圆锥角膜是一种常见的与遗传相关的致盲性角膜疾病。其致病基因的发掘与鉴定一直是圆锥角膜研究领域的热点和难点。已报道的致病基因仅能解释很少一部分人的发病，大部分病人的病因仍是不明。我们前期研究发现，国外已报道的相关位点在中国圆锥角膜人群中不能重复，提示中国群体中极可能有新的相关基因区域。临床上我们诊断了两个圆锥角膜双胞胎家系，前期基因筛查排除了已报道致病基因突变致病的可能。因此课题组利用全外显子组测序技术对2个家系中的8名核心成员进行了测序，并通过位点的整合、过滤、功能预测及注释等生物信息学手段初步筛选出了332个功能性变异，下一步拟对数据进一步分析（遗传模式、新生突变及双生子差异分析），以找出新的致病基因突变；并在500散发病例和500正常对照中进行验证，确定致病基因突变谱；最后通过体内外模型研究其作用机制。本研究将进一步阐明圆锥角膜的发病机理，为圆锥角膜早期诊断及治疗提供新靶点和思路。

Keratoconus (KC) is a common blinding corneal disease, and heredity plays a key role in its development. Detection and identification of the pathogenic gene has being a research hotspot and difficulty in this field. However, the reported pathogenic genes explain only a small percentage of KC. The etiology of most patients is still unknown. Our previous study found that the reported genetic Loci in abroad cannot be repeated in Chinese keratoconus population, which suggested that there may be novel genetic loci in our population. . Our group collected two KC twins pedigrees, and excluded the reported candidate gene mutation by sequencing. Therefore, we did exome sequence on eight core members of these two families (twins and their parents) to find a new candidate gene. Through bioinformatics analysis, including data integration, filtering, function prediction and annotation, we detected 332 functional variations preliminarily. Next, we plan to further analyze the data (including genetic models, novel mutations and twin difference analyses), and find out the possible pathogenic gene mutations. Moreover, the gene will be validated in additional independent 500 sporadic KC cases and 500 normal controls in order to evaluate the contribution of the gene to KC. Finally, study the gene function in vivo and in vitro models and reveal the underlying pathogenic mechanism. This research will further clarify the mechanism of keratoconus and provide new clues for diagnosis and treatment of keratoconus.