Chiari畸形属于后脑发育畸形中的一类，其发生机制迄今尚不明确。以往研究多基于影像学及临床功能而无法在遗传学以及细胞分子层面予以确切地解释。因此，从遗传病因学入手来揭示该病的发生及发展具有重要的意义。 在Chiari畸形家系中寻找突变基因是揭示该病致病模式的新思路，然而以往研究受限于较少的样本例数及检测技术，Chiari畸形的遗传学研究仍处于理论阶段。在大样本家系中采用准确且高效的基因测序技术有利于全面地筛查突变基因及阳性的功能位点。 本课题首次对家族性Chiari畸形患者进行新一代测序技术（全基因组外显子测序），筛选出候选基因，结合后续的家系及大规模散发病例的验证，以探寻能准确反映Chiari畸形发生及发展的致病基因，明确突变基因的功能，同时进行Chiari畸形家系的表型分析以及遗传图谱的绘制，进一步深入推测其可能存在遗传模式。

Chiari malformation (CM) is part of a pathological continuum of hindbrain malformations and relates to a volumetrically reduced posterior fossa. Despite decades of research, the exact etiology and pathogenesis of CMI remain virtually obscure. To our knowledge, previous studies primarily focused on the clinical and radiographic characteristics of CM with the underlying molecular genetic underpinnings being largely overlooked. Consequently, characterizing the genetic contribution to CM could yield valuable insight into the complex pathogenesis of this disorder. Screening genetic mutations utilizing CM families provides a novel approach in the investigation of its genetic etiology. To date, however, no underlying culprit genes have been identified, largely due to the limited clinical cases and techniques. Therefore, the combination of more accurate and efficient sequencing techniques and large CM families will undoubtedly help to better identify the mutant genes as well as the positive functional sites. By virtue of advanced gene-sequencing technology (whole exome sequencing), this study firstly aims to identify candidate genes associated with familial CM. In conjunction with subsequent validation using CM families and large-scale sporadic cases, we also attempt to identify the core culprit genes, and if possible, the functions of those mutant genes. Furthermore, through phenotypic analyses and genetic mapping, we expect to explore the potential genetic models of familial CM.