This is the first genetic variant for hypoparathyroidism identified in any domestic animal species. Testing is now available.
“For Thoroughbred owners and breeders, the loss of a foal has tremendous economic and emotional impacts,” said first author Victor Rivas, who conducted the project as part of his undergraduate training in Finno’s laboratory. “It is important to promote safe and strategic breeding habits by actively breeding horses genetically screened not only for EFIH but for other diseases that may impact quality of life.”
Foals affected with EFIH suffer from low blood calcium concentrations, resulting in involuntary muscle contractions, muscle stiffness that leads to a stiff gait and can progress to an inability to stand, seizures, fevers, and an abnormally fast pulse. Parathyroid hormone is typically produced to increase calcium levels in the body, but in these foals concentrations are low or “inappropriately” normal (i.e., they should be high due to the low calcium). Affected foals die or are euthanized due to poor prognosis. Necropsy results reveal underdeveloped or absent parathyroid glands.
Previously termed idiopathic hypocalcemia, EFIH has been observed in Thoroughbred foals up to 35 days of age. Disease onset and progression are likely determined by the amount of calcium in the diet early in life. This can vary based on dam milk calcium concentration and the amount of milk ingested.
In the current study, the researchers determined an autosomal recessive mode of inheritance and performed whole genome sequencing of two affected foals. A mutation in the rap guanine nucleotide exchange factor 5 (RAPGEF5) gene was present in two copies (homozygous) in both foals. They further analyzed the variant in a frog developmental model and demonstrated loss of function of the RAPGEF5 protein leading to aberrant development. Based on these data, the researchers hypothesize that RAPGEF5 might play a role in the derivation of the parathyroid gland during development.
Researchers have not identified the variant in individuals from 12 other breeds. The allele frequency for the RAPGEF5 variant in an expanded set of 82 randomly selected, unaffected Thoroughbreds was 0.018. An unbiased allele frequency study has not been performed, so the allele frequency in the larger Thoroughbred population is currently unknown.
“The next steps are to assess the allele frequency in a large population of randomly selected Thoroughbreds,” said Finno. “Additionally, we have discussed collaborating with Dr. Nathan Slovis at Hagyard Equine Medical Institute in Kentucky to test for the variant in cases of ‘sudden death’ in Thoroughbred foals.”
The clinical presentation of EFIH is similar to human familial hypoparathyroidism. Because the RAPGEF5 gene is highly conserved across species, it is a potential new candidate gene for primary hypoparathyroidism in humans, the researchers said.