The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.

钙敏感受体（CaSR）调节血清钙浓度。CASR功能丧失或功能获得性突变分别导致家族性低钙血症性高钙血症1型（FHH1）或常染色体显性低钙血症1型（ADH1），但是FHH1或ADH1的人群患病率尚不清楚。在来自单个美国医疗保健系统的DiscovEHR队列中，从51,289名身份不明的个体的全外显子序列中鉴定了罕见的CASR变体。我们整合了生物信息学的致病性分类，平均血清Ca浓度和遗传模式，以鉴定潜在的FHH1或ADH1变异体，并使用序列内核关联测试（SKAT）来鉴定罕见的变异体相关疾病。我们确定了预测的杂合功能丧失CASR38个无关的个体中有6个不同的无意义/移码变体和12个不同的错义变体，其中21个是高钙血症。Missense CASR在两个无关的低血钙个体中鉴定出变异。功能研究表明，所有与高钙血症相关的错义变体均损害异源表达，质膜靶向和/或信号转导，而与低钙血症相关的错义变体则增加表达，质膜靶向和/或信号转导。因此，在51,289个队列中确定了38个具有FHH1遗传诊断的个体和2个具有ADH1遗传诊断的个体，该人群中FHH1的患病率为74.1 / 10万，ADH1的患病率为3.9 / 10万。结合所有无意义，移码和错义功能丧失变异的SKAT揭示了与心血管疾病，神经疾病和其他疾病的相关性。总之，FHH1是高钙血症的常见原因，