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

基亚里1型畸形（CMI）是一种以扁桃体疝为特征的先天性畸形， 从小脑进入脊柱顶部CMI可能影响多达1/1280的人，包括 各种症状，如严重头痛、感觉障碍和心脏异常。据估计 65-80%的CMI患者会发展成脊髓炎，这是一种脊髓中充满液体的囊肿， 包括失去运动控制在内的损害。因为基亚里I型畸形只能通过磁共振诊断 磁共振成像（MRI），研究其病因才刚刚开始;因此，鉴于其频率，这种情况 被大大低估了高度侵入性手术是CMI的唯一治疗方法， 患者的症状有所改善。家族聚集性研究，包括一致性双胞胎， 共分离的遗传条件支持CMI病因学的遗传成分。目前 病因学的主要理论是“后颅窝太小”，但这一理论背后的遗传成分 还不清楚识别潜在的基因和/或基因将有助于识别高风险个体， 早期干预，这项工作将支持靶向治疗的发展，以治疗慢性， 通常是顽固性的疼痛。 通过各种各样的初步研究，我们已经确定，有一个潜在的遗传基础， 至少是非综合征性基亚里I型畸形的子集。此外，在一个基因组上进行的初始基因组筛选 相对较小的一组家庭表现出两个主要的兴趣区域。基于这些发现，我们 我建议继续调查一些非综合征性基亚里I型畸形家族的假设， 有一个潜在的遗传基础，可以通过遗传分析确定。假设是 通过对我们的CMI家族进行高密度全基因组关联筛选进行测试和扩展 队列以确认和进一步缩小先前的感兴趣基因组区域区域，精细定位以鉴定 最小候选间隔，并测试候选基因的疾病相关变异的证据。

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.