先天性外中耳畸形是一种常见的耳部发育异常疾患，在我国的发病率为5.18/万人，为第二大颅面部先天缺陷疾病。约90%的患者存在患侧听力障碍，严重影响身心健康。国内外针对非综合征型外中耳畸形的遗传病因学研究较少，至今未找到确信的致病基因。本研究组前期的流行病学研究显示，遗传因素是我国非综合征型外中耳畸形的主因。我们已完成的候选基因关联研究鉴定出若干和外中耳发育相关的基因突变，但它们对该病的贡献不足5%，提示在基因组上仍有许多新的致病基因有待发掘。本课题组拟采用全基因组关联研究的方法，运用两阶段研究策略在全基因组范围内探寻我国非综合征型外中耳畸形的易感位点。采用GoldenGate的方法在大样本中验证候选易感位点，并确定易感基因。检测易感基因内的所有致病突变位点，并在细胞水平研究突变对易感基因编码蛋白功能的影响。本研究将为外中耳畸形的病因学研究，遗传咨询以及可预期的基因治疗提供遗传学支持。

Microtia can be defined as a malformation of the external and middle ear with varying severity ranging from minimal structural abnormalities to total absence of the earlobe that results can range from mild distortion of the anatomic landmarks to the complete absence of the ear. The prevalence rate of microtia in China is about 5.18 per 10000 newborns. Greater than 90% of individuals with microtia experience conductive hearing disorder on the affected side, which have great influence to patients' life quality. Previous studies on nonsyndromic microtia were mainly focused on plastic surgery and environment causes. Thus far, no confident genetic risk factors were reported. Our epidemiology study showed that the disease is greatly affected by genetic risks in Chinese populations. Our published results from a candidate gene association study showed that some variants associated with nonsyndromic microtia, but they explained less than 5% of the trait variance，which indicate that further study is needed to give deeper insight on the etiology of microtia. Therefore, the next step is to find other susceptibility genes of nonsyndromic microtia at genome-wide level with an association study. The aim of our study is to explore the potential relationship between genetic factors and congenital microtia. Two-staged genome-wide association study will be employed to identify the new susceptibility genes of nonsyndromic microtia in Chinese people.we will detect more causal variants in susceptibility genes and conduct functional experiments to determine their effects on coding protein. Our results will not only improve the etiology knowledge of microtia, but also be helpful for genetic consultation and future gene therapy.

先天性外中耳畸形是一种常见的耳部发育异常疾患，在我国的发病率为5.18/万人，为第二大颅面部先天缺陷疾病。约90%的患者存在患侧听力障碍。本研究组前期的流行病学研究显示，遗传因素是我国非综合征型外中耳畸形的主因。本课题组采用全基因组关联研究的方法，针对942份病例和2012份对照病例进行基因分型。运用两阶段研究策略在全基因组范围内探寻我国非综合征型外中耳畸形的易感位点。采用Sequenom的方法在大样本中验证13个易感基因。该研究成果发表于《Nature communications》。本研究将为外中耳畸形的病因学研究，遗传咨询以及可预期的基因治疗提供遗传学支持。