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Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships.
Journal of Human Genetics ( IF 2.6 ) Pub Date : 2020-03-10 , DOI: 10.1038/s10038-020-0738-6 Damilola Olubando 1, 2 , Claire Hopton 1, 2 , James Eden 1 , Richard Caswell 3 , N Lowri Thomas 4 , Stephen A Roberts 5 , Deborah Morris-Rosendahl 6, 7 , Luigi Venetucci 8, 9 , William G Newman 1, 2, 10
Journal of Human Genetics ( IF 2.6 ) Pub Date : 2020-03-10 , DOI: 10.1038/s10038-020-0738-6 Damilola Olubando 1, 2 , Claire Hopton 1, 2 , James Eden 1 , Richard Caswell 3 , N Lowri Thomas 4 , Stephen A Roberts 5 , Deborah Morris-Rosendahl 6, 7 , Luigi Venetucci 8, 9 , William G Newman 1, 2, 10
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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is predominantly caused by heterozygous missense variants in the cardiac ryanodine receptor, RYR2. However, many RYR2 missense variants are classified as variants of uncertain significance (VUS). We systematically re-evaluated all RYR2 variants in healthy individuals and those with CPVT or arrhythmia using the 2015 American College of Medical Genomics guidelines. RYR2 variants were identified by the NW Genomic Laboratory Hub, from the published literature and databases of sequence variants. Each variant was assessed based on minor allele frequencies, in silico prediction tools and appraisal of functional studies and classified according to the ACMG-AMP guidelines. Phenotype data was collated where available. Of the 326 identified RYR2 missense variants, 55 (16.9%), previously disease-associated variants were reclassified as benign. Application of the gnomAD database of >140,000 controls allowed reclassification of 11 variants more than the ExAC database. CPVT-associated RYR2 variants clustered predominantly between amino acid positions 3949-4332 and 4867-4967 as well as the RyR and IP3R homology-associated and ion transport domains (p < 0.005). CPVT-associated RYR2 variants occurred at more conserved amino acid positions compared with controls, and variants associated with sudden death had higher conservation scores (p < 0.005). There were five potentially pathogenic RYR2 variants associated with sudden death during sleep which were located almost exclusively in the C-terminus of the protein. In conclusion, control sequence databases facilitate reclassification of RYR2 variants but the majority remain as VUS. Notably, pathogenic variants in RYR2 are associated with death in sleep.
中文翻译：
儿茶酚胺能性多形性室性心动过速患者中RYR2错义变异的分类和相关性揭示了表型关系。
儿茶酚胺能性多形性室性心动过速（CPVT）主要是由心脏瑞丹碱受体RYR2中的杂合错义变体引起的。但是，许多RYR2错义变体被分类为不确定重要性（VUS）的变体。我们根据2015年美国医学基因组学学会指南，系统地重新评估了健康个体和CPVT或心律失常患者的所有RYR2变异。RYR2变体由NW基因组实验室中心从已发表的文献和序列变体数据库中鉴定。根据次要等位基因频率，计算机预测工具和功能研究评估对每种变异进行评估，并根据ACMG-AMP指南进行分类。表型数据在可用的地方进行整理。在326个RYR2错义变体中，有55个（16.9％）先前与疾病相关的变体被重新分类为良性。超过140,000个控件的gnomAD数据库的应用允许比ExAC数据库更多地对11个变体进行重新分类。CPVT相关的RYR2变体主要在氨基酸位置3949-4332和4867-4967以及RyR和IP3R同源相关和离子转运域之间聚集（p <0.005）。与对照组相比，CPVT相关的RYR2变体出现在更保守的氨基酸位置，与猝死相关的变体具有更高的保守评分（p <0.005）。与睡眠中突然死亡相关的五个潜在致病性RYR2变体几乎完全位于该蛋白质的C端。结论，控制序列数据库有助于RYR2变体的重新分类，但是大多数仍为VUS。值得注意的是，RYR2中的致病变异与睡眠中的死亡有关。
更新日期：2020-04-24
中文翻译：
儿茶酚胺能性多形性室性心动过速患者中RYR2错义变异的分类和相关性揭示了表型关系。
儿茶酚胺能性多形性室性心动过速（CPVT）主要是由心脏瑞丹碱受体RYR2中的杂合错义变体引起的。但是，许多RYR2错义变体被分类为不确定重要性（VUS）的变体。我们根据2015年美国医学基因组学学会指南，系统地重新评估了健康个体和CPVT或心律失常患者的所有RYR2变异。RYR2变体由NW基因组实验室中心从已发表的文献和序列变体数据库中鉴定。根据次要等位基因频率，计算机预测工具和功能研究评估对每种变异进行评估，并根据ACMG-AMP指南进行分类。表型数据在可用的地方进行整理。在326个RYR2错义变体中，有55个（16.9％）先前与疾病相关的变体被重新分类为良性。超过140,000个控件的gnomAD数据库的应用允许比ExAC数据库更多地对11个变体进行重新分类。CPVT相关的RYR2变体主要在氨基酸位置3949-4332和4867-4967以及RyR和IP3R同源相关和离子转运域之间聚集（p <0.005）。与对照组相比，CPVT相关的RYR2变体出现在更保守的氨基酸位置，与猝死相关的变体具有更高的保守评分（p <0.005）。与睡眠中突然死亡相关的五个潜在致病性RYR2变体几乎完全位于该蛋白质的C端。结论，控制序列数据库有助于RYR2变体的重新分类，但是大多数仍为VUS。值得注意的是，RYR2中的致病变异与睡眠中的死亡有关。
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