Impact of CNVs on outcomes for infants with single ventricle heart defects

CNV 对单心室心脏缺陷婴儿结局的影响

基本信息

批准号：
7952346
负责人：
Lisa Edelmann
金额：
$ 25.43万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7952346
关键词：
22q11 Age Age-Months Aneuploidy Angiotensin-Converting Enzyme Inhibitors Benign Biological Markers Birth Weight Cardiac Characteristics Child Childhood Chromosome abnormality Clinical Clinical Research Clinical Trials Clinical Trials Network Cohort Studies Common Ventricle Complex Congenital Heart Defects Copy Number Polymorphism Defect Development Diagnosis Disease Down Syndrome Early treatment Enalapril Enrollment Ethnic Origin Etiology Event Frequencies Funding Future Genetic Genetic Polymorphism Genome Genomics Genotype Goals Growth Head circumference Heart Heart Diseases Height Hereditary Disease Heterogeneity Human Genome Project Hybridization Array Hypoplastic Left Heart Syndrome Individual Infant Infant Development Inferior Lesion Measures Medical Mental Retardation Modification Molecular Abnormality Morbidity - disease rate Neurocognitive Newborn Infant Operative Surgical Procedures Organ Outcome Outcome Study Parents Pathologic Patients Physiology Placebos Prevalence Procedures Race Randomized Recurrence Research Risk Sampling Scanning Seminal Sex Characteristics Source Subgroup Survivors Syndrome Technology Testing Time Turner&apos s Syndrome Weight arm clinical care cohort comparative genomic hybridization congenital heart disorder gene discovery high risk human disease improved infant outcome instrument mortality novel public health relevance reconstruction response sex standard of care tool

项目摘要

DESCRIPTION (provided by applicant): A seminal discovery deriving from the Human Genome Project is that our genomes harbor a substantial number of deletions and duplications. With the technical means to find them, we now know that large de novo copy number variations (CNVs) underlie a wide range of human disease including congenital heart defects (CHD). Pathologic CNVs are particularly prevalent among individuals with CHD plus mental retardation or other organ involvement. To date, studies of CNVs in CHD have focused on characterizing their types in selected patients or on using these genomic events to drive gene discovery. Here, the PI intends to study the biomarker of rare CNVs >500 kb in two cohorts of infants with CHD with single ventricle, particularly hypoplastic left heart syndrome, obtained from Pediatric Heart Network (PHN) clinical trials. The fundamental goal of this research is to determine the impact of pathologic CNVs on typical endpoints used in CHD clinical research: neurocognitive development and somatic growth. Two PHN trials, Infants with Single Ventricle (ISV) and Single Ventricle Reconstruction (SVR), enrolled newborns with single ventricle physiology and then randomized them to two treatment arms (ISV: enalapril vs. placebo; SVR: Norwood procedure vs. Norwood with Sano modification procedure). Both trials assessed survivors at 14 months of age with identical measures of somatic growth and neurocognitive development. Genomic DNAs were amassed prospectively for ISV and are being collected for the SVR Extension. In SPECIFIC AIM 1, we will test the hypothesis that pathologic CNVs >500 kb are prevalent among infants with single ventricle defects (expected frequency of 15%) and that those subjects who are positive for this biomarker will be skewed with respect to specific cardiac diagnosis. We will scan genomic DNAs with array comparative genomic hybridization (aCGH), confirm potential pathogenic CNVs and then dichotomize subjects as positive for this pathologic CNVs (genotype+) or negative for them (genotype-). Then, we will assess the frequency of pathologic large CNVs, compare entry characteristics of sex, race/ethnicity, birth weight, cardiac diagnoses in the genotype+ and - groups. We will also examine specific CNVs to determine the prevalence of specific genetic diagnoses (e.g., Turner syndrome), known karyotypic abnormalities associated with CHD, and recurrent chromosome aberrations potentially defining new syndromes. In SPECIFIC AIM 2, we hypothesize that the neurocognitive and somatic growth outcomes of the genotype+ subgroup will be inferior to the genotype- subgroup. To test these, we will compare the genotype+ and - subgroups with respect to neurocognitive outcomes at 14 months of age as measured with the Bayley Scales of Infant Development-II instrument as well as the somatic growth endpoints of weight-, height-, and head circumference-for-age Z-scores at that same time point. We will also assess the impact of genotype on the results of the ISV and SVR trials (neither trial outcome has been released). That is, we will determine if the presence of the genotype+ subjects confounded trial outcomes. Taken as a whole, we are leveraging advances in genomic technologies to delineate a biomarker for genetic mechanisms leading to complex CHD. Successfully completed, the findings will be important for clinical care and clinical trials of children with single ventricle heart defects and likely CHD more broadly. PUBLIC HEALTH RELEVANCE: This project seeks to establish large genomic events (deletions and duplications) as a biomarker that is determinative factor for neurocognitive and somatic growth outcomes in children with particular forms of congenital heart disease. If successful, use of genomic scanning will become standard of care for infants with such heart disease and essential for future clinical trials.

