Genotype-Phenotype Discordance in Long QT Syndrome

长 QT 综合征的基因型-表型不一致

• 批准号: 8766406
• 负责人: Isabelle Deschenes
• 金额: $ 57.49万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766406
• 关键词: Accounting; Action Potentials; Affect; Arrhythmia; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cells; Cessation of life; Clinical; Clinical Management; Complex; Data; Defect; Defibrillators; Disease; Electrocardiogram; Engineering; Environment; Event; Family; Family member; Fathers; Fingerprint; GTPase Gene; Gene-Modified; Genes; Genetic; Genome; Genotype; Heart; Heart Atrium; Human; Implant; In Vitro; Incidence; Individual; Inheritance Patterns; Inherited; Intervention; Ion Channel; Long QT Syndrome; Membrane; Methods; Missense Mutation; Modeling; Muscle Cells; Mutation; Pathology; Patients; Penetrance; Phenotype; Physiological; Potassium; Potassium Channel; Predisposition; Process; Property; Proteins; Research Proposals; Risk; Son; Symptoms; System; Testing; Transfection; Universities; Variant; Ventricular; Ventricular Arrhythmia; Work; clinical phenotype; disease-causing mutation; exome sequencing; genetic variant; high risk; induced pluripotent stem cell; insight; multidisciplinary; mutation carrier; novel; nuclease; public health relevance; sudden cardiac death; trafficking; trait

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.

描述（由申请人提供）：心脏猝死（SCD）是一项灾难性事件，在美国每年最多可造成450,000人死亡。在SCD高风险的患者中，有遗传性心律不齐的患者。长QT综合征（LQT）是一组遗传性心律失常的一个例子，该心律失常会在心脏膜电流中产生缺陷。直接结果，LQTS与ECG上的QT间隔延长有关，心律不齐以及SCD的发生率增加。在LQTS2中，在编码HERG的KCNH2基因中已经确定了超过两百个错义突变，而绝大多数被认为是蛋白质加工和运输缺陷的特征，导致钾流量急剧减少。但是，正如许多在许多常染色体显性心脏通道病中所观察到的那样，这些患者的遗传和临床表型的模式很复杂，并且通常表现出不完全的渗透率，在这种情况下，疾病引起的突变载体是无症状的。这种可变临床表达性的原因尚不清楚，但在本研究建议中，我们将通过测试修饰符基因有助于可变临床表达性的假设来研究这个问题。我们在Metrohealth和Case Western Reserve University的多学科小组在临床上学习，并在体外携带了一个大型的“ Cleveland” LQT2家族，携带HERG突变R752W。在研究的101名家庭成员中，有26个人带有HERG R752W突变。然而，只有5个受遗传影响的家庭成员中存在症状性LQT，因此说明了疾病不完全的外观。我们假设改变疾病的基因的存在可以解释该LQT2家族中观察到的基因型 - 表型不一致。在此提案中，我们将使用与患者衍生的诱导多能干细胞（IPS）区分的外显子体测序和心肌细胞（IPS）区分的外显子体测序和心肌细胞来阐明该LQT2家族中不完全渗透的机制。我们假设患者衍生的IPS分化的心肌细胞（IPS-CM）忠实地概括了仲虫病理学，而迄今为止，外来测序揭示的迄今未知的候选基因揭示了可变的表型渗透率。该提案的目的是：1。确定候选修饰符基因，导致LQT2家族中不完全渗透。 2。阐明源自LQT2家族成员的人类心肌细胞的电生理变异性。 3。确定修饰基因变异的候选疾病的表型。我们将通过研究显示不一致的临床表型的密切相关的LQT2 HERG R752W载体对（即父子和SIB对）来执行这些目标。我们认为，当前的提案将提供一个基本的机械解释，在大型LQT2家族中可能会出现基因型 - 表型不一致。这对个性化的临床管理具有潜在的重大影响，并将为旨在调节心脏功能失调的离子通道的个性化药理干预提供新的目标。