Chang Jeremy B, Barnhill Connor P, Apostolov Alexander M, Soliai Marcus M, Hecker Julian, Nierenberg Jovia L, Stapleton Smith Lyndsay M, Mathew Arun S, Zeng Xue, Diao Jiayin, Fernando C Dilanka, Chen Qingwen, Dulken Ben W, Petukhov Aleksandr, Altman Russ, Josephs Tracy M, Lasky-Su Jessica A, Gorvin Caroline M, Roberts Mary Scott, Adler Scott H, Fox Jonathan C, Lange Christoph, Ji Sun-Gou
BridgeBio Pharma, 3160 Porter Drive, Suite 250, Palo Alto, CA 94304, USA.
BridgeBio Pharma, 3160 Porter Drive, Suite 250, Palo Alto, CA 94304, USA.
Am J Hum Genet. 2025 Aug 7;112(8):1818-1832. doi: 10.1016/j.ajhg.2025.06.013. Epub 2025 Jul 14.
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.
基因组测序技术的应用揭示了导致罕见单基因疾病的基因变异相对常见，这就引发了变异致病性的问题。1型常染色体显性低钙血症（ADH1）是一种罕见的甲状旁腺功能减退的遗传形式，由CASR编码的钙敏感受体（CaSR）中的功能获得性（GoF）变异引起。我们在英国生物银行（UKB；n = 433,793）、全民健康研究项目（AOU；n = 229,987）和麻省总医院布莱根生物银行（n = 39,081）中研究了GoF CASR变异的患病率、外显率和表现度。先前报告的与ADH1相关变异的个体确实表现出ADH1症状，包括低钙血症（UKB中为60%，AOU中为78%）。然而，不到一半的人有与ADH1相关的诊断代码（UKB中为17%，AOU中为44%），这表明这些生物银行中存在ADH1个体，但可能未被充分诊断。然后，我们开发了一种评分算法，并鉴定出9个低频ADH1相关变异，通过对非手术性甲状旁腺功能减退个体（n = 169）进行基因测序和体外功能试验进一步验证了这些变异。相对于先前报告的ADH1相关变异，这9个变异具有中等效应和频率，在血清钙方面形成了一个等位基因系列，单独就造成了大致相当于所有先前报告的ADH1相关变异的症状负担。我们的研究表明，具有ADH1相关症状的由CASR中GoF导致的低钙血症未被充分诊断，对CASR变异的基因型-表型关系有了更深入的了解，并表明罕见疾病相关基因中的变异可能导致比目前认识到的更大的症状负担。