描述（由申请人提供）：人类基因组计划的一项开创性发现是，我们的基因组含有大量的缺失和重复。有了找到它们的技术手段，我们现在知道大量的从头拷贝数变异（CNV）是包括先天性心脏病（CHD）在内的多种人类疾病的基础。病理性 CNV 在患有先心病且智力低下或其他器官受累的个体中尤其普遍。迄今为止，对先心病 CNV 的研究主要集中在确定选定患者的 CNV 类型或利用这些基因组事件来推动基因发现。在这里，PI 打算研究两组单心室先心病（尤其是左心发育不全综合征）婴儿的罕见 CNVs > 500 kb 的生物标志物，这些婴儿是从儿科心脏网络 (PHN) 临床试验中获得的。本研究的基本目标是确定病理性 CNV 对 CHD 临床研究中使用的典型终点的影响：神经认知发育和躯体生长。两项 PHN 试验，即单心室婴儿 (ISV) 和单心室重建 (SVR)，招募了具有单心室生理学的新生儿，然后将他们随机分配到两个治疗组（ISV：依那普利与安慰剂；SVR：诺伍德手术与诺伍德与 Sano 治疗）修改程序）。两项试验均采用相同的躯体生长和神经认知发育指标对 14 个月大的幸存者进行了评估。为 ISV 前瞻性地积累了基因组 DNA，并为 SVR 扩展收集基因组 DNA。在 SPECIFIC AIM 1 中，我们将检验以下假设：病理性 CNV >500 kb 在单心室缺陷婴儿中普遍存在（预期频率为 15%），并且该生物标志物呈阳性的受试者的特定心脏诊断将出现偏差。我们将使用阵列比较基因组杂交 (aCGH) 扫描基因组 DNA，确认潜在的致病性 CNV，然后将受试者分为该病理性 CNV 阳性（基因型+）或阴性（基因型-）。然后，我们将评估病理性大 CNV 的频率，比较基因型 + 和 - 组的性别、种族/民族、出生体重、心脏诊断的输入特征。我们还将检查特定的 CNV，以确定特定遗传诊断（例如特纳综合征）的患病率、与 CHD 相关的已知核型异常以及可能定义新综合征的复发性染色体畸变。在 SPECIFIC AIM 2 中，我们假设基因型+亚组的神经认知和躯体生长结果将逊于基因型-亚组。为了测试这些，我们将比较基因型 + 和 - 亚组在 14 个月大时的神经认知结果（使用贝利婴儿发育量表 II 仪器测量）以及体重、身高和头部的体细胞生长终点同一时间点的年龄别周长 Z 分数。我们还将评估基因型对 ISV 和 SVR 试验结果的影响（两项试验结果均未发布）。也就是说，我们将确定基因型+受试者的存在是否会混淆试验结果。总的来说，我们正在利用基因组技术的进步来描绘导致复杂先心病的遗传机制的生物标志物。如果成功完成，这些发现对于患有单心室心脏缺陷和更广泛的可能先心病的儿童的临床护理和临床试验非常重要。公共健康相关性：该项目旨在建立大型基因组事件（缺失和重复）作为生物标志物，作为患有特定形式先天性心脏病的儿童的神经认知和躯体生长结果的决定因素。如果成功，基因组扫描的使用将成为患有此类心脏病的婴儿的护理标准，并且对于未来的临床试验至关重要。