A Nonsense Variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is Associated with Idiopathic Hypocalcemia in Thoroughbred foals

A total of two Thoroughbred (TB) hypocalcemia-affected foals presenting muscle fasciculations, tachycardia, loss of limb maneuverability, recurrent seizure episodes, and profoundly lowered calcium concentrations were clinical evaluated. Foals were admitted and full clinical exams were performed; no gross abnormalities were identified, PTH concentrations were inappropriately normal given remarkably low total and ionized calcium concentration in blood. Other causes for profound hypocalcemia were excluded. Due to poor prognosis of the disease, both foals were requested to be euthanized. Blood samples from both foals as well as their mares was obtained. A full necropsy was performed on both foals, revealing no gross and histological abnormalities in cerebrum, cerebellum, spinal cord, thyroid, spleen, heart, muscle, gluteal muscle, liver, lung, and brainstem; collection of parathyroid tissue was attempted, yet not identified despite extensive search. Due to no gross abnormalities found at necropsy, its similarity with human, and exclusivity to only the TB breed, both foals, their clinically healthy dams, and two additional unrelated healthy control TB horses were whole-genome sequenced at roughly 12X coverage and a whole-genome association study (WGAS) was performed.