| Title: | A calcium-sensing receptor allelic series and underdiagnosis of genetically driven hypocalcemia |
| Journal: | American Journal of Human Genetics |
| Published: | 14 Jul 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40664210/ |
| DOI: | https://doi.org/10.1016/j.ajhg.2025.06.013 |
| URL: | https://www.cell.com/ajhg/pdf/S0002-9297(25)00244-7.pdf |
Publication 16990
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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.</p>
13 Keywords
- Adult
- Aged
- Alleles
- Female
- Gain of Function Mutation
- Humans
- Hypocalcemia
- Hypoparathyroidism
- Male
- Middle Aged
- Penetrance
- Receptors, Calcium-Sensing
- United Kingdom
23 Authors
- Jeremy B. Chang
- Connor P. Barnhill
- Alexander M. Apostolov
- Marcus M. Soliai
- Julian Hecker
- Jovia L. Nierenberg
- Lyndsay M. Stapleton Smith
- Arun S. Mathew
- Xue Zeng
- Jiayin Diao
- C. Dilanka Fernando
- Qingwen Chen
- Ben W. Dulken
- Aleksandr Petukhov
- Russ Altman
- Tracy M. Josephs
- Jessica A. Lasky-Su
- Caroline M. Gorvin
- Mary Scott Roberts
- Scott H. Adler
- Jonathan C. Fox
- Christoph Lange
- Sun-Gou Ji
1 Application
| Application ID | Title |
|---|---|
| 62375 | Validating targets and optimizing development of therapies for rare Mendelian Disorders using UK BioBank dataset |
Enabling scientific discoveries that improve human health