Genomic studies of secundum atrial septal defects

继发孔房间隔缺损的基因组研究

• 批准号: 8289467
• 负责人: BRUCE D GELB
• 金额: $ 76.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289467
• 关键词: Area; Atrial Heart Septal Defects; Automobile Driving; Base Pairing; Biopsy; Candidate Disease Gene; Cardiac; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular system; Caring; Cessation of life; Child; Childhood; Clinical Protocols; Clinical Trials; Code; Complex; Congenital Abnormality; Congenital Heart Defects; Counseling; DNA; DNA Resequencing; Data Set; Defect; Developmental Delay Disorders; Event; Exons; Family; Funding; Gene Mutation; Genes; Genetic; Genetic screening method; Genomics; Heart; Heart Atrium; Instruction; Lead; Leukocytes; Mosaicism; Mutate; National Heart, Lung, and Blood Institute; New York City; Pathogenesis; Patient Recruitments; Patients; Point Mutation; Prevalence; Proteins; Randomized; Research; Research Infrastructure; Research Personnel; Risk; Sampling; Scanning; Septum primum; Systems Biology; Technology; Testing; Variant; Work; clinical care; comparative; comparative genomic hybridization; congenital heart disorder; gene discovery; insight; metropolitan; novel; peripheral blood; premature; programs; research study; standard of care

DESCRIPTION (provided by applicant): We seek to collaborate with other centers forming the Pediatric Cardiac Genomics Consortium in order to accelerate clinical protocols investigating the genetic causes and contributions to congenital heart disease (CHD). Our proposed center will be a mini-consortium, drawing potential subjects from two moderate-sized New York city metropolitan area CHD programs, each overseen locally by pediatric cardiologists who will work with research coordinators, and will leverage existing infrastructure for CHD patient recruitment from a previous NHLBI-funded SCCOR program. The proposed clinical protocol for this center will focus on the genetics of secundum atrial septal defects (2¿ ASDs). 2¿ ASDs constitute roughly 10% of CHD and can occur in syndromic and non-syndromic forms; several causative genes are known. SPECIFIC AIM 1 will test the hypotheses that large copy number variants (CNVs) cause 2¿ ASDs with extra-cardiac abnormalities and that rare small de novo CNVs cause isolated 2¿ ASDs. Array comparative genomic hybridization (aCGH) will be used to detect CNVs and comparative quantitative PCR used to confirm them. In SPECIFIC AIM 2, we hypothesize that genes implicated in the pathogenesis of 2¿ ASDs through rare large-scale genomic events are more commonly mutated through single-base pair substitutions. To test this, we will focus on candidate genes identified by novel de novo loss CNVs from the studies for SPECIFIC AIM 1. Further, we hypothesize that as-yet-unknown 2¿ ASD genes encode proteins that are functionally networked with those encoded by genes already identified as causing 2¿ ASDs when mutated. We will explore that using a systems biology approach, seeding with currently known 2¿ ASD genes, to generate protein interaction networks. Candidate gene lists from both approaches will be tested using resequencing of coding exons In 2¿ ASD subjects and controls. In SPECIFIC AIM 3, we hypothesize that somatically acquired point mutations in 2¿ ASD genes contribute to the pathogenesis of those defects. To test this idea, we will use matched genomic DNA samples extracted from peripheral blood leucocytes and atrial septum primum biopsies from subjects with 2¿ ASDs and resequence the set of currently known 2¿ ASD genes. We will also resequence a comparable number of unrelated genes in order to determine the background rate of somatic mosaicism. Taken as a whole, we are leveraging advances in genomics technology to delineate the range of gene mutations and genetic mechanisms that lead to 2¿ ASD. Successfully completed, the findings will be important for clinical care and clinical trials, and may provide insights into how to find genetic causes for other forms of CHD. RELEVANCE (See instructions): Congenital heart defects are the commonest form of birth defects and, despite substantial progress in care, continue to result in significant illness and premature death. For most heart defects, the cause is unknown but genetics is believed to be a critical one. Here, we will participate in a research network devoted to uncovering genetic causes of cardiovascular disease in children and specifically propose to study abnormal openings between the upper chambers of the heart, known as atrial septal defects.

描述（由申请人提供）： 我们寻求与形成小儿心脏基因组学联盟的其他中心合作，以加快研究对先天性心脏病（CHD）遗传原因和贡献的临床方案。我们拟议的中心将是一个迷你官员，从两个中等规模的纽约市大都会区域冠心病计划中吸引了潜在的对象，每个计划都由儿科心脏病专家在当地监督，他们将与研究协调员合作，并将利用现有的基础设施从先前的NHLBI资助的Scccor计划中招募CHD患者。该中心的拟议临床方案将重点放在Secundum心房间隔缺陷的遗传学上（2¿ASDS）。 ASD构成约10％的CHD，可以发生在综合征和非综合征形式中；已知几个严重的基因。特定的目标1将检验大型拷贝数变异（CNV）引起的假设，导致2届ASDS具有外部异常，并且罕见的小型从头CNV会导致孤立的2¿ASDS。阵列比较基因组杂交（ACGH）将用于检测CNV和用于确认它们的比较定量PCR。在特定的目标2中，我们假设通过罕见的大规模基因组事件在2届ASD的发病机理中实现的基因更常见地通过单基对替代而突变。为了测试这一点，我们将重点关注从研究的新从头损失CNV鉴定出的特定目标1的候选基因。此外，我们假设尚未尚未尚未尚未尚未尚未尚不确定的ASD基因编码与已经识别为导致2 aSD的基因编码的基因编码的蛋白质，这些蛋白质在功能上进行了网络。我们将探索使用系统生物学方法，并与当前已知的2届ASD基因接种，以产生蛋白质相互作用网络。两种方法中的候选基因列表将使用2届ASD受试者和对照组中的编码外显子进行重新方程。在特定的目标3中，我们假设在2¿ASD基因中体外获得的点突变有助于这些缺陷的发病机理。为了测试这一想法，我们将使用匹配的基因组DNA样品，这些基因组DNA样品从外周血白细胞细胞和心房隔膜生活检中提取，这些受试者具有2？ASD的受试者和重新配置当前已知的2¿ASD基因的集合。为了确定体细胞镶嵌的背景速率，我们还将重新定位数量可比的无关基因。从总体上讲，我们利用基因组技术的进步来描述导致2 ASD的基因突变和遗传机制的范围。这些发现成功完成，对于临床护理和临床试验至关重要，并且可能会提供有关如何找到其他形式的CHD遗传原因的见解。相关性（请参阅说明）：先天性心脏缺陷是先天缺陷的最常见形式，并且成功的医疗服务取得了长足进展，继续导致重大疾病和早期死亡。对于大多数心脏缺陷，原因是未知的，但遗传学被认为是关键的原因。在这里，我们将参加一个研究网络，该研究网络致力于发现儿童心血管疾病的遗传原因，并特别提出了研究心脏上腔（称为心房间隔缺陷）之间异常开口的建议。