Abstract
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.