From the Stanford Cardiovascular Institute (J.C.W., P.G.).
Department of Medicine, Division of Cardiology, Stanford University School of Medicine (J.C.W., P.G.).
Circ Res. 2019 Aug 30;125(6):653-658. doi: 10.1161/CIRCRESAHA.119.315209. Epub 2019 Aug 29.
Long-QT syndrome, a frequently fatal inherited arrhythmia syndrome caused by genetic variants (congenital) or drugs (acquired), affects 1 in 2000 people worldwide. Its sentinel event is often sudden cardiac death, which makes preclinical diagnosis by genetic testing potentially life-saving. Unfortunately, clinical experience with genetic testing has shown that it is difficult to correctly identify genetic variants as disease causing. These current deficiencies in accurately assigning pathogenicity led to the discovery of increasing numbers of rare variants classified as variant of uncertain significance. To overcome these challenges, new technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) genome editing can be combined with human induced pluripotent stem cell-derived cardiomyocytes to provide a new approach to decipher pathogenicity of variants of uncertain significance and to better predict arrhythmia risk. To that end, the overarching goal of our network is to establish the utility of induced pluripotent stem cell-based platforms to solve major clinical problems associated with long-QT syndrome by determining how to (1) differentiate pathogenic mutations from background genetic noise, (2) assess existing and novel variants associated with congenital and acquired long-QT syndrome, and (3) provide genotype- and phenotype- guided risk stratification and pharmacological management of long-QT syndrome. To achieve these goals and to further advance the use of induced pluripotent stem cells in disease modeling and drug discovery, our team of investigators for this Leducq Foundation Transatlantic Networks of Excellence proposal will work together to (1) improve differentiation efficiency, cellular maturation, and lineage specificity, (2) develop new assays for high throughput cellular phenotyping, and (3) train young investigators to clinically implement patient-specific genetic modeling.
长 QT 综合征是一种常见的致命遗传性心律失常综合征，由基因突变（先天性）或药物（获得性）引起，全球每 2000 人中就有 1 人受到影响。其标志性事件通常是心脏性猝死，这使得通过基因检测进行临床前诊断具有潜在的救生作用。不幸的是，基因检测的临床经验表明，很难正确识别致病的基因突变。这些目前在准确确定致病性方面的缺陷导致越来越多的被归类为意义不明的变异的罕见变异的发现。为了克服这些挑战，可以将新技术（如成簇规律间隔短回文重复序列（CRISPR）基因组编辑）与人类诱导多能干细胞衍生的心肌细胞相结合，为破译意义不明的变异的致病性并更好地预测心律失常风险提供新方法。为此，我们网络的总体目标是建立基于诱导多能干细胞的平台的实用性，通过确定如何（1）区分致病性突变与背景遗传噪声，（2）评估与先天性和获得性长 QT 综合征相关的现有和新型变异，以及（3）提供基因型和表型指导的长 QT 综合征风险分层和药理学管理，以解决与长 QT 综合征相关的主要临床问题。为了实现这些目标并进一步推进诱导多能干细胞在疾病建模和药物发现中的应用，我们的这个莱杜克基金会跨大西洋卓越网络提案的研究团队将共同努力：（1）提高分化效率、细胞成熟度和谱系特异性，（2）开发用于高通量细胞表型分析的新测定法，以及（3）培训年轻研究人员以临床实施患者特异性基因建模。
