Resolving Incomplete Penetrance in the Cardiomyopathies and Channelopathies

描述(申请人提供)：心肌病(CMPS)和通道病(CLP)是衰弱的心肌和传导系统遗传性疾病，在美国总共影响100多万患者，可导致心力衰竭和心脏性猝死。虽然一些CMP/CLP是零星发生的，但许多表现出很强的家族遗传模式。基因检测将对CMP/CLP基因的了解应用于患者及其家人的护理。在任何给定的患者中，如果一个人知道导致他们病情的实际突变，就可以非常容易地确定其他家庭成员是否携带这种突变，从而促进仔细的监测和潜在的预防性治疗。值得注意的是，尽管在许多情况下，我们确切地知道是哪种突变导致了特定家庭的疾病，但在预测某个特定的个体可能会发生什么时，我们往往能做的很少。这种现象，即并不是所有遗传突变的人都会患上疾病，这种现象称为不完全外显。它不仅影响中医和慢性前列腺炎，而且几乎影响所有遗传性疾病。不完全外显被归因于基因和环境之间复杂的相互作用，因此许多修饰影响可以影响疾病的严重程度。尽管这在概念上是一个令人满意的解释，但它对评估患者的风险几乎没有帮助。即使是在这种高度可遗传的疾病中，这种准确预测的失败也会产生真正的实际后果，比如在决定植入除颤器或推荐等疗法时，这些疗法本身就有很大的风险。在这项建议中，我描述了一种循序渐进的方法来开始解决CMPS/CLP中的不完全外显。我首先确定人类群体中的哪些基因变异可能会改变中医和CLP的疾病严重程度。这一步需要利用大规模并行基因组技术的显著最新进展，在这种技术中，数万种变异可以同时被询问它们对调控基因活动的影响。有了这个变异目录，人们就可以建立分析来评估基因组中每个这些位置的患者的状态，以及确定潜在的因果突变的识别(S)。最后一步也是观察实际的CMP/CLP患者，并确定修改基因变异的知识是否有助于预测谁可能患上严重疾病，谁的病程较轻。

DESCRIPTION (provided by applicant): Cardiomyopathies (CMPs) and channelopathies (CLPs) are debilitating inherited diseases of the heart muscle and conduction system, which collectively affect well over one million patients in the United States, and can lead to heart failure and sudden cardiac death. Although some CMP/CLPs arise sporadically, many show a strong pattern of familial inheritance. Genetic testing applies knowledge of CMP/CLP genes towards the care of patients and their family members. In any given patient, if one knows the actual mutation responsible for their condition, one can very easily determine if other family members carry it, thereby facilitating careful surveillance and potential preventive therapies. Remarkably, despite knowing in many cases exactly which mutation causes the diseases in a given family, we can often do very little when it comes to predicting what is likely to befall a specific individual. This phenomenon, where not all individuals who inherit a mutation actually develop a disease is known as incomplete penetrance. It affects not only CMPs and CLPs, but nearly all inherited disease. Incomplete penetrance has been ascribed to the complex interplay between genes and environment, so that many modifying influences can influence the severity of the disease. Although this represents a conceptually satisfying explanation, it does little to help assess risk in patients. This failure of accurate prognostication, even in such highly heritable diseases, has real practical consequences, such as when it comes to deciding on such therapies as implantation of a defibrillator or recommendation, which themselves carry significant risk. In this proposal, I describe a stepwise approach to beginning to resolve incomplete penetrance in CMPs/CLPs. I first identify which genetic variants in the human population are likely to modify severity of disease in the CMPs and CLPs. This step requires harnessing remarkable recent advances in massively parallel genomic technology, where tens of thousands of variants can be interrogated at once for their effect on regulating gene activity. With this catalogue of variants in hand, one can build assays to assess the status of patients at each of these positions in the genome, as well as determine the identify of the underlying causal mutation(s). The final step is too look at actual CMP/CLP patients, and determine whether knowledge of modifying genetic variation can help predict who is likely to develop severe disease, and who will have a milder course.