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Elucidation of the genetic etiology of Costello Syndrome

阐明科斯特洛综合征的遗传病因

基本信息

批准号：
7555629
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
项目类别：
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/7555629
关键词：
Affect Age Benign Blood specimen Candidate Disease Gene Cardiac Cell Line Cells Characteristics Child Childhood Chromosome abnormality Clinical Clinical Management Cohort Studies Constitutional Costello syndrome DNA Sequence Analysis Databases Development Developmental Delay Disorders Diagnosis Disease Embryonal Rhabdomyosarcoma Enrollment Evaluation Failure Fibroblasts Freezing Gene Mutation Genes Genetic Genetic Predisposition to Disease Genome Genome Scan Genomics Growth Human Development Hybridization Array Karyotype Knowledge Lead Location Malignant Childhood Neoplasm Malignant Neoplasms Microarray Analysis Molecular Molecular Analysis Molecular Profiling Mutation Neoplasms Neurofibromatosis 1 Noonan Syndrome Normal Cell Paraffin Embedding Pathogenesis Pathologic Pathway interactions Patients Pattern Predisposition Recurrence Regulation Reporting Research Ethics Committees Research Personnel Resolution Scanning Siblings Specimen Study Subject Syndrome Testing Western Blotting Work base clinical Diagnosis clinical phenotype cohort comparative genomic hybridization craniofacial early childhood extracellular genetic disorder diagnosis improved insight lymphoblastoid cell line member programs response stressor tumor tumor progression tumorigenesis

项目摘要

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.

科斯特洛综合征（CS）是一种遗传病因不明的多发先天性异常综合征，患者具有典型的畸形特征、生长障碍、严重的神经发育迟缓和患幼儿癌症的倾向。这种遗传性疾病的诊断完全基于临床。虽然绝大多数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，即努南综合征（NS）和神经纤维瘤病-1（NF-1）有表型重叠。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的表型相似性，CS患者在Ras途径中具有先天性/体质性改变。在这个项目中，我们将利用一个独特的CS患者队列，通过鉴定和表征CS基因来验证这一假设。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，这将包括扫描CS患者基因组的组成性畸变（Aim 2），扫描CS患者和类似类型的散发性肿瘤的肿瘤基因组的共有畸变，可以精确定位CS中遗传缺陷的位点（Aim 3），功能评估CS患者的基因组，以及对CS患者的基因组进行功能评估。 CS细胞中Ras途径或其他候选物的测序（目标4）和Ras途径或其他候选物的测序（目标5）。 CS基因的鉴定将导致对CS患者进行分子诊断的能力。这反过来将改善这些患者的临床管理。由于广泛的表型效应在儿童CS中看到，遗传病因的阐明不仅有助于我们深入了解癌症的原因和进展，而且还可以了解这样的基因是如何参与正常人类发育的调节。此外，我们可能会发现，CS患者的恶性肿瘤是独特的，零星出现强调了解这些癌症的发病机制，并最终促进治疗的重要性。开发适当的治疗方法。此外，从本研究中获得的信息将增加我们对常见儿科问题的理解，如先天性心脏畸形和神经发育迟缓。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development.

DOI：
10.1111/j.1365-2133.2011.10744.x
发表时间：
2012-03
期刊：
The British journal of dermatology
影响因子：
0
作者：
Siegel DH;Mann JA;Krol AL;Rauen KA
通讯作者：
Rauen KA

The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation.

DOI：
10.1016/j.gde.2009.04.001
发表时间：
2009-06
期刊：
CURRENT OPINION IN GENETICS & DEVELOPMENT
影响因子：
4
作者：
Tidyman, William E.;Rauen, Katherine A.
通讯作者：
Rauen, Katherine A.

Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors.

DOI：
10.1093/hmg/ddp186
发表时间：
2009-07-15
期刊：
Human molecular genetics
影响因子：
3.5
作者：
Anastasaki C;Estep AL;Marais R;Rauen KA;Patton EE
通讯作者：
Patton EE

Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations.

DOI：
10.1002/ajmg.a.33342
发表时间：
2010-04
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
影响因子：
2
作者：
Rauen, Katherine A.;Tidyman, William E.;Estep, Anne L.;Sampath, Srirangan;Peltier, Henry M.;Bale, Sherri J.;Lacassie, Yves
通讯作者：
Lacassie, Yves

Juvenile xanthogranuloma in Noonan syndrome.