A calcium-sensing receptor allelic series and underdiagnosis of genetically driven hypocalcemia

The availability of genomic sequencing has revealed that variants in genes that cause rare monogenic disorders are relatively common, which raises the question of variant pathogenicity. Autosomal-dominant hypocalcemia type 1 (ADH1) is a rare genetic form of hypoparathyroidism caused by gain-of-function (GoF) variants in the calcium-sensing receptor (CaSR) encoded by CASR. We examined the prevalence, penetrance, and expressivity of GoF CASR variants in the UK Biobank (UKB; n = 433,793), All of Us (AOU; n = 229,987), and Mass General Brigham Biobank (n = 39,081). Individuals with previously reported ADH1-associated variants indeed showed ADH1 symptoms, including hypocalcemia (60% in the UKB and 78% in AOU). However, less than half had an ADH1-relevant diagnosis code (17% in the UKB and 44% in AOU), suggesting that individuals with ADH1 are present in these biobanks but may be underdiagnosed. We then developed a scoring algorithm and identified nine low-frequency ADH1-associated variants, which were further validated using genetic sequencing of individuals with nonsurgical hypoparathyroidism (n = 169) and an in vitro functional assay. These nine variants have an intermediate effect and frequency relative to previously reported ADH1-associated variants, completing an allelic series with respect to serum calcium, and alone are responsible for a symptom burden roughly equivalent to all previously reported ADH1-associated variants. Our work indicates that hypocalcemia due to GoF in CASR with ADH1-associated symptoms is underdiagnosed, provides a deeper understanding of the genotype-phenotype relationship of CASR variants, and illustrates that variants in genes underlying rare disorders may cause a much greater symptom burden than currently appreciated.