Genotype-Phenotype Discordance in Long QT Syndrome

描述（由申请人提供）：心源性猝死（SCD）是一种灾难性事件，在美国每年导致多达450，000人死亡。SCD高危患者中有遗传性心律失常。长QT综合征（LQTS）是一组遗传性心律失常的一个例子，它会导致心脏膜电流的缺陷。作为直接结果，LQTS与ECG上QT间期延长、室性心律失常和SCD发生率增加相关。在LQTS 2中，已在编码hERG的KCNH 2基因中鉴定出超过200个错义突变，其中绝大多数被认为以蛋白质加工和运输缺陷为特征，导致钾电流急剧减少。然而，如在许多常染色体显性心脏通道病中常见的，这些患者的遗传模式和临床表型是复杂的，并且通常显示不完全的遗传，其中致病突变携带者是无症状的。这个变量的临床表现力的原因还没有很好地理解，但在本研究建议，我们将调查这个问题，通过测试的假设，修饰基因有助于变量的临床表现力。我们在MetroHealth和凯斯西储大学的多学科小组在临床和体外研究了一个携带hERG突变R752 W的大型“克利夫兰”LQT 2家族。在研究的101名家庭成员中，有26人携带hERG R752 W突变。然而，有症状的LQTS仅存在于5个遗传受影响的家庭成员中，从而说明该疾病的不完全消退。我们假设疾病修饰基因的存在可以解释在LQT 2家族中观察到的基因型-表型不一致性。在这个提议中，我们将使用外显子组测序和从患者来源的诱导多能干细胞（iPS）分化的心肌细胞来阐明LQT 2家族中不完全逆转录的机制。我们假设患者来源的iPS分化的心肌细胞（iPS-CM）忠实地再现了致心律失常的病理学，并且迄今为止未知的候选基因通过外显子组测序揭示了可变的表型心律失常。本提案的目的是：1.鉴定LQT 2家族中负责不完全转录的候选修饰基因。2.阐明源自LQT 2家族成员的人心肌细胞的电生理学变异性。3.确定候选疾病修饰基因变体的表型。我们将通过研究表现出不一致临床表型的密切相关的LQT 2 hERG R752 W载体对（即父亲/儿子和同胞对）来实现这些目标。我们相信，目前的建议将提供一个基本的，机械的解释，基因型-表型不一致，可以出现在一个大的LQT 2家族。这对个性化临床管理具有潜在的重大影响，并将为旨在调节心脏中功能失调的离子通道的个性化药物干预提供新的靶点。

DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) is a catastrophic event that accounts for up to 450,000 deaths each year in the US. Among patients at high risk for SCD are those with inherited cardiac arrhythmias. Long QT syndrome (LQTS) is one example of a group of inherited cardiac arrhythmias that produces defects in cardiac membrane currents. As a direct consequence, LQTS has been associated with prolongation of the QT interval on the ECG, ventricular arrhythmias, and an increased incidence of SCD. In LQTS2 well over two hundred missense mutations have been identified in the KCNH2 gene encoding hERG with the overwhelming majority thought to be characterized by protein processing and trafficking defects leading to a drastic reduction in potassium currents. However, as commonly observed in many autosomal dominant cardiac channelopathies the pattern of inheritance and clinical phenotypes of these patients are complex and often display incomplete penetrance, where disease-causing mutation carriers are asymptomatic. The causes for this variable clinical expressivity are not well understood but in the present research proposal, we will investigate this question by testing the hypothesis that modifier genes contribute to the variable clinical expressivity. Our multidisciplinary group at MetroHealth and Case Western Reserve University has studied clinically as well as in vitro a large 'Cleveland' LQT2 family carrying the hERG mutation R752W. Out of the 101 family members studied, 26 individuals carried the hERG R752W mutation. However, symptomatic LQTS was present in only 5 of the genetically affected family members thus illustrating incomplete penetrance of the disease. We hypothesize that the presence of disease modifying genes can explain the genotype-phenotype discordance observed in this LQT2 family. In this proposal, we will elucidate the mechanisms of incomplete penetrance in this LQT2 family using exome sequencing and cardiomyocytes differentiated from patient derived induced pluripotent stem cells (iPS). We hypothesize that patient-derived iPS differentiated cardiomyocytes (iPS-CM) faithfully recapitulate the arrythmogenic pathology and that heretofore unknown candidate genes revealed by exome sequencing account for variable phenotypic penetrance. The aims of this proposal are: 1. Identify candidate modifier genes responsible for incomplete penetrance in a LQT2 family. 2. Elucidate electrophysiological variability of human cardiomyocytes derived from LQT2 family members. 3. Determine the phenotype of candidate disease modifying gene variants. We will perform these aims by studying closely related LQT2 hERG R752W carrier pairs (i.e. father/son and sib pair) that display discordant clinical phenotype. We believe that the current proposal will offer a fundamental, mechanistic explanation by which genotype-phenotype discordance can arise in a large LQT2 family. This holds potentially significant ramifications for personalized clinical management and will offer novel targets for personalized pharmacologic intervention aimed at the modulation of dysfunctional ion channels in the heart.