Investigating the Genotype-Phenotype Relationships that Underlie Congenital Disorders with Cardiovascular Symptoms through Population-scale Analyses

项目摘要/摘要 孟德尔病虽然个别罕见，但总体上是常见的。近1%的人有 可以追溯到单个基因的医学状况。这一点对于患有 心血管疾病。基因检测现已普遍应用于临床实践。因此，它已经 很明显，我们对基因突变是如何导致孟德尔病的理解并不完整。 一些带有有害基因突变的患者表现出非常严重的症状，而另一些患者几乎完全是 不受影响。即使是像马凡这样具有严重心血管症状的儿童期起病的疾病也是如此 综合症。了解疾病严重程度的范围对诊断、预后、 和管理。过去，人们使用队列研究和案例系列来收集这类信息， 但这些产生了关于疾病异质性的不完整和有偏见的观点。因此，研究的新方法 孟德尔病的遗传和表型多样性是迫切需要的。 人口规模的生物库链接到电子健康记录(EHR)可以提供一个较少偏见的观点 基因型与表型的关系。受试者被包括在这些数据集中，而不管他们的医疗状况如何 历史。EHR数据还提供了每个受试者的详细表型信息。最后，这些生物库现在 包括数十万个个体，以前所未有的规模捕捉罕见的基因变异。作为一名 结果，我们假设种群规模的生物库可以提供对基因型到表型的新见解。 先天性心血管综合征(CCSS)的潜在关系。这一假设将分两个阶段进行检验。 明确的目标。在目标1中，我们将使用生物库来开发可重复总结CCS的量化分数- 相关表型严重程度。这些特征有多种用途。在目标2中，我们将使用它们来构建 直接从序列预测CCS相关稀有变异体表型效应的计算模型 背景。一旦得到验证，这些模型应该会减少临床实践中的诊断不确定性。 我是一名临床遗传学家和内科科学家，致力于提高医疗保健的质量 提供给孟德尔病患者。从长远来看，我计划开发一个独立的研究计划， 使用复杂的临床和基因数据集来提高我们对孟德尔疾病风险、变异性、 和进步。我的K38研究提案与这些目标完全一致。此外，它还将提供 有价值的职业发展。将获得电子病历数据分析和统计遗传学方面的新技术技能， 学术技能也是如此，比如写助学金。在颁奖期间，我将得到以下领域的领导人的指导 生物医学数据科学和人类遗传学，包括Atul Butte博士和Neil Risch博士。最后，K38 该奖项将成为未来资助机会和研究独立性的跳板。因此， K38 STARRTS奖将成为我作为一名内科科学家发展中的一个重要里程碑。

PROJECT SUMMARY/ABSTRACT Although individually rare, Mendelian diseases are collectively common. Nearly 1% of people have a medical condition that can be traced back to a single gene. This is particularly true for patients with cardiovascular disease. Genetic testing is now commonly employed in clinical practice. As a result, it has become clear that we have an incomplete understanding of how genetic mutations cause Mendelian disease. Some patients with deleterious mutations display very severe symptoms while others are almost entirely unaffected. This is true even for childhood-onset disorders with severe cardiovascular symptoms, like Marfan Syndrome. Understanding the range of disease severity has important implications for diagnosis, prognosis, and management. In the past, cohort studies and case series have been used to gather this type of information, but these yield incomplete and biased views of disease heterogeneity. Therefore, new methods for studying Mendelian disease genetic and phenotypic diversity are urgently needed. Population-scale biobanks linked to electronic health records (EHRs) can provide a less biased view of genotype-to-phenotype relationships. Subjects are included in these datasets regardless of their medical history. EHR data also provides detailed phenotypic information on each subject. Finally, these biobanks now include hundreds of thousands of individuals, capturing rare genetic variation on an unprecedented scale. As a result, we hypothesize that population-scale biobanks can provide new insight into the genotype-to-phenotype relationships that underlie congenital cardiovascular syndromes (CCSs). This hypothesis will be tested in two specific aims. In Aim 1, we will use biobanks to develop quantitative scores that reproducibly summarize CCS- related phenotypic severity. These traits have multiple applications. In Aim 2, we will use them to build computational models that predict the phenotypic effects of CCS-related rare variants directly from sequence context. Once validated, these models should reduce diagnostic uncertainty in clinical practice. I am a clinical geneticist and physician-scientist devoted to improving the quality of healthcare provided to Mendelian disease patients. Long term, I plan to develop an independent research program that uses complex clinical and genetic datasets to improve our understanding of Mendelian disease risk, variability, and progression. My K38 research proposal is entirely consistent with these goals. In addition, it will provide valuable career development. New technical skills in EHR data analysis and statistical genetics will be acquired, as will academic skills like grant writing. During the award, I will be mentored by leaders in the fields of biomedical data science and human genetics, including Dr. Atul Butte and Dr. Neil Risch. Finally, the K38 award will serve as springboard for future funding opportunities and research independence. Therefore, the K38 StARRTS award will serve as a critical milestone in my development as a physician scientist.