ArticleAmerican journal of human genetics2020
Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.
Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 2 of them syntheses that pooled it.
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Who cites it
53 citing papers in PubMed, 2 syntheses or guidelines pooled it, 74 citations in OpenAlex.
- Case Report: Calcium sensing receptor gene gain of function mutations: a case series and report of 2 novel mutations.Frontiers in endocrinology · 2023Pooled it
- Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2022Pooled it
- Clinical and genetic insights into Autosomal Dominant Hypocalcemia type 1: a single-center case series including genotype-phenotype correlations, pregnancy outcomes, and novel CASR variants.Journal of endocrinological investigation · 2026Article
- Functional assessment of a constitutively activatingJournal of the Endocrine Society · 2026Article
- Increasing incidence and prevalence of biochemically confirmed primary hyperparathyroidism in Stockholm, 2006-2020.The Journal of clinical endocrinology and metabolism · 2026Article
- Clinical characteristics of chinese patients with autosomal dominant hypocalcemia type 1: a single-center study.Journal of endocrinological investigation · 2026Article
- Significantly elevated calcium levels and gallstone disease in a patient with familial hypocalciuric hypercalcaemia.Endocrinology, diabetes & metabolism case reports · 2026Article
- Peri-kidney transplant management in autosomal dominant hypocalcaemia type 1.Pediatric nephrology (Berlin, Germany) · 2026Article
- Article
- Identification and functional characterization of a novel nonsense mutation ofGenes & diseases · 2026Article
- Clinical and molecular characterization of familial hypocalciuric hypercalcemia in an endocrine practice: a case series of 25 patients.JBMR plus · 2026Article
- Clinical and Genetic Profile of Chinese Familial Hypocalciuric Hypercalcemia Type 1 (FHH1): A Retrospective Study.Endocrine · 2026Article
- Case Report: Palopegteriparatide as a novel therapeutic option in pediatric autosomal dominant hypocalcemia type 1.Frontiers in endocrinology · 2026Article
- A novel gain-of-function mutation (W818R) of calcium-sensing receptor in a family with autosomal dominant hypocalcemia type 1.Frontiers in endocrinology · 2026Article
- Case report: A Newly Identified G-protein Subunit α-11 Loss-of-Function Variant Causing Familial Hypocalciuric Hypercalcemia Type 2 in an Italian Kindred.Frontiers in endocrinology · 2026Article
- Genetic screening in a large Chinese cohort of adult-onset non-surgical hypoparathyroidism.Endocrine · 2025Article
- Novel Variants and Clinical Heterogeneity in Pediatric Calcium Metabolism Disorders Identified Through High-Yield Tiered Genetic Testing in a Taiwanese Cohort.Medicina (Kaunas, Lithuania) · 2025Article
- A novel chemoreactive calcilytic for the potential treatment of autosomal dominant hypocalcemia.Acta pharmaceutica Sinica. B · 2025Article
- Bone Health and Linear Growth in Children With Familial Hypoparathyroidism Treated With Human Parathyroid Hormone 1-34.The Journal of clinical endocrinology and metabolism · 2025Article
- A calcium-sensing receptor allelic series and underdiagnosis of genetically driven hypocalcemia.American journal of human genetics · 2025Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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