A novel missense variant of the calcium-sensing receptor gene associated with familial hypocalciuric hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is a rare genetic disorder caused by inactivating variants of the calcium-sensing receptor gene (<i>CASR</i>), <i>GNA11</i>, and <i>AP2S1</i> genes, which lead to decreased intracellular receptor activity. Typical biochemical features include hypercalcemia and hypocalciuria, while PTH 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 caused by a previously unreported missense variant, c.496A>C, p.(Ser166Arg), located in exon 4 of <i>CASR</i>. 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 destabilizes for the tertiary structure of the protein and may induce conformational changes. An 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 <i>CASR</i> and reinforces the clinical utility of multidisciplinary assessment for adults presenting with unexplained hypercalcemia.