Identification of Dosage Sensitive Genes on 18q

18q 剂量敏感基因的鉴定

• 批准号: 6709630
• 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/6709630
• 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（由申请人提供）：每180名活出生的婴儿中的一个患有染色体异常，使其成为残疾的主要原因。现在，人类基因组序列数据允许鉴定与每种动脉造型相关的特定基因，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大型多学科团队：18号染色体临床研究中心。在此，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。该模型可能广泛适用于其他染色体异常。 18q的缺失是染色体异常中最常见的，但尚未鉴定出剂量敏感基因的剂量敏感基因，其半合子性导致单倍症不足，因此是表型。我们的目标是在18Q上识别剂量敏感基因，并表征该半合子的临床后果。在我们对18号染色体综合症的丰富经验的基础上，我们建议将特定的关键表型特征（宿异激素缺乏症，生长激素缺乏症，散文/狭窄/狭窄的耳道，自闭症，left裂和严重的发育延迟）与染色体18Q（关键区域）的缺失（关键区域）的缺失相关联。为了将这个关键区域进一步缩小到候选基因（或基因），我们将研究具有特定表型的核​​型正常儿童（例如，降解障碍），并在先前确定的第18染色体上的关键区域中寻找微缺失。该策略已经用于认同候选基因，使候选基因负责负责甲状腺素化表型。特定表型人群中候选基因的测序将确定其他基于18Q染色体疾病的人。然后，将在临床上评估具有基于18q的染色体疾病的核型正常儿童，以确定表达的频谱。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，它将开始将结合结合的基因型成分拼凑在一起，以产生具有18Q缺失的儿童的完整表型。