski JP, Brym P, Babis W, Kalykova AS, Otebayev ZM, Kabylbekova DI, Baneh H, Romanov MN. Uncovering Genetic Diversity and Adaptive Candidate Genes in the Mugalzhar Horse Breed Using Whole-Genome Sequencing Data. Animals (Basel) 2025 Sep 11;15(18).
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  3. Nair S, Li X, Anderson TJC, Platt RN. Pooled, Long-read Sequencing for Structural Variant Characterization in Schistosome Populations. Genome Biol Evol 2025 Jul 3;17(7).
    doi: 10.1093/gbe/evaf127pubmed: 40576093google scholar: lookup
  4. Liu X, Peng Y, Zhang X, Wang X, Chen W, Kou X, Liang H, Ren W, Khan MZ, Wang C. Coloration in Equine: Overview of Candidate Genes Associated with Coat Color Phenotypes. Animals (Basel) 2024 Jun 17;14(12).
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