A novel missense variant in the calcium-sensing receptor gene in a dog with hypercalcemia.

Abstract

A 5-year-old female spayed Border Collie cross was evaluated for a 3-year history of hypercalcemia. Abnormalities were not detected on physical examination. Parathyroid hormone (PTH) concentration was at the upper end of the reference interval, but diagnostic imaging did not identify any enlarged or ectopic parathyroid tissue. Hypercalcemia failed to resolve with unilateral parathyroidectomy, or administration of bisphosphonates, and calcimimetics. Despite hypercalcemia, urine calcium excretion was inappropriately low, consistent with Familial Hypocalciuric Hypercalcemia described in humans with calcium sensing receptor gene (CASR) mutations. Exonic sequencing of CASR of this dog revealed homozygosity for a missense variant (Glu649Lys, NP_001074978.1) with predicted pathogenicity. The variant was not present in whole genome sequencing variant calls from 2,782 dogs, including 43 Border Collies. This report identifies a CASR variant as the likely cause of hypercalcemia in this dog. Clinical suspicion for a CASR variant should occur when younger dogs present for persistent hypercalcemia, inappropriate normocalciuria, and elevated PTH concentration.