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: 9324036
• 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/9324036
• 关键词: Alleles; Bioinformatics; Candidate Disease Gene; Cardiac Myocytes; Cardiovascular system; Childhood; Clinical; Code; Collection; Computer software; Copy Number Polymorphism; DNA; Data; Data Set; Databases; Development; Diagnosis; Diagnostic; Disease; Disease model; Enrollment; Exhibits; Family; Foundations; Genealogy; Genes; Genome; Genomics; Genotype; Goals; Heart; Heritability; Heterozygote; Institutional Review Boards; Interdisciplinary Study; Investigation; Knowledge; Link; Medical Records; Methodology; Mining; Multicenter Studies; National Heart, Lung, and Blood Institute; Nucleotides; Outcome; Parents; Participant; Patients; Pediatric Cardiac Genomics Consortium; Pediatric cardiology; Penetrance; Phenotype; Play; Population Database; Publishing; RNA Splicing; Recruitment Activity; Reporting; Research; Research Infrastructure; Research Personnel; Resources; Role; Sampling; Scientist; Site; Solid; Surface; Technology; Transcend; Universities; Untranslated RNA; Utah; Variant; Work; base; clinically relevant; congenital heart disorder; design; exome; gene discovery; genetic pedigree; genetic variant; genome sequencing; genomic data; genotyped patients; induced pluripotent stem cell; innovation; knowledge base; neurodevelopment; novel; outcome forecast; outcome prediction; portability; predict clinical outcome; proband; public health relevance; segregation; success; tool; whole genome

 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（由适用提供）：尽管分配了大量资源，但先天性心脏病（CHD）的基因组基础在很大程度上尚不清楚，在从头开始的单一核苷酸和拷贝数变种中，占CHD的一小部分。我们假设（1）（1）罕见的罕见不完全占主导地位，简单的隐性和复合 - 杂合子疾病模型是“缺失的遗传力” o CHD的很大一部分，以及（2）有害变体的基因组载荷，以及与某些CHD引起的（其他造成的）造成的特征相关的多重符号，但与其他造成的杂物相关的是，他们的临床是造成的，并在其造成的杂物中均与他们的杂物相关。冠心。我们的主要目标是将犹他州中心建立为儿科心脏基因组学联盟（PCGC）的组成伙伴，并与其他PCGC中心合作，以（1）为患者提供PCGC，专业知识和软件，这些专业知识和软件将确定CHD缺失的遗传性； （2）通过定义与CHD引起的等位基因相关的多形图，并确定有害变体的基因组负荷来定义与相关的临床结果相关的基因组变异。目前，PCGC缺乏两种关键的诊断方法，阻碍了其定义冠心基因组基础及其结果的能力：（1）能够在不完全占主导地位，简单隐性的，简单的隐性和复合型杂化疾病模型和（2）基于家族的整个培训的方法上，能够计算出不完全占主导地位的生物信息学管道，并确定了铜制的整个疾病，并确定了铜制的整个疾病，并确定了铜制的无元素，并确定了铜制的杂物。地区。我们认为，PCGC概率和父母三重奏中从头变异的鉴定仅代表冰山一角，许多基因和等位基因仍然未被发现。该建议涵盖了将以非常实用的方式使PCGC受益的创新方法。该提案利用了最近验证和新兴的生物信息学技术，该技术提供了四种基本功能：（1）无论它们位于基因组编码，基因间，剪接站点等中，都可以估计变体的功能影响； （2）计算质疑患者基因型的能力，不仅针对从头等位基因，而且还具有不完全渗透性的优势，简单隐性和复合杂合子疾病模型的能力； （3）在谱系，表型信息和患者特异性诱导的多能干细胞衍生的心肌细胞中进行这些分析的能力； （4）共享患者管理和财团协作分析结果的能力。总而言之，我们的建议旨在通过利用犹他大学设计的新颖工具来填补CHD周围“缺失”的知识差距，该工具能够对个人基因组/外显子组序列，患者表型描述和谱描述和谱系以及患者特定的表达数据进行集成计算，所有这些都在强大的统计框架中。