Identification of Dosage Sensitive Genes on 18q

18q 剂量敏感基因的鉴定

• 批准号: 6845358
• 负责人: JANNINE De Mars CODY
• 金额: $ 32.71万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-14 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845358
• 关键词: child (0-11); chromosome deletion; chromosome disorders; clinical research; gene deletion mutation; gene expression; gene mutation; human subject; magnetic resonance imaging; myelinopathy; phenotype; polymerase chain reaction

DESCRIPTION (provided by applicant): One of every 180 live-born infants has a chromosome abnormality making it a leading cause of disability. Human genome sequence data now permits the identification of specific genes associated with each aneusomy, the correlation of these genes with specific phenotypes, and ultimately therapeutic options. Toward this end, we have established and sustained a large multidisciplinary team: The Chromosome 18 Clinical Research Center. Herein, we propose a model for identifying the specific gene(s) associated with each phenotypic feature of 18q deletions (dosage sensitive genes). The model may be widely applicable to other chromosome abnormalities. Deletions of 18q are among the most common of the chromosome abnormalities, yet no dosage sensitive genes have been identified whose hemizygosity results in haploinsufficiency and therefore a phenotype. Our goal is to identify dosage sensitive genes on 18q and to characterize the clinical consequences of this hemizygosity. Building on our extensive experience with the chromosome 18 syndromes, we propose to correlate specific key phenotypic features (dysmyelination, growth hormone deficiency, atretic/stenotic ear canals, autism, cleft palate, and severe developmental delay) with the deletion of particular regions of chromosome 18q (critical region). To further narrow this critical region to a candidate gene (or genes), we will study karyotypically normal children with a specific phenotype (e.g., dysmyelination) and search for microdeletions in the previously identified critical region on chromosome 18. This strategy has already been used to identity a candidate gene responsible for the dysmyelination phenotype. Sequencing of the candidate gene in the phenotype specific population will identify additional individuals with chromosome 18q based disease. Then, the karyotypically normal child with chromosome 18q based disease will be clinically assessed to determine the spectrum of expressivity. This last step will initiate the process of comprehensively defining the phenotype resulting from deletion or mutation of an individual dosage sensitive gene. Furthermore, it will begin to piece together the genotypic components that combine to generate the full phenotype of a child with an 18q deletion.

描述(申请人提供)：每180个活产婴儿中就有一个有染色体异常，使其成为导致残疾的主要原因。人类基因组序列数据现在可以识别与每个肿瘤相关的特定基因，这些基因与特定表型的相关性，以及最终的治疗选择。 为此，我们建立并维持了一个庞大的多学科团队：18号染色体临床研究中心。在这里，我们提出了一个模型，用于识别与18q缺失(剂量敏感基因)的每个表型特征相关的特定基因(S)。该模型可广泛应用于其他染色体异常。 18q缺失是最常见的染色体异常之一，但目前还没有鉴定出剂量敏感基因，这些基因的半合导致单倍性不足，从而形成表型。我们的目标是识别18q上的剂量敏感基因，并表征这种半合性的临床后果。基于我们对18号染色体综合征的广泛经验，我们建议将特定的关键表型特征(髓鞘障碍、生长激素缺乏、闭锁/狭窄、自闭症、腭裂和严重发育迟缓)与18q染色体特定区域(关键区域)的缺失相关联。为了进一步将这个关键区域缩小到一个或多个候选基因，我们将研究具有特定表型(例如髓鞘功能障碍)的核型正常儿童，并在之前发现的18号染色体上的关键区域寻找微缺失。这一策略已经被用于确定与髓鞘功能障碍表型相关的候选基因。对表型特定群体中的候选基因进行测序将识别出更多带有18q染色体疾病的个体。然后，将对患有18q染色体疾病的核型正常儿童进行临床评估，以确定其表达谱。这最后一步将启动全面定义由单个剂量敏感基因的缺失或突变引起的表型的过程。此外，它将开始拼凑基因成分，这些基因成分结合在一起，产生一个18q缺失的儿童的完整表型。