先天性小耳畸形的发病率近年来逐年上升，是继唇裂、腭裂之后最常见的面部畸形，严重影响患者及其家属的身心健康，研究发现遗传因素在其发病机制中起重要作用。本课题在收集和初步总结了30个非综合征性小耳畸形家系临床和流行病学资料的基础上，通过对的全基因组扫描，经连锁分析获得可能的最小易感区段，并经单倍型推演及微卫星验证确定；然后利用第二代DNA测序技术进行全基因组外显子组测序，逐步锁定致病基因，并经家系成员、散发性先天性小耳畸形患者和健康对照组验证新发现的致病基因；通过体外实验如构建质粒、定点诱变、细胞转染等技术进行致病基因的功能研究，探讨相关调控分子在耳廓胚胎发育异常中的作用，探索国人非综合征性先天性小耳畸形的遗传因素和发病机制。

The incidence of microtia increased gradually in recent years. It is the most common facial deformity following cleft lip and cleft palate. Research found that genetic factors play an important role in its pathogenesis. In this study, we collected and summarized clinical and epidemiological data of 30 nonsyndromic microtia families. After the genome-wide search and linkage analysis, the smallest possible predisposing genes section was obtained and confirmed by haplotype deduction and micro-satellite validation. Then exome sequencing of whole genome was done by the second-generation DNA sequencing technology to gradually lock disease genes. These newly discovered disease genes were verified in family members, sporadic congenital microtia patients and healthy control group. Function studies on disease genes were done by in vitro experiments, such as plasmids construction, site-directed mutagenesis, cell transfection. The role of relevant regulatory molecules in the abnormal development of auricle in embryos and genetic factors and pathogenesis of non-syndromic congenital microtia in Chinese were explored.

先天性小耳畸形在头面部先天畸形中发病率排第二位，对患者的容貌有较大影响，常给患者及其家庭造成较大的心理负担。本课题以研究遗传因素在非综合症性先天性小耳畸形发生中的作用为主要目的，试图探索可能的发病原因和发病机理。主要研究内容包括：1）小耳畸形耳廓软骨组织BMP5和Wnt5a的SNP突变检测；2）同卵双生非共患小耳畸形患者全外显子组测序的初步研究；3）一例同卵双生非共患小耳畸形家系的全基因组测序的初步研究。通过大量的检测和数据分析，我们发现以下结果：1）BMP5基因第183位的氨基酸由L突变为F，这个位点氨基酸的突变可能引起小耳畸形的几率比较大；2）3对确认为同卵双生非共患小耳畸形患者与正常同胞之间进行外显子组测序，从7047个位点筛选出3个符合显性遗传模式的基因；3）一例同卵双生非共患小耳畸形家系父母及两个孩子的全基因组测序，发现该家系中患者携带有MUC4基因平衡易位，可能与该患者的发病有关。