Growing Pains in Cardiovascular Genetics.
Growing Pains in Cardiovascular Genetics.
复制标题
心血管遗传学中的“成长的烦恼”。
DOI：
10.1161/circulationaha.118.035933
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发表时间：
2018
期刊：
影响因子：
37.8
通讯作者：
Roden,DanM
中科院分区：
文献类型：
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作者：
Roden,DanM
半个多世纪以前，心脏病专家——当时还没有经过专业认证的心脏病专家——开始报告一些不寻常的表型，比如QT间期过长或左心室异常肥厚，这些都是家族遗传的，会导致年轻人猝死。在20世纪80年代和90年代，在大家庭中进行的连锁分析确定了第一批疾病基因，具有里程碑意义的发现对于理解心脏的基本生理和病理生理过程至关重要，为家庭提供咨询，定义通常不完整的外显率，以及识别在这些第一批疾病基因中编码区变异缺失的表型阳性患者。在这些患者中，早期严格的基于连锁的研究确定的疾病途径暗示了介导这些心血管遗传表型的新候选基因。因此，例如，一旦β-肌球蛋白重链突变在肥厚性心肌病中被识别出来，编码其他收缩蛋白的基因就成为合乎逻辑的候选者；同样，离子通道基因或修饰因子是致心律失常右室心肌病的通道病变和桥粒体蛋白的候选基因。因此，我们现在有了一长串主要心血管遗传疾病的致病基因，测序成本和效率的显著提高使基于面板的测序得到了广泛应用。尽管这些进步改善了对受影响患者及其家属的护理，但最新一期《循环》杂志上的2篇论文强调了在大量患者群体中越来越多地使用这些面板的逻辑上的潜在缺陷。
More than half a century ago, heart specialists—there were no board-certified cardiologists yet—began to report unusual phenotypes like very long QT intervals or extraordinary left ventricular hypertrophy that ran in families and caused sudden death in the young. In the 1980s and 90s, linkage analysis in large families identified the first disease genes, landmark discoveries that have been critical for understanding basic physiological and pathophysiological processes in the heart, counseling families, defining penetrance that is so often incomplete, and identifying phenotype-positive patients in whom coding region variants in these first disease genes were absent. In those patients, disease pathways defined by early rigorous linkage-based studies implicated new candidate genes for mediating these cardiovascular genetic phenotypes. So, for example, once β-myosin heavy chain mutations were identified in hypertrophic cardiomyopathy, genes encoding other contractile proteins became logical candidates; similarly, ion channel genes or modifiers were candidates in channelopathies and desmosomal proteins in arrhythmogenic right ventricular cardiomyopathy. As a result, we now have long lists of disease genes for major cardiovascular genetic diseases, and dramatic improvements in sequencing costs and efficiencies have enabled widespread application of panelbased sequencing. Although these advances have improved care of affected patients and their families, 2 papers in the current issue of Circulation1, 2 highlight potential flaws in the logic that underlies increasing use of these panels across large patient populations.