Copy Number Alterations in Genomic Disorders

描述（由申请人提供）：许多人类疾病由相对较大的基因组区域的微缺失和微复制引起。这些重排可以导致一个或多个基因的拷贝数改变（CNA）。由微缺失和微重复引起的病症可以表现为患者的多个先天性异常（MCA）。在这些患者中观察到的最常见的表型特征包括全面发育迟缓、智力迟钝、心脏缺陷和颅面差异。因此，由CNA介导的疾病被称为“基因组疾病”，因为基因组的大区域被改变，导致多器官系统的疾病。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，称为低拷贝重复或片段性重复（SD），其可包含高达5%的人类基因组。尽管SD和基因组疾病之间存在这种已知的相关性，但相当大比例的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，主要是由于低分辨率的诊断技术标准用于分子细胞遗传学。我们假设，一个显着比例的儿童与MCA有一个亚显微镜CNA是不明显的标准基因检测。我们相信，这些CNA中的相当一部分可能是由SD或人类基因组内的其他不稳定结构介导的。我们将通过使用高分辨率微阵列分析MCA患者以检测致病的CNA来检验这一假设。此外，在重排断点处的基因组序列的分析将有助于确定CNA的比例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患者中改变的基因组区域将使我们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基因的作用，这些基因可能对早期人类发育途径至关重要。相关性：许多儿童患有遗传性疾病，由于目前用于检测的方法的局限性而无法诊断。这些儿童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缺失或重复的基因组区域将允许鉴定在正常发育中重要的基因。

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.