A novel missense variant of the calcium-sensing receptor gene (CASR) associated with familial HYPOCALCIURIC hypercalcemia

Abstract Familial hypocalciuric hypercalcemia (FHH) is a rare genetic disorder, due to inactivating variants of the calcium-sensing receptor gene (CASR) or GNA11 and AP2S1 genes, which lead to decreased intracellular receptor activity. Typical biochemical features include hypercalcemia and hypocalciuria, while parathyroid hormone serum levels may be inappropriately normal or high. Despite the finding of hypercalcemia, the disorder has a benign course and patients usually do not require any therapeutical intervention. We describe a man with FHH due to a previously unreported missense variant, c.496A C, p.(Ser166Arg), falling in exon 4 of CASR. The same variant was subsequently found in the father who presented with asymptomatic hypercalcemia. The variant was classified as “likely pathogenic”. In silico analysis predicted that the variant is destabilizing for the tertiary structure of the protein and may induce conformational changes. In vitro functional assay on HEK293 transfected cells demonstrated that the variant likely disrupts calcium binding and transport by CaSR. The present case expands the mutational spectrum of CASR and reinforces the clinical utility of multidisciplinary assessment for adults presenting with unexplained hypercalcemia.