Copy Number Alterations in Genomic Disorders

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。这些重排可导致一个或多个基因的拷贝数改变（CNAs）。由微缺失和微重复引起的疾病可以表现为患者的多重先天性异常（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，心脏缺陷和颅面差异。因此，由CNAs介导的疾病被称为“基因组紊乱”，因为基因组的大部分区域发生改变，导致多器官系统紊乱。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重复（SDs），可占人类基因组的5%。尽管已知SDs与基因组疾病之间存在相关性，但很大比例的SDs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，但目前主要由于分子细胞遗传学标准使用的诊断技术分辨率低而无法检测到。我们假设相当大比例的MCA患儿有亚微观的CNA，这在标准基因检测中并不明显。我们认为，这些CNAs中有相当一部分可能是由SDs或人类基因组中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患者来检验这一假设，以检测致病的cna。此外，对重排断点处基因组序列的分析将有助于确定由SDs等易感基因组结构介导的CNAs比例。本提案的目的是确定MCA患者中以前无法检测到的致病CNAs。鉴定MCA患者的基因组区域改变将有助于更好地理解这组疾病的潜在机制。然后我们可以开始评估基因在这些区域的作用，这些区域可能对人类早期发育途径至关重要。相关性：由于目前使用的检测方法的限制，许多儿童患有无法诊断的遗传性疾病。这些孩子可能有非常小的缺失和重复，这只能通过允许全基因组分析的技术来检测。对先天缺陷患者中缺失或复制的基因组区域的识别，将使对正常发育重要的基因的识别成为可能。

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.