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

• 批准号: 7654349
• 负责人: ALLISON E ASHLEY-KOCH
• 金额: $ 42.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/7654349
• 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

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的丘脑丘脑丘脑呈现为脊柱顶部的顶部。 CMI可能会影响1280人中的多达1人，并包括各种症状，例如严重的头痛，感觉干扰和心脏异常。据估计，有65-80％的CMI患者患有脊髓脊髓溶血症，脊髓中充满液体的囊肿，可能导致神经损伤，包括失去运动控制。由于Chiari I型畸形仅通过磁共振成像（MRI）诊断，因此对其病因的研究才刚刚开始。因此，鉴于其频率，这种情况被大大研究了。高度侵入性手术是CMI的唯一治疗方法，只有40-60％的治疗患者表现出改善的症状。家族聚集研究，包括一致的双胞胎和遗传条件，支持CMI病因的遗传成分。当前，病因的主要理论是“后窝太小”，但是该理论背后的遗传成分尚不清楚。鉴定潜在的基因和/或基因将有助于对高危个体进行早期干预的识别，这项工作将支持靶向治疗剂的发展，以治疗与这种情况相关的慢性（通常是棘手的疼痛）。通过各种初步研究，我们确定至少一部分非综合性chiari I型畸形存在基本遗传基础。此外，相对较小的家族的初始基因组筛选显示了两个主要的关注区域。基于这些发现，我们建议继续研究以下假设：某些非综合性Chiari I型畸形家族具有基本的遗传基础，可以通过遗传分析来鉴定。该假设将通过在我们的CMI家族队列上进行高密度的整个基因组关联筛查来检验和扩展，以确认并进一步缩小感兴趣的基因组区域的先前区域，详细映射以识别最小候选间隔，并测试候选基因，以证明与疾病相关的变异证据。 公共卫生相关性：Chiari 1型畸形（CMI）是一种发育异常，其特征是将大脑区域催眠到脊柱顶部，可能影响1280人中的1人。 CMI的症状包括严重的头痛，感觉干扰和心脏异常。我们已经确定，非综合症CMI存在基本的遗传基础。为了鉴定该疾病的基因，我们建议1）在我们的CMI家族上执行整个基因组关联筛查，2）确认并进一步狭窄的感兴趣的基因组区域的先前区域，以及3）测试候选基因，以证明与疾病相关变异的证据。