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

描述（由申请人提供）：Chiari 1型畸形（CMI）是一种先天性畸形，其特征是小脑扁桃体突出到脊柱顶部。每1280人中就有1人患有CMI，包括严重头痛、感觉障碍和心脏异常等各种症状。据估计，65-80%的CMI患者会出现脊髓空洞，这是一种脊髓内充满液体的囊肿，可导致包括运动控制丧失在内的神经损伤。由于Chiari I型畸形仅通过磁共振成像（MRI）诊断，对其病因的研究才刚刚开始；因此，考虑到它的频率，这种情况的研究还远远不够。高度侵入性手术是治疗慢性心肌梗死的唯一方法，只有40-60%的患者症状得到改善。家族聚集性研究，包括同型双胞胎和同居遗传条件，支持CMI病因的遗传成分。目前，病因的主要理论是“后窝过小”，但这一理论背后的遗传成分尚不清楚。确定一个潜在的基因和/或基因将有助于识别高风险个体进行早期干预，这项工作将支持靶向治疗的发展，以治疗与这种情况相关的慢性，通常是难治性疼痛。通过各种初步研究，我们已经确定，有一个潜在的遗传基础，至少一个亚群的非综合征型奇亚氏I型畸形。此外，对一个相对较小的家族群体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的假设。该假设将通过在我们的CMI家族队列中进行高密度全基因组关联筛选来验证和扩展，以确认并进一步缩小先前感兴趣的基因组区域，精细定位以确定最小候选间隔，并测试候选基因以寻找疾病相关变异的证据。

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.