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: 8278630
• 负责人: ALLISON E ASHLEY-KOCH
• 金额: $ 38.9万
• 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/8278630
• 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; theories; therapeutic target; web site

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.

Chiari 1型畸形（CMI）是一种先天性异常，其特征是扁桃体的疝气 小脑进入脊柱的顶部。 CMI可能会影响1280人中的1人，其中包括 各种症状，例如严重的头痛，感觉干扰和心脏异常。估计 65-80％的CMI患者会出现脊髓念珠菌，这是脊髓中的液体囊肿，可导致神经 损坏，包括失去电动机控制。因为Chiari I型畸形仅通过磁性诊断 共鸣成像（MRI），对其病因的研究才刚刚开始。因此，鉴于其频率，这种情况 被大量研究了。高度侵入性手术是CMI的唯一治疗方法，仅40-60％ 患者表现出症状的改善。家族聚集研究，包括一致的双胞胎， 遗传条件支持CMI病因的遗传成分。目前， 病因的主要理论是一个“后窝太小”，但是该理论背后的遗传成分 不清楚。识别潜在的基因和/或基因将有助于对高风险个体的识别 较早的干预措施，这项工作将支持开发有针对性的治疗剂，以治疗慢性， 通常棘手，疼痛与这种情况有关。 通过各种初步研究，我们确定AT存在基本的遗传基础 至少是非合成Chiari I型畸形的子集。此外，在A上的初始基因组屏幕 相对较小的家庭表现出了两个主要的关注区域。基于这些发现，我们 提议继续研究某些非综合性Chiari I型畸形家族的假设 具有可以通过遗传分析来鉴定的基本遗传基础。假设将是 通过在我们的CMI家族上执行高密度整个基因组关联屏幕进行测试和扩展 群体确认并进一步缩小了感兴趣的基因组区域的先前区域，并进行精细映射以识别 最小候选间隔和测试候选基因是否有与疾病相关的差异证据。