Long QT Syndrome: Population, Genetic & Cardiac Studies

描述(申请人提供)：这项拟议的研究是一项多学科、多中心的合作研究，旨在继续研究长QT综合征(LQTS)的临床、心脏和遗传学方面的问题。LQTS是一种遗传性通道病，具有延迟的心室复极，并以晕厥和猝死表现为发作性恶性心律失常。目前，已经在LQTS中发现了6个离子通道基因(KCNQ1、HERG、SCNhA、MINK、MIRP1和KCNJ2)上的300多个突变。这项为期五年的研究活动将：1)继续升级、扩大和收集目前在LQTS注册中心登记的900个LQTS活跃家庭(5,508个活跃家庭成员)的临床和遗传学数据；2)开发一个使用不同时间来源(从出生，以及从10岁、20岁和40岁)的多变量预后风险评分系统；3)评估LQTS疗法的有效性和局限性；以及4)扩大对LQTS基因-表型关系的调查。从功能上讲，该拨款包括四个部分：临床部分，涉及六个已在注册中心登记并正在积极跟踪LQTS家族的临床中心；基因部分，涉及四个经验丰富的分子遗传实验室；生物统计学部分，将提供研究设计和统计数据分析方面的专业知识；以及中央协调和数据中心，将提供数据管理和计划各个组成部分的协调。这一综合研究计划在以下方面提供了巨大的前景：1)改善LQTS患者的诊断、管理和治疗；2)为患有广泛心脏疾病的患者提供与复极相关的心律失常的分子基础的基本了解。

DESCRIPTION (provided by applicant): The proposed research is a multidisciplinary, multicenter, collaborative study to continue the investigation of the clinical, cardiac, and genetic aspects of the Long QT Syndrome (LQTS) - a heritable channelopathy with delayed ventricular repolarization and episodic malignant arrhythmias manifest by syncope and sudden death. Presently, over 300 mutations on 6 ion-channel genes (KCNQ1, HERG, SCNhA, minK, MIRP1, and KCNJ2) have been identified in LQTS. The five-year research activity will: 1) continue to upgrade, expand, and collect clinical and genetic data on 900 active LQTS families (5,508 active family members) currently enrolled in the LQTS Registry; 2) develop a multivariate prognostic risk-scoring system using different time origins (from birth, and from age 10, 20, and 40 years); 3) evaluate the effectiveness and limitations of LQTS therapies; and 4) expand investigations into LQTS genotype-phenotype relationships. Functionally, the grant has four sections: a clinical section involving six clinical centers that have enrolled and are actively following the LQTS families in the Registry; a genotype section involving four experienced molecular genetic laboratories; a biostatistical section that will provide expertise in study design and statistical data analyses; and a central coordination and data center that will provide data management and coordination of the various components of the program. This integrated research program offers a substantial prospect of: 1) improving the diagnosis, management, and treatment of individuals affected with LQTS; and 2) providing a fundamental understanding of the molecular basis of repolarization-related cardiac arrhythmias in patients with a broad spectrum of cardiac disorders.