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

项目摘要/摘要 现在，测序个人基因组的成本比许多常规医疗程序都要低。由此产生的愿景是 每个人都将在生命的早期进行基因组测序，以实现个性化的医疗建议 疾病预防和药物选择。然而，这一愿景的一个主要问题是正确解释 发现了数量惊人的新奇和稀有的变种。在其他情况下，新的诊断测试可以是 在比较有和没有障碍的大量人群的研究中进行基准和验证以确定 积极结果的预测价值。然而，在基因测序的背景下，对大多数人来说，阳性测试 变异不能应用于足够多的杂合子个体，以确定与疾病的关联。 KCNH2(又名：KCNH2)致病变异体HERG基因--心肌细胞关键的钾通道基因 复极)可导致年轻人心源性猝死，并使携带者易受药物诱发 心律不齐。KCNH2的遗传变异导致了~6%的尸检阴性突然原因不明 青壮年死亡占婴儿猝死综合征病例的1%左右。此外，在杂合子中 KCNH2基因变异携带者，女性发生严重事件(包括心脏骤停)的总体风险更大 死亡)，产后增加。因为KCNH2中大多数与疾病相关的变异是 罕见的完整外显子组测序有可能在生命早期发现风险更高的个体，而不是 表型表现。然而，即使在KCNH2变异体的杂合子携带者中，也肯定与 对于疾病，并不是所有人都表现出相同的表型。 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 建议使用以下工具合并各种人口、功能、计算和隔离数据的标准 有几个描述了启发式方法。我们的基本假设是临床上有意义的知识丢失了 将这些变种特有的数据压缩成二分分类。来调查这件事 假设，我们将前瞻性地生成KCNH2中所有错义变体的体外数据，建立预测 疾病外显性模型，并验证结果预测对心律失常和 在电子医疗记录和基因组学网络(Emerge)中观察到的变异的心脏事件，a Leducq Transatlantic Network和英国生物库。

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.