Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population
Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population
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DOI：
10.1016/j.ajhg.2020.04.006
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发表时间：
2020-06-04
影响因子：
9.8
通讯作者：
Breitwieser, Gerda E.
中科院分区：
文献类型：
--
作者：
Dershem, Ridge;Gorvin, Caroline M.;Breitwieser, Gerda E.
钙敏感受体(CaSR)调节血清钙浓度。CaSR功能缺失或功能获得突变分别导致家族性低钙尿性高钙血症1型(FHH1)或常染色体显性遗传性低钙血症1型(ADH1)，但FHH1或ADH1的人群流行率尚不清楚。在来自单一美国医疗保健系统的DiscovEHR队列中的51,289名未识别的个体的整个外显子序列中发现了罕见的CaSR变体。我们结合生物信息学致病分类、平均血钙浓度和遗传模式来识别潜在的FHH1或ADH1变异，并使用序列核关联测试(SKAT)来识别罕见的变异相关疾病。我们在38名无关个体中鉴定了预测的功能丧失杂合性CaSR变种(6个不同的无义/移码变种和12个不同的错义变种)，其中21人患有高钙血症。在两名无关的低血钙症患者中发现了错义CaSR变异。功能研究表明，所有与高钙相关的错义变体都削弱了异源表达、质膜靶向和/或信号转导，而与低钙相关的错义变体则增加了异源表达、质膜靶向和/或信号转导。因此，在51,289个队列中，确认了38名FHH1基因诊断患者和2名ADH1基因诊断患者，使FHH1和ADH1在该人群中的患病率分别为74.1/10万和3.9/10万。Skat结合了所有无意义、移码和错义功能丧失变异，揭示了与心血管、神经和其他疾病的关联。总之，FHH1是高钙血症的常见原因，其患病率与原发性甲状旁腺功能亢进症相似，并与疾病风险改变有关，而ADH1是非手术甲状旁腺功能减退症的主要原因。
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 hypercalcemiaassociated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemiaassociated 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.