Bridging the Gap between Genomics and Clinical Outcomes in CHD

缩小先心病基因组学与临床结果之间的差距

• 批准号: 8950472
• 负责人: MARTIN TRISTANI-FIROUZI
• 金额: $ 40.08万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8950472
• 关键词: Accounting; Alleles; Bioinformatics; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiology; Cardiovascular system; Childhood; Clinical; Clinical Data; Code; Collection; Computer software; Copy Number Polymorphism; DNA; Data; Data Set; Databases; Development; Diagnosis; Diagnostic; Disease; Disease model; Enrollment; Exhibits; Family; Foundations; Genes; Genome; Genomics; Genotype; Goals; Heart; Heritability; Heterozygote; Institutional Review Boards; Investigation; Knowledge; Link; Medical Records; Methodology; Mining; Multicenter Studies; National Heart, Lung, and Blood Institute; Nucleotides; Outcome; Parents; Participant; Patients; Penetrance; Phenotype; Play; Population Database; Publishing; Qualifying; RNA Splicing; Reporting; Research; Research Infrastructure; Research Personnel; Resources; Role; Sampling; Scientist; Site; Solid; Surface; Technology; Transcend; Universities; Untranslated RNA; Utah; Variant; Work; abstracting; base; congenital heart disorder; design; empowered; exome sequencing; gene discovery; genetic pedigree; genetic variant; genome sequencing; induced pluripotent stem cell; innovation; knowledge base; neurodevelopment; novel; outcome forecast; proband; public health relevance; segregation; success; tool

 DESCRIPTION (provided by applicant): Despite the allocation of significant resources, the genomic basis of congenital heart disease (CHD) remains largely unknown in that rare and de novo single nucleotide and copy-number variants account for a small fraction of CHD. We hypothesize that (1) rare incompletely dominant, simple recessive, and compound- heterozygote disease models account for a very significant fraction of the "missing heritability" o CHD and (2) the genomic load of deleterious variants, together with pleomorphies associated with some CHD-causing alleles (but not others), influence clinical outcomes in a manner that transcends their immediate contribution to the primary CHD. Our principal goal is to establish the Utah Center as an integral partner of the Pediatric Cardiac Genomics Consortium (PCGC) and to work collaboratively with other PCGC centers in order to (1) provide the PCGC with the patients, expertise and software that will identify the missing heritability of CHD; and (2) associate genomic variants with relevant clinical outcomes by defining the pleomorphies associated with CHD-causing alleles and by determining the genomic load of deleterious variants. Currently, the PCGC is lacking two key diagnostic approaches that hinder its ability to define the genomic basis for CHD and its outcomes: (1) a robust bioinformatics pipeline that is capable of computing on incompletely dominant, simple recessive, and compound-heterozygote disease models, and (2) a family-based whole-genome sequencing approach that is powered to identify novel CHD alleles in coding and non-coding regions. We argue that the identification of de novo variants in PCGC proband-parent trios represents only the tip of the iceberg, with many genes and alleles still undiscovered. This proposal encompasses innovative methodologies that will benefit the PCGC in a very practical manner. This proposal capitalizes on a recently validated and emerging bioinformatics technology that provides four basic functionalities: (1) the ability to estimate the functional impact of variants no matter where they lie in the genome coding, intergenic, splice sites, etc.; (2) the ability to computationally interrogate patient genotypes not only for dominant de novo alleles, but also for incompletely penetrant dominant, simple recessive, and compound heterozygote disease models; (3) the ability to carry out these analyses in the context of pedigrees, phenotype information, and expression data from patient-specific induced pluripotent stem cell-derived cardiomyocytes; and (4) the capability to share results for patient management and consortium-wide collaborative analyses. In summary, our proposal aims to fill the knowledge gap of "missing heritability" surrounding CHD by leveraging novel tools designed at the University of Utah that enable integrated computation on personal genome/exome sequences, patient phenotype descriptions and pedigrees, and patient-specific expression data, all in a robust statistical framework.

 描述（由申请人提供）：尽管分配了大量资源，但先天性心脏病（CHD）的基因组基础仍然很大程度上未知，因为罕见和从头的单核苷酸和拷贝数变异仅占先天性心脏病的一小部分（。 1) 罕见的不完全显性、简单隐性和复合杂合子疾病模型占 CHD“遗传性缺失”的很大一部分；(2) 有害变异的基因组负载，以及与一些引起冠心病的等位基因（但不是其他）相关的多态性，其影响临床结果的方式超越了它们对原发性冠心病的直接贡献。我们的主要目标是将犹他中心建立为儿科心脏基因组学联盟的不可或缺的合作伙伴。 PCGC）并与其他 PCGC 中心合作，以便 (1) 为 PCGC 提供识别 CHD 缺失遗传性的患者、专业知识和软件；以及 (2) 将基因组变异与相关相关联；目前，PCGC 缺乏两种关键的诊断方法，阻碍了其确定 CHD 基因组基础及其结果的能力：(1)强大的生物信息学流程，能够计算不完全显性、简单隐性和复合杂合子疾病模型，以及 (2) 基于家族的全基因组测序方法，能够识别新型先心病我们认为，PCGC 先证者亲本三人组中的从头变异的鉴定仅代表冰山一角，许多基因和等位基因仍未被发现。该提案包含了将有利于 PCGC 的创新方法。该提案以一种非常实用的方式利用了最近经过验证的新兴生物信息学技术，该技术提供了四种基本功能：（1）能够估计变异的功能影响，无论它们位于基因组编码的哪个位置，基因间、剪接位点等；(2) 不仅能够通过计算询问患者基因型的显性从头等位基因，还能够针对不完全渗透显性、简单隐性和复合杂合子疾病模型进行计算；这些分析涉及患者特异性诱导多能干细胞来源的心肌细胞的谱系、表型信息和表达数据；(4) 能够共享患者管理结果和总之，我们的提案旨在通过利用犹他大学设计的新工具来填补围绕先心病“遗传性缺失”的知识空白，这些工具能够对个人基因组/外显子组序列、患者表型描述和谱系进行综合计算。 ，以及患者特异性表达数据，全部都在一个强大的统计框架中。