Linkage and candidate gene analysis in non-syndromic Chiari type I

非综合征 Chiari I 型连锁和候选基因分析

基本信息

批准号：
8073454
负责人：
ALLISON E ASHLEY-KOCH
金额：
$ 36.84万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8073454
关键词：
Address Affect Biological Assay Brain Brain region Candidate Disease Gene Cerebellum Chromosomes, Human, Pair 9 Chronic Code Collaborations Collection Congenital Heart Defects Custom Cyst Data Deglutition Disorders Development Diagnosis Diagnostic Disease Dysarthria Early treatment Ensure Etiology Family Frequencies Genes Genetic Genetic Polymorphism Genome Genomics Genotype Headache Hereditary Disease Image Individual Intractable Pain Lead Liquid substance Magnetic Resonance Imaging Maps Medical center Mutation Mutation Detection Nerve Newsletter Ocular Headaches Oligonucleotides Operative Surgical Procedures Paraxial Mesoderm Patient Care Patients Phenotype Population Posterior Fossa Protocols documentation Research Scanning Screening procedure Sensory Signs and Symptoms Sleep Apnea Syndromes Spinal Cord Symptoms Syringomyelia Testing Tonsil Translations Twin Multiple Birth Variant Vertebral column Work base cohort common treatment cost density genetic analysis genetic association genome wide association study high risk interest malformation motor control novel patient advocacy group positional cloning prenatal psychologic public health relevance theories therapeutic target web site

项目摘要

DESCRIPTION (provided by applicant): Chiari type 1 malformation (CMI) is a congenital anomaly characterized by the herniation of the tonsils of the cerebellum into the top of the spinal column. CMI could affect as many as 1 in 1280 people and includes varied symptoms such as severe headaches, sensory disruptions, and cardiac abnormalities. It is estimated that 65-80% of CMI patients develop syringomyelia, a fluid filled cyst in the spinal cord that can lead to nerve damage including loss of motor control. Because Chiari type I malformation is only diagnosed by magnetic resonance imaging (MRI), research into its etiology is only beginning; thus, given its frequency, this condition is vastly understudied. Highly invasive surgery is the only treatment for CMI with only 40-60% of treated patients showing improvement in their symptoms. Familial aggregation studies, including concordant twins, and cosegregating genetic conditions support a genetic component to CMI etiology. Currently, the predominant theory for etiology is a "too small posterior fossa," but the genetic component behind this theory is unclear. Identifying an underlying gene and/or genes will aide identification of high-risk individuals for earlier interventions, and this work will support the development of targeted therapeutics to treat the chronic, often intractable, pain associated with this condition. Through a variety of preliminary studies, we have established that there is an underlying genetic basis for at least a subset of non-syndromic Chiari type I malformations. Furthermore, an initial genomic screen on a relatively small group of families demonstrated two primary regions of interest. Based on these findings, we propose to continue investigating the hypothesis that some non-syndromic Chiari type I malformation families have an underlying genetic basis that can be identified through genetic analysis. The hypothesis will be tested and expanded by performing a high density whole genome association screen on our CMI family cohort to confirm and further narrow previous regions of genomic region(s) of interest, fine mapping to identify the minimum candidate interval, and testing candidate genes for evidence of disease-associated variation. PUBLIC HEALTH RELEVANCE: Chiari type 1 malformation (CMI) is a developmental anomaly characterized by the herniation of a region of the brain into the top of the spinal column and could affect as many as 1 in 1280 people. Symptoms of CMI include severe headaches, sensory disruptions, and cardiac abnormalities. We have established that there is an underlying genetic basis for non-syndromic CMI. To identify the genes underlying this disease we propose to 1) perform a whole genome association screen on our CMI families, 2) confirm and further narrow previous regions of genomic region(s) of interest, and 3) test candidate genes for evidence of disease-associated variation.

描述（由申请人提供）：Chiari 1 型畸形（CMI）是一种先天性异常，其特征是小脑扁桃体突出到脊柱顶部。 CMI 可能影响多达 1,280 人中的 1 人，并包括多种症状，如严重头痛、感觉障碍和心脏异常。据估计，65-80% 的 CMI 患者会出现脊髓空洞症，这是一种脊髓内充满液体的囊肿，可导致神经损伤，包括运动控制丧失。由于Chiari I型畸形只能通过磁共振成像（MRI）来诊断，因此对其病因的研究才刚刚开始；因此，考虑到这种情况的发生频率，人们对这种情况的研究还远远不够。高侵入性手术是 CMI 的唯一治疗方法，只有 40-60% 的治疗患者症状有所改善。家族聚集研究（包括一致双胞胎）和共分离遗传条件支持 CMI 病因学的遗传因素。目前，病因学的主要理论是“后颅窝太小”，但该理论背后的遗传成分尚不清楚。识别一个或多个潜在基因将有助于识别高危个体以进行早期干预，这项工作将支持开发靶向疗法来治疗与这种情况相关的慢性、通常是顽固性疼痛。通过各种初步研究，我们已经确定至少一部分非综合征性 Chiari I 型畸形有潜在的遗传基础。此外，对相对较小的一组家庭进行的初步基因组筛选显示了两个主要的感兴趣区域。基于这些发现，我们建议继续研究以下假设：一些非综合征型 Chiari I 型畸形家族具有可通过遗传分析识别的潜在遗传基础。该假设将通过对我们的 CMI 家族队列进行高密度全基因组关联筛选来测试和扩展，以确认并进一步缩小感兴趣的基因组区域的先前区域，精细作图以确定最小候选区间，并测试候选基因寻找与疾病相关的变异的证据。公共卫生相关性：Chiari 1 型畸形 (CMI) 是一种发育异常，其特征是大脑某个区域突出到脊柱顶部，可能影响多达千分之一的人。 CMI 的症状包括严重头痛、感觉障碍和心脏异常。我们已经确定非综合征性 CMI 有潜在的遗传基础。为了确定这种疾病背后的基因，我们建议 1) 对我们的 CMI 家族进行全基因组关联筛选，2) 确认并进一步缩小感兴趣的基因组区域的先前区域，以及 3) 测试候选基因以获取疾病证据-相关变异。