Integrating KCNH2 Variant-Specific Features and Heterozygote Phenotypes to Estimate Long QT Penetrance

项目概要/摘要 测序一个人的基因组现在比许多常规的医疗程序花费更少。由此产生的愿景是 每个人都将在生命早期进行基因组测序， 疾病预防和药物选择。然而，这一愿景的一个主要问题是对 大量发现的新的和罕见的变体。在其他情况下，可以使用新的诊断测试。 在比较有和没有疾病的大人群的研究中进行基准和验证，以确定 阳性结果的预测值。然而，在基因测序的背景下， 变体不能应用于足够的杂合个体以确定与疾病的关联。 KCNH 2中的致病性变体（a.k.a.心肌细胞关键钾通道基因hERG 复极）可导致年轻人心脏性猝死，并使携带者易患药物诱导的 心律不齐KCNH 2的遗传变异导致约6%的尸检阴性突发不明原因 婴儿猝死综合征病例中约有1%。此外，在杂合子中， KCNH 2变异携带者，女性发生严重事件（包括突发性心脏病）的总体风险更高。 死亡），这是在产后期间增加。由于KCNH 2中的大多数疾病相关变体是 罕见的全外显子组测序有可能在生命早期识别出那些风险更大的个体， 表现型。然而，即使在KCNH 2变异的杂合子携带者中， 在疾病中，并不是所有人都发展出相同的表型。 为了应对变异解释的挑战，美国医学遗传学和基因组学学院 建议标准，以纳入变异人口，功能，计算和分离数据，使用 几个描述了化学。我们的基本假设是，临床上有意义的知识丢失 在将这些变体特异性数据压缩为二分分类中。调查这一 假设，我们将前瞻性地生成KCNH 2中所有错义变体的体外数据， 模型的疾病发病率，并验证由此产生的预测对心律失常的发病率， 在电子病历和基因组学网络（eMERGE）中观察到的变异体的心脏事件， Leducq跨大西洋网络和英国生物银行。

PROJECT SUMMARY/ABSTRACT Sequencing an individual’s genome now costs less than many routine medical procedures. A resulting vision is that everyone will have their genome sequenced early in life to enable individualized medical advice about disease prevention and drug selection. A major concern with this vision, however, is proper interpretation of the overwhelming volume of discovered novel and rare variants. In other contexts, a new diagnostic test can be benchmarked and validated in studies that compare large populations with and without a disorder to determine the predictive value of a positive result. In the genetic sequencing context, however, a positive test for most variants cannot be applied to enough heterozygous individuals for a definitive association with disease. Pathogenic variants in KCNH2 (a.k.a. hERG, a cardiac potassium channel gene critical for cardiomyocyte repolarization) can cause sudden cardiac death in the young and can predispose carriers to drug-induced arrhythmias. Genetic variants in KCNH2 are responsible for ~ 6% of autopsy-negative sudden unexplained death in the young and ~ 1% of sudden infant death syndrome cases. Additionally, among heterozygous carriers of variants in KCNH2, women are at greater overall risk of a severe event (including sudden cardiac death) which is increased in the postpartum period. Since most disease-associated variants in KCNH2 are rare, full exome sequencing has the potential to identify those individuals at greater risk early in life before any phenotype manifests. However, even among heterozygous carriers of KCNH2 variants definitively associated with disease, not all develop the same phenotype. To address the challenge of variant interpretation, the American College of Medical Genetics and Genomics suggests criteria to incorporate variant population, functional, computational, and segregation data using several described heuristics. Our foundational hypothesis is that clinically meaningful knowledge is lost in the compression of these variant-specific data to a dichotomous classification. To investigate this hypothesis, we will generate in vitro data for all missense variants in KCNH2 prospectively, build a prediction model of disease penetrance, and validate resulting predictions against the incidence of arrhythmias and cardiac events for variants observed in the Electronic Medical Records and Genomics Network (eMERGE), a Leducq Transatlantic Network, and the UK Biobank.