Copy Number Alterations in Genomic Disorders

基因组疾病中的拷贝数改变

• 批准号: 8017985
• 负责人: TAMIM H SHAIKH
• 金额: $ 25.28万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-27 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8017985
• 关键词: Architecture; Child; Chromosome abnormality; Clinical; Congenital Abnormality; Congenital Heart Defects; Copy Number Polymorphism; DNA Sequence; DNA Sequence Rearrangement; Data; Databases; Detection; Development; Developmental Delay Disorders; Diagnosis; Diagnostic Procedure; Disease; Enrollment; Face; Fluorescent in Situ Hybridization; General Population; Genes; Genetic; Genetic screening method; Genome; Genomics; Genotype; Goals; Hereditary Disease; Human; Human Genetics; Human Genome; Imagery; Individual; Karyotype determination procedure; Link; Mediating; Mental Retardation; Methods; Microarray Analysis; Molecular; Molecular Cytogenetics; Online Systems; Pathway interactions; Patients; Pediatric Hospitals; Phenotype; Philadelphia; Population; Recurrence; Research Personnel; Resolution; Role; Sequence Analysis; Techniques; Testing; Time; base; body system; computerized data processing; design; genome-wide; homologous recombination; improved; microdeletion; novel; programs; research clinical testing

DESCRIPTION (provided by applicant): Numerous human disorders arise from microdeletions and microduplications of relatively large genomic regions. These rearrangements can result in copy number alterations (CNAs) of one or more genes. Conditions arising from microdeletions and microduplications can manifest as multiple congenital anomalies (MCA) in patients. The most common phenotypic features observed in these patients include global developmental delay, mental retardation, cardiac defects and cranio-facial differences. Thus, diseases mediated by CNAs are referred to as 'genomic disorders' as large regions of the genome are altered leading to disorders in multiple organ systems. Many of the recurrent genomic disorders are mediated by aberrant homologous recombination between highly identical blocks of DNA sequences referred to as low copy repeats or segmental duplications (SDs) which may comprise up to 5% of the human genome. Despite this known correlation between SDs and genomic disorders, a significant proportion of SDs have not yet been associated with disease- causing genomic rearrangements. This observation suggests that other SD-mediated genomic disorders may exist but are currently undetectable mainly due to the low resolution of diagnostic techniques standardly used in molecular cytogenetics. We hypothesize that a significant proportion of children with MCA have a submicroscopic CNA that is not evident on standard genetic testing. We believe that a substantial number of these CNAs may be mediated by SDs or other unstable architecture within the human genome. We will test this hypothesis by analyzing patients with MCA using high resolution microarrays in order to detect disease-causing CNAs. Further, analysis of the genomic sequences at the rearrangement breakpoints will help determine what proportion of CNAs are mediated by predisposing genome architecture like SDs. The goal of this proposal is to identify previously undetectable, disease-causing CNAs in patients with MCA. The identification of genomic regions altered in MCA patients will allow a better understanding of the mechanisms underlying this group of disorders. We can then begin to assess the role of gene(s) in these regions that may be critical to early human developmental pathways. Relevance: Many children have genetic diseases that are undiagnosed due to limitations in current methods used for testing. These children may have very small deletions and duplications which can only be detected by techniques that allow a genomewide analysis. The identification of genomic regions that are deleted or duplicated in patients with birth defects will allow the identification of genes that are important in normal development.

描述（由申请人提供）：许多人类疾病是由相对较大的基因组区域的微缺失和微重复引起的。这些重排可能导致一个或多个基因的拷贝数改变（CNA）。微缺失和微重复引起的病症可表现为患者的多种先天性异常 (MCA)。在这些患者中观察到的最常见的表型特征包括整体发育迟缓、智力迟钝、心脏缺陷和颅面部差异。因此，由 CNAs 介导的疾病被称为“基因组疾病”，因为基因组的大部分区域发生改变，导致多个器官系统的疾病。许多复发性基因组疾病是由高度相同的 DNA 序列块之间的异常同源重组介导的，这些 DNA 序列块被称为低拷贝重复或片段重复 (SD)，可能占人类基因组的 5%。尽管已知 SD 与基因组疾病之间存在相关性，但很大一部分 SD 尚未与引起疾病的基因组重排相关。这一观察结果表明，其他 SD 介导的基因组疾病可能存在，但目前无法检测到，主要是由于分子细胞遗传学中标准使用的诊断技术的分辨率较低。我们假设很大一部分 MCA 儿童具有亚显微 CNA，而标准基因检测并不明显。我们相信，大量的 CNA 可能是由 SD 或人类基因组内其他不稳定的结构介导的。我们将通过使用高分辨率微阵列分析 MCA 患者来检验这一假设，以检测致病的 CNA。此外，对重排断点处的基因组序列进行分析将有助于确定有多少比例的 CNA 是由易感基因组结构（如 SD）介导的。该提案的目标是识别 MCA 患者中以前无法检测到的致病 CNA。鉴定 MCA 患者基因组区域的改变将有助于更好地理解这组疾病的机制。然后我们可以开始评估这些区域中可能对人类早期发育途径至关重要的基因的作用。相关性：由于当前检测方法的局限性，许多儿童患有未确诊的遗传性疾病。这些孩子可能有非常小的缺失和重复，只能通过允许全基因组分析的技术来检测。鉴定出生缺陷患者中删除或重复的基因组区域将有助于鉴定在正常发育中重要的基因。