Unraveling correlations between Mendelian and common disease using functional genomics

项目总结/摘要 基于临床、基因组学、表观遗传学和其他学科整合的个体化诊断和治疗 生物标志物代表了精准医疗的前景。虽然大多数精准医疗计划都是针对 对于癌症治疗和常见病，影响超过5%的人口，这一建议 旨在将精准医学的目标带到那些受罕见孟德尔遗传疾病影响的人身上。目标 我的研究小组的一个目标是通过透镜来揭示孟德尔定律与常见疾病之间的关系 罕见的孟德尔综合征我们的总体方法将整合多个功能基因组研究 （RNA-seq和ChIP-seq）从罕见的孟德尔综合征患者到全基因组可用的药物 关联研究（GWAS）数据。利用这些数据，我们将实现以下并行目标：1）揭示 罕见疾病的潜在生物学机制，2）它们与与以下疾病相关的遗传基因座的交叉 常见疾病。我们将把我们的研究重点放在新的遗传综合征的全球发展迟缓， 我们首先鉴定为由KAT 6A（赖氨酸（K）乙酰转移酶6A）中的从头突变引起。KAT 6A属于 乙酰转移酶基因家族的一个成员，其主要功能之一是修饰组蛋白并控制乙酰转移酶基因的表达。 一系列下游基因的表达。在目标1中，我们将使用患者- 衍生的真皮成纤维细胞系，并产生功能基因组数据，如RNA-seq和ChIP-seq。 这些数据将被整合，以确定高优先级的靶基因，并在人类细胞系中进行功能验证。 目的2将解决孟德尔疾病突变影响基因表达的假设， 常见疾病（即自身免疫性疾病，自闭症），从而改变常见疾病的风险。 将进行神经认知、行为和发育表型分析，以量化共存的常见 疾病表型，并将与个体功能基因组数据和疾病特异性GWAS整合。 这些研究的发现将提高我们解释孟德尔基因突变对人类遗传学的影响的能力。 在一个单一的人，从而提供了一个孟德尔和常见的疾病基因座之间的关键联系， 疾病在这样做的过程中，我们将推进针对孟德尔疾病的精准医学方法， 最终目标是确定合理的基因靶点，用于确定这些罕见疾病的未来治疗方法， 条件

PROJECT SUMMARY/ABSTRACT Individualized diagnosis and treatment based on the integration of clinical, genomic, epigenetic and other biomarkers represent the promise of precision medicine. While most precision medicine initiatives are geared towards cancer treatment and common disease, which affect more than 5% of the population, this proposal seeks to bring the goals of precision medicine to those affected by rare Mendelian genetic diseases. The goal of my research group is to unravel the relationships between Mendelian and common disease through the lens of rare Mendelian syndromes. Our overarching approach will integrate multiple functional genomic studies (RNA-seq and ChIP-seq) from patients with rare Mendelian syndromes to publically available genome wide association study (GWAS) data. Using these data, we will achieve the parallel objectives of 1) revealing the underlying biological mechanisms of rare disease and 2) their intersection with genetic loci associated with common diseases. We will focus our study on the novel genetic syndrome of global developmental delay that we first identified as caused by de novo mutations in KAT6A (Lysine (K) acetyltransferase 6A). KAT6A belongs to a family of acetyltransferase genes and one of its main functions is to modify histones and control the expression of a wide set of downstream genes. In Aim 1, we will identify KAT6A target genes using patient- derived dermal fibroblast cell lines and generate functional genomic data such as RNA-seq and ChIP-seq. These data will be integrated to identify high priority target genes and functionally validated in human cell lines. Aim 2 will address the hypothesis that Mendelian disease mutations affect expression of genes underlying common disease (i.e. autoimmune disease, autism) thereby altering the risk of common disease. Neurocognitive, behavioral and developmental phenotyping will be performed to quantify co-existing common disease phenotypes and will be integrated with individual functional genomic data and disease-specific GWAS. Findings from these studies will advance our ability to interpret the influence of Mendelian gene mutations on common disease loci within a single individual, thus providing a critical link between Mendelian and common disease. In doing so, we will advance precision medicine approaches with respect to Mendelian disease, with the ultimate goal of identifying rational gene targets to use in identification of future therapies for these rare conditions.