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

描述（由申请方提供）：基亚里1型畸形（CMI）是一种先天性异常，其特征为小脑扁桃体疝入脊柱顶部。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患者发展为脊髓炎，脊髓中充满液体的囊肿，可导致神经损伤，包括运动控制丧失。由于基亚里I型畸形只能通过磁共振成像（MRI）诊断，对其病因的研究才刚刚开始;因此，鉴于其发生频率，这种情况还远远没有得到充分研究。高度侵入性手术是CMI的唯一治疗方法，只有40-60%的治疗患者的症状得到改善。家族聚集性研究，包括一致的双胞胎，和共分离的遗传条件支持CMI病因的遗传成分。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尚不清楚。识别潜在的基因和/或基因将有助于识别早期干预的高风险个体，这项工作将支持靶向治疗药物的开发，以治疗与这种疾病相关的慢性，通常是顽固性的疼痛。通过各种初步研究，我们已经确定，有一个潜在的遗传基础，至少一个子集的非综合征型基亚里I型畸形。此外，对一个相对较小的家族群体进行的初始基因组筛选显示了两个主要的感兴趣区域。基于这些发现，我们建议继续调查的假设，一些非综合征型基亚里I型畸形的家庭有一个潜在的遗传基础，可以通过遗传分析确定。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验证和扩展该假设，以确认并进一步缩小先前的感兴趣基因组区域区域，精细定位以确定最小候选间隔，并测试候选基因以获得疾病相关变异的证据。 公共卫生相关性：基亚里1型畸形（CMI）是一种发育异常，其特征是大脑的一个区域疝入脊柱顶部，可能影响多达1/1280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，有一个潜在的遗传基础的非综合征型CMI。为了鉴定导致这种疾病的基因，我们建议1）对我们的CMI家族进行全基因组关联筛选，2）确认并进一步缩小先前感兴趣的基因组区域的区域，以及3）测试候选基因以获得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.