Abstract
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.
Highlights
The calcium-sensing receptor (CaSR), encoded by CASR on chromosome 3q21.1, is a 1,078 amino acid class C G protein-coupled receptor that is highly expressed in calcitropic tissues including parathyroid glands and kidneys.[1]
Of the 57 variants predicted to be likely pathogenic or pathogenic, 12 were associated with hypercalcemia in 23 individuals, and 2 hypocalcemia-associated variants were identified in 3 individuals (Figure S2)
Bioinformatics reduced the query set to 55% of total rare variants (57 LP/P variants from a total of 104), and subsequent serum Ca concentration analysis identified the 25% of total rare variants that were potentially associated with familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1) phenotypes
Summary
The calcium-sensing receptor (CaSR), encoded by CASR on chromosome 3q21.1, is a 1,078 amino acid class C G protein-coupled receptor that is highly expressed in calcitropic tissues including parathyroid glands and kidneys.[1]. FHH1 accounts for $65% of cases, and is an autosomal-dominant condition characterized by lifelong elevations of serum calcium concentrations and normal or elevated serum parathyroid hormone (PTH) concentrations.[5] FHH1 is usually asymptomatic and requires no intervention,[5] it has a serum biochemical profile similar to primary hyperparathyroidism (PHPT), which is typically treated by parathyroidectomy. Distinguishing FHH1 from PHPT, generally done by assessing urinary Ca2þ excretion, i.e., $80% of FHH-affected individuals are hypocalciuric (Ca creatinine clearance ratio [CCCR] < 0.01) versus
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