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

ABSTRACT Background 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. Animals 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 and Clinical Importance 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.