Elucidation of the genetic etiology of Costello Syndrome

阐明科斯特洛综合征的遗传病因

• 批准号: 6851354
• 负责人: Katherine Anna Rauen
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6851354
• 关键词: cell line; children; clinical research; comparative genomic hybridization; congenital disorders; developmental disease /disorder; developmental genetics; diagnosis design /evaluation; disease /disorder etiology; functional /structural genomics; gene expression; gene mutation; genetic disorder; genetic disorder diagnosis; guanine nucleotide binding protein; human genetic material tag; human subject; neoplasm /cancer genetics; neurofibromatosis; nucleic acid sequence; orphan disease /drug; patient oriented research; pediatric neoplasm /cancer; phenotype; rhabdomyosarcoma; syndrome

Costello syndrome (CS) is a multiple congenital anomaly syndrome of unknown genetic etiology whereby patients have characteristic dysmorphic features, growth failure, significant neurodevelopmental delay and a predisposition to develop early childhood cancers. The diagnosis of this genetic disorder is made solely on a clinical basis. Although the vast majority of the cases with CS have been sporadic, the inheritance of CS remains unclear and the genetic basis is unknown. Patients with CS have phenotypic overlap with other cancer syndromes, namely Noonan syndrome (NS) and neurofibromatosis-1 (NF-1). These syndromes are caused by genetic mutations that result in activation of the Ras pathway. The hypothesis of this proposal is that due to the phenotypic similarity to NS and NF-1, patients with CS have a congenital/constitutional alteration in the Ras pathway. In this project, we will take advantage of a unique cohort of patients with CS to test this hypothesis by the identification and characterization of the gene(s) for CS. This will entail continued expansion of this cohort (Aim 1). We will use a multifaceted molecular approach for gene identification, which will include scanning CS patient genomes for constitutional aberrations (Aim 2), scanning genomes of tumors from CS patients and from sporadic tumors of similar type for shared aberrations that may pinpoint the locus of the genetic defect in CS (Aim 3), functional evaluation of the Ras pathway or other candidates in CS cells (Aim 4) and sequencing of Ras pathway or other candidates (Aim 5). Identification of the CS gene will lead to the ability to molecularly diagnose patients with CS. This, in turn, will improve the clinical management of these patients. Because of the wide phenotypic effect seen in children with CS, the elucidation of the genetic etiology will not only help us gain great insight into the cause and progression of cancer, but also understand how such a gene is involved in the regulation of normal human development. In addition, we may discover that malignancies from CS patients are unique to those that arise sporadically underscoring the importance of understanding the pathogenesis of these cancers and ultimately facilitating the development of appropriate therapies. Furthermore, information gained from this study will increase our understanding of common pediatric issues such as congenital cardiac anomalies and neurodevelopmental delay.

Costello 综合征 (CS) 是一种遗传病因未知的多发性先天性异常综合征，患者具有特征性的畸形特征、生长障碍、显着的神经发育迟缓以及罹患早期儿童癌症的倾向。这种遗传性疾病的诊断仅基于临床基础。 尽管绝大多数CS病例是散发性的，但CS的遗传仍不清楚，遗传基础也不清楚。 CS 患者与其他癌症综合征有表型重叠，即努南综合征 (NS) 和神经纤维瘤病 1 (NF-1)。这些综合征是由导致 Ras 通路激活的基因突变引起的。该提议的假设是，由于与 NS 和 NF-1 的表型相似，CS 患者的 Ras 通路存在先天性/体质性改变。在这个项目中，我们将利用一组独特的 CS 患者，通过识别和表征 CS 基因来检验这一假设。这将需要继续扩大这一群体（目标 1）。我们将使用多方面的分子方法进行基因鉴定，其中包括扫描 CS 患者基因组的结构性畸变（目标 2）、扫描 CS 患者的肿瘤基因组和类似类型的散发性肿瘤的基因组以寻找可能查明 CS 遗传缺陷位点的共享畸变（目标 3）、功能评估 CS 细胞中的 Ras 通路或其他候选通路（目标 4）以及 Ras 通路或其他候选通路的测序（目标 5）。 CS 基因的鉴定将能够对 CS 患者进行分子诊断。反过来，这将改善这些患者的临床管理。由于CS儿童具有广泛的表型效应，阐明其遗传病因不仅有助于我们深入了解癌症的病因和进展，而且还能了解该基因如何参与人类正常发育的调节。此外，我们可能会发现，CS 患者的恶性肿瘤不同于那些偶发的恶性肿瘤，这强调了了解这些癌症发病机制并最终促进癌症治疗的重要性。 开发适当的疗法。此外，从这项研究中获得的信息将增加我们对常见儿科问题的理解，例如先天性心脏异常和神经发育迟缓。