Yamauchi Kohei, Ku Matthew, Mitchell Devyn W, Shen Alex, Dauda Kundivy, Vanags Loren, Schmeckpeper Jeffrey, Knollmann Bjorn C, O'Neill Matthew J, Kroncke Brett M
Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Shiga Prefecture, Japan.
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
medRxiv. 2025 Mar 21:2025.03.20.25324327. doi: 10.1101/2025.03.20.25324327.
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is strongly associated with rare missense variants in , the gene encoding the intracellular calcium release channel RyR2. Precision medicine is complicated by incomplete penetrance, particularly in the case of -CPVT variants.
To improve structural understanding and clinical actionability of -CPVT incomplete penetrance.
We curated 179 manuscripts reviewed by three individuals to extrapolate -CPVT missense variant genotype-phenotype relationships. Purportedly neutral control variants were ascertained from missense variants observed in gnomAD and ClinVar. We performed an -CPVT Bayesian penetrance analysis by conditioning a CPVT penetrance prior on variant-specific features ( and structural) calibrated by heterozygote phenotypes. We compared the calibration of our Bayesian penetrance estimates and our previous described structural density metric with predictors REVEL, AlphaMissense and ClinVar annotations, using Spearman rank-order correlations, and Brier Scores. Penetrance estimates were superimposed upon a cryo-EM structure of RyR2 to investigate 'hot-spot' heterogeneity.
From the literature and gnomAD, we identified 1,014 affected missense heterozygotes (468 unique variants) among a total of 622,575 heterozygotes (5,181 unique variants). Among the predictors, our Bayesian prior score had the highest Spearman rank-order and lowest Brier scores, respectively (0.19; 0.0090), compared to ClinVar (0.083; 0.019), REVEL (0.16; 0.018), or AlphaMissense (0.18; 0.018). Penetrance estimates for all missense variants are prospectively hosted at our Variant Browser website.
Bayesian penetrance scores outperform current tools in evaluating variant penetrance. We provide prospective CPVT penetrance values for 29,242 missense variants at our online Variant Browser.
儿茶酚胺能多形性室性心动过速（CPVT）与编码细胞内钙释放通道兰尼碱受体2（RyR2）的基因中的罕见错义变异密切相关。精准医学因不完全外显率而变得复杂，尤其是在 RyR2 - CPVT 变异的情况下。
提高对 RyR2 - CPVT 不完全外显率的结构理解和临床可操作性。
我们整理了由三人审阅的 179 篇手稿，以推断 RyR2 - CPVT 错义变异的基因型 - 表型关系。从 gnomAD 和 ClinVar 中观察到的错义变异中确定所谓的中性对照变异。我们通过在由杂合子表型校准的变异特异性特征（功能和结构）上设定 CPVT 外显率先验值，进行了 RyR2 - CPVT 贝叶斯外显率分析。我们使用斯皮尔曼等级相关性和布里尔分数，将我们的贝叶斯外显率估计值和我们之前描述的结构密度指标的校准与预测工具 REVEL、AlphaMissense 和 ClinVar 注释进行比较。将外显率估计值叠加在 RyR2 的冷冻电镜结构上，以研究“热点”异质性。
从文献和 gnomAD 中，我们在总共 622,575 个杂合子（5,181 个独特变异）中鉴定出 1,014 个受影响的错义 RyR2 杂合子（468 个独特变异）。在预测工具中，与 ClinVar（0.083；0.019）、REVEL（0.16；0.018）或 AlphaMissense（0.18；0.018）相比，我们的贝叶斯先验分数分别具有最高的斯皮尔曼等级相关性和最低的布里尔分数（0.19；0.0090）。所有 RyR2 错义变异的外显率估计值前瞻性地存放在我们的变异浏览器网站上。
在评估变异外显率方面，贝叶斯外显率分数优于当前工具。我们在在线变异浏览器上为 29,242 个 RyR2 错义变异提供前瞻性的 CPVT 外显率值。
