Equine Familial Isolated Hypoparathyroidism (EFIH): What You Need to Know Before Breeding Thoroughbreds

Equine Familial Isolated Hypoparathyroidism (EFIH) is a fatal genetic disorder identified in Thoroughbred foals, characterized by low blood calcium levels leading to muscle stiffness, seizures, and, ultimately, death. The condition is inherited in an autosomal recessive manner, meaning that foals with two copies of the causative genetic variant are affected.

EFIH manifests in foals up to 35 days old, presenting with symptoms such as involuntary muscle contractions, a stiff gait progressing to an inability to stand, seizures, fever, and rapid pulse. These clinical signs are associated with low blood calcium concentrations and inadequately low or normal parathyroid hormone levels. Necropsy findings often reveal underdeveloped or absent parathyroid glands.

Gene Information

The genetic basis for EFIH is a nonsense variant in the Rap Guanine Nucleotide Exchange Factor 5 gene (RAPGEF5) that replaces a serine in the protein product with a stop codon (c.2624C>A p.Ser875*), leading to a truncated protein with decreased functionality. RAPGEF5 plays a crucial role in intracellular signaling pathways, particularly those involved in cyclic AMP (cAMP)-dependent signaling and calcium homeostasis. In affected horses, this variant in RAPGEF5 disrupts normal parathyroid gland function, impairing PTH synthesis and secretion.

References

Rivas, V. N., Magdesian, K. G., Fagan, S., Slovis, N. M., Luethy, D., Javsicas, L. H., Caserto, B. G., Miller, A. D., Dahlgren, A. R., Peterson, J., Hales, E. N., Peng, S., Watson, K. D., Khokha, M. K., & Finno, C. J. (2020). A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals. PLoS Genetics, 16(9), e1009028. doi: 10.1371/journal.pgen.1009028