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）：心源性猝死 (SCD) 是一种灾难性事件，在美国每年导致多达 45 万人死亡。患有遗传性心律失常的患者属于 SCD 高危患者。长 QT 综合征 (LQTS) 是一组导致心脏膜电流缺陷的遗传性心律失常的一个例子。作为直接后果，LQTS 与心电图 QT 间期延长、室性心律失常和 SCD 发病率增加有关。在 LQTS2 中，编码 hERG 的 KCNH2 基因中已鉴定出超过 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，正如在许多常染色体显性心脏通道病中常见的那样，这些患者的遗传模式和临床表型很复杂，并且经常表现出不完全外显率，其中致病突变携带者无症状。这种可变临床表达性的原因尚不清楚，但在目前的研究计划中，我们将通过检验修饰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 和凯斯西储大学的多学科小组对携带 hERG 突变 R752W 的大型“克利夫兰”LQT2 家族进行了临床和体外研究。在研究的 101 名家庭成员中，有 26 人携带 hERG R752W 突变。然而，只有 5 名受遗传影响的家庭成员出现有症状的 LQTS，因此说明该疾病的外显率不完全。我们假设疾病修饰基因的存在可以解释在该 LQT2 家族中观察到的基因型-表型不一致。在本提案中，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该 LQT2 家族不完全外显的机制。我们假设患者来源的 iPS 分化心肌细胞 (iPS-CM) 忠实地再现了致心律失常的病理学，并且外显子组测序揭示的迄今为止未知的候选基因解释了可变的表型外显率。该提案的目的是： 1. 确定导致 LQT2 家族不完全外显的候选修饰基因。 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 LQT2 hERG R752W 携带者对（即父/子和同胞对）来实现这些目标。我们相信，当前的提案将为大型 LQT2 家族中可能出现的基因型-表型不一致提供基本的机制解释。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功能失调的离子通道的个性化药物干预提供新的目标。