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

Chiari 1型畸形(CMI)是一种先天性畸形，其特征是扁桃体脱出。 小脑进入脊柱顶端。CMI可能影响多达1280人中的1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患者患有脊髓空洞症，这是一种脊髓内充满液体的囊肿，可以通向神经 损坏，包括马达失控。因为Chiari I型畸形只能通过磁学诊断 磁共振成像(MRI)，对其病因的研究才刚刚开始；因此，鉴于其频率，这种情况 人们对它的研究还远远不够。高侵袭性手术是CMI的唯一治疗方法，仅有40%-60%的患者接受了治疗 患者的症状有所改善。家族聚集性研究，包括和谐双胞胎， 而共同隔离的遗传条件支持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 目前还不清楚。识别一个和/或一个或多个潜在基因将有助于识别高危个体 早期干预，这项工作将支持开发有针对性的疗法来治疗慢性、 顽固性疼痛通常与这种情况有关的顽固性疼痛 通过多项初步研究，我们已确定AT有潜在的遗传基础。 至少是非综合征型Chiari I型畸形的一个子集。此外，一个初始的基因组筛选 相对较小的家庭群体显示出两个主要感兴趣的领域。基于这些发现，我们 建议继续调查一些非综合征型Chiari I型畸形家系 有潜在的遗传基础，可以通过遗传分析来识别。假设将是 通过对我们的CMI家族进行高密度全基因组关联筛查进行了测试和扩展 队列确认并进一步缩小先前基因组感兴趣区域(S)的区域，精细作图以鉴定 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。

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.