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Journal of veterinary internal medicine2025; 39(3); e70081; doi: 10.1111/jvim.70081

Allele Frequencies and Genotypes for the Ryanodine Receptor 1 Variant Causing Malignant Hyperthermia and Fatal Rhabdomyolysis With Hyperthermia in Horses.

Abstract: Fatal anesthesia-induced malignant hyperthermia (MH) and rhabdomyolysis with hyperthermia documented in Quarter Horses (QH) breeds are caused by a missense variant in the ryanodine receptor 1 gene (RYR1: XP_023505430.1.:p.(R2454G), designated as MH). The reported cases to date have all been heterozygous, and the allele frequency is suspected to be low. Objective: To determine an accurate estimate of MH allele frequency in multiple horse breeds and investigate whether homozygous animals exist in the population. Methods: In total, 159 227 horses from 16 breeds who were either submitted for clinical evaluation (n = 1500) or genetic testing (n = 157 727) were included. Methods: Prospective study using banked DNA samples from two diagnostic laboratories determined the presence, zygosity, and estimated population MH allele frequencies. Results: The MH allele was exclusively detected in 391 QH, 18 Paints (PT), one Appaloosa (AP), and one QH-Clydesdale cross with similar allele frequencies (QH = 0.0013 and PT and AP = 0.0012). In cases submitted for clinical evaluation, death occurred as anesthesia-induced MH or severe acute rhabdomyolysis with hyperthermia (≥ 42°C, 107.6°F) in 51% of N/MH horses. Nineteen of the 20 fatal cases were young males (median: 9 years old, range: 9 months-14 years). No MH homozygotes were detected in either cohort evaluated. Conclusions: Homozygotes for the MH allele were not identified, and thus might be incompatible with life, but additional testing is needed to confirm. Although the allele frequency was low, being heterozygous poses a risk of death if anesthesia, stress, concurrent illness, breeding, or other stresses occur.
© 2025 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.
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Publication Date: 2025-04-29 PubMed ID: 40298507PubMed Central: PMC12038935DOI: 10.1111/jvim.70081Google Scholar: Lookup
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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 research article focuses on the study of the frequency of the gene variant causing malignant hyperthermia (MH) and lethal rhabdomyolysis (muscle breakdown) with hyperthermia in horses. The researchers also aim to find out if homozygous animals (animals with two copies of the variant gene) exist in the population.

Objectives and Methods

  • The research aimed to determine the accurate estimate of the frequency of the MH gene in multiple horse breeds and to investigate the existence of homozygous animals in the population.
  • The study included 159,227 horses from 16 breeds who were either submitted for clinical evaluation or genetic testing.
  • The researchers used DNA samples from two diagnostic laboratories to determine the presence, zygosity (whether horses have one copy (heterozygous) or two copies (homozygous) of the variant gene), and estimated population MH allele frequencies.

Results

  • The MH allele was predominantly detected in Quarter Horses, with a few instances in Paints, one Appaloosa, and one Quarter Horse-Clydesdale cross. The allele frequencies among these breeds were similar.
  • Among the cases submitted for clinical evaluation, in more than half of the cases, death occurred due to anesthesia-induced MH or severe acute rhabdomyolysis with hyperthermia, predominantly in young males.
  • No homozygous animals were detected in the study population, suggesting that carrying two copies of the MH allele may not be compatible with life.

Conclusions

  • The research concluded that there were no homozygous animals detected for the MH allele, meaning carrying two copies of the MH gene may not be compatible with life.
  • Additional testing is recommended to confirm the hypothesis about the non-existence of homozygotes.
  • Though the allele’s frequency was found to be low, horses carrying a single copy (being heterozygous) are at risk of death if they undergo anesthesia, stress, concurrent illness, breeding, or face other stresses.

The study emphasizes the potential risks associated with the MH gene, and although it is found in a low frequency, it carries significant risk factors, particularly in specific horse breeds. Therefore, understanding this genetic variant’s patterns can help manage and possibly reduce these risks in horse populations.

Cite This Article

APA
Aleman M, McCue M, Bellone RR. (2025). Allele Frequencies and Genotypes for the Ryanodine Receptor 1 Variant Causing Malignant Hyperthermia and Fatal Rhabdomyolysis With Hyperthermia in Horses. J Vet Intern Med, 39(3), e70081. https://doi.org/10.1111/jvim.70081

Publication

Journal of veterinary internal medicine
ISSN: 1939-1676
NlmUniqueID: 8708660
Country: United States
Language: English
Volume: 39
Issue: 3
Pages: e70081
PII: e70081

Researcher Affiliations

Aleman, Monica
  • Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, California, USA.
McCue, Molly
  • Comparative and Molecular Biosciences, Department of Veterinary Population Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Bellone, Rebecca R
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California, USA.

MeSH Terms

  • Animals
  • Horses
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Rhabdomyolysis / veterinary
  • Rhabdomyolysis / genetics
  • Malignant Hyperthermia / genetics
  • Malignant Hyperthermia / veterinary
  • Horse Diseases / genetics
  • Horse Diseases / mortality
  • Genotype
  • Gene Frequency
  • Male
  • Prospective Studies
  • Female

Grant Funding

  • UC Davis Veterinary Genetics Laboratory
  • #V435AM2 / UC Davis Equine and Comparative Neurology Research Group

Conflict of Interest Statement

Rebecca R. Bellone is affiliated with the University of California, Davis, Veterinary Genetics Laboratory, a facility that offers genetic testing for malignant hyperthermia and other veterinary genetics diagnostic testing. The other authors declare no conflicts of interest.

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