Pandora will never regret having opened her box: reappraisal of genes associated with CPVT and SQTS
Pandora will never regret having opened her box: reappraisal of genes associated with CPVT and SQTS
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潘多拉永远不会后悔打开了她的盒子：重新评估与 CPVT 和 SQTS 相关的基因
DOI：
10.1093/eurheartj/ehab794
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Ai T.
中科院分区：
文献类型：
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作者：
Horie M;Ohno S;Ai T.
在2015年美国医学遗传学和基因组学学院（ACMG）时代之前，1通过高通量测序鉴定的遗传变异由没有评分系统的个体实验室解释。临床基因组资源（ClinGen）由国家人类基因组研究所建立，旨在建立一个中央公共资源，以根据ACMG指南定义基因-疾病关联和变异解释。1-3评分系统由两部分组成：为了区分真实的致病变异与非显著的遗传噪声，首先进行详细的家族级联遗传分析，揭示家族成员间基因型-表型的共分离，确认所述特定临床特征与所述变体的存在相关。经典的连锁分析就是基于这一概念。其次，可以通过采用疾病模型，如基因工程动物和从患者来源的诱导多能干细胞（iPS）分化的心肌细胞，实验评估由变异体引起的功能结果。最近，通过使用基于CRISPR/Cas9的基因编辑技术，高通量功能测定已经成为可能，该技术提供了深度突变扫描方法。[4]在这方面，虽然电生理学方法是传统的，而且有点过时，但它可以用于研究大多数遗传性心脏病，因为它们大多数是离子通道病。负责编码调节心肌兴奋-收缩的蛋白质的基因。这些基因的变体表现出功能的丧失或获得，这反过来又破坏了正常心律的产生。值得庆幸的是，由于40多年前发明的膜片钳技术，我们有更多关于遗传性心律失常基因的出版物，而不是其他心脏疾病。最后，我们可以使用计算机预测分析软件供公众使用。最近，一种新型的统计遗传分析方法正在整合所有先证者和家族成员的所有临床和遗传数据，为变异注释提供了一种有前途的方法。6基于RyR 2的冷冻电子显微镜3D结构，计算机分析也可能有希望用于估计RYR 2变体的功能。7
Before the era of the American College of Medical Genetics and Genomics (ACMG) 2015, 1 genetic variants identified by highthroughput sequencing were interpreted by individual laboratories without scoring systems. The Clinical Genome Resource (ClinGen) was founded by the National Human Genome Research Institute to build a central public resource to define gene–disease association and variant interpretation based upon the ACMG guidelines. 1–3 The scoring system is composed of two parts: genetic evidence including the number of probands and segregations, and experimental functional evidence including in vitro, in vivo, and in silico data.In order to distinguish a real pathogenic variant from nonsignificant genetic noise, first a detailed familial cascade genetic analysis reveals the co-segregation of genotype–phenotype among family members, confirming that the specific clinical features are associated with the presence of the variant. The classical linkage analysis is based on this concept. Second, functional outcomes caused by the variant can be experimentally assessed by employing the disease model, such as genetically engineered animals and cardiomyocytes differentiated from patient-derived induced pluripotent stem (iPS) cells. More recently, high-throughput functional assays have become possible by using CRISPR/Cas9-based gene editing technology which offers deep mutational scanning approaches. 4 In this regard, though conventional and slightly old fashioned, the electrophysiological method can be employed for the study of most inherited cardiac arrhythmic disorders because most of them are ion channelopathies. The genes responsible encode the proteins regulating myocardial excitation–contraction. The variants of these genes show loss or gain of function, which in turn disrupts the generation of normal heart rhythm. Thankfully, due to the patch–clamp technique, 5 which was invented> 40 years ago, we have more publications available on genes causative for inherited arrhythmias than other cardiac disorders. Finally, we have access to an in silico prediction analysis software for public use. More recently, a novel type of statistical genetic profiling is integrating all clinical and genetic data from all probands and family members, offering a promising approach for variant annotation. 6 Based on the cryo-electron microscopy 3D structure of RyR2, in silico analysis may also be promising for the estimation of the function of RYR2 variants. 7