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Gene or Region: RAPGEF5
Reference Variant: C
Mutant Variant: A
Affected Breeds: Thoroughbred, Thoroughbred crosses, other Thoroughbred-influenced breeds
Research Confidence: High - Strong association in studied population
Explanation of Results: efih/efih = homozygous for Equine Familial Isolated Hypoparathyroidism, trait expressed efih/n = heterozygous for Equine Familial Isolated Hypoparathyroidism, carrier n/n = no variant detected
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.
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.
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
Junctional Epidermolysis Bullosa (JEB), also known as red foot disease or hairless foal syndrome, results in the inability to produce the proteins needed to keep the skin on the body. Affected foals exhibit symptoms within days of birth, including blisters at the pressure points, detatchment of the hooves, and oral ulcers. As there is no treatment, affected foals are humanely euthanized.
Kissing Spines Susceptibility (KSS) evaluates a horses genetic risk for developing Kissing Spines. Horses diagnosed with Kissing Spines will have two or more dorsal spinous processes that are too close together, touch, or even overlap. This bone-on-bone grinding causes varying degrees of pain, and thus decreased mobility.
Lavender foal syndrome (LFS), also known as coat color dilution lethal, is a neurological dysfunction in newborn foals. Symptoms are apparent at birth and include seizures, severe hyper-extension of limbs, neck and back, stiff paddling leg movements, involuntary eye movement and inability to stand or sit upright. The coat usually has a dilute color that ranges in shade from silver to a pale lavender/pink. As there is no treatment, affected foals are humanely euthanized.
