Identification of Dosage Sensitive Genes on 18q

描述（由申请人提供）：每180个活产婴儿中就有一个染色体异常，这是导致残疾的主要原因。人类基因组序列数据现在允许识别与每个异染色体相关的特定基因，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18 q缺失的每个表型特征相关的特定基因（剂量敏感基因）。该模型可广泛应用于其他染色体异常。 18 q缺失是最常见的染色体异常之一，但尚未鉴定出半合子性导致单倍性不足并因此导致表型的剂量敏感性基因。我们的目标是确定18 q上的剂量敏感基因，并描述这种半合子的临床后果。基于我们在18号染色体综合征方面的丰富经验，我们建议将特定的关键表型特征（髓鞘形成障碍、生长激素缺乏、耳道闭锁/狭窄、自闭症、腭裂和严重发育迟缓）与18号染色体特定区域（关键区域）的缺失相关联。为了进一步缩小这一关键区域的候选基因（或基因），我们将研究具有特定表型的核型正常儿童（例如，髓鞘形成障碍）和在先前鉴定的18号染色体上的关键区域中寻找微缺失。这一策略已经被用于识别负责髓鞘形成障碍表型的候选基因。对表型特异性群体中的候选基因进行测序将鉴定具有基于染色体18 q的疾病的另外的个体。然后，将临床评估具有基于染色体18 q的疾病的核型正常儿童以确定表达谱。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，它将开始将基因型成分拼凑在一起，这些基因型成分联合收割机组合产生18 q缺失儿童的完整表型。

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.