Resolving Incomplete Penetrance in the Cardiomyopathies and Channelopathies

描述（由申请人提供）：心肌病（CMPs）和通道病（CLPs）是使心脏肌肉和传导系统衰弱的遗传性疾病，在美国总共影响超过100万患者，并可导致心力衰竭和心源性猝死。虽然有些CMP/CLPs是偶然出现的，但许多CMP/CLPs表现出强烈的家族遗传模式。基因检测将CMP/CLP基因的知识应用于患者及其家属的护理。在任何一个病人身上，如果一个人知道导致他们病情的实际突变，他就可以很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治疗。值得注意的是，尽管在许多情况下，我们确切地知道哪个突变导致了特定家庭的疾病，但在预测特定个体可能发生的情况时，我们往往无能为力。并非所有遗传突变的个体都会患上某种疾病，这种现象被称为不完全外显。它不仅影响cmp和clp，而且影响几乎所有的遗传性疾病。不完全外显率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。虽然这是一个概念上令人满意的解释，但它对评估患者的风险帮助不大。即使在这种高度遗传的疾病中，这种准确预测的失败也会产生实际后果，例如在决定植入除颤器或推荐等治疗方法时，这些治疗方法本身就存在重大风险。在本提案中，我描述了一种逐步开始解决cmp / clp中不完全外显率的方法。我首先确定了人群中哪些基因变异可能会改变cmp和clp的疾病严重程度。这一步骤需要利用大规模并行基因组技术的显著进展，在这种技术中，可以一次询问成千上万的变异，以了解它们对调节基因活动的影响。有了这个变异目录，人们就可以建立检测方法来评估患者在基因组中每个位置的状态，并确定潜在的因果突变的识别。最后一步是观察实际的CMP/CLP患者，并确定修改遗传变异的知识是否有助于预测谁可能发展为严重疾病，谁将有较轻的病程。

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.