全基因组连锁分析结合新一代靶向捕获测序技术定位杯状耳畸形罕见大家系致病突变

先天性耳部畸形是影响耳廓位置和形态的常见出生缺陷，人群中约有5%的样本有不同程度的耳部发育畸形。杯状耳是其中的一种，约占各种先天性耳部畸形的10%；区别于其他常见的耳部畸形，杯状耳多为双侧，具有明显的遗传倾向。国内外针对杯状耳畸形的报道多侧重于其治疗方法的改进，缺乏针对发病机制的深入探讨。本课题组将选择遗传模式符合孟德尔规律的杯状耳大家系，采用经典的连锁分析结合当前的二代测序技术鉴定易感基因的策略查找致病突变；进一步在杯状耳散发病例及正常对照人群中进行验证，确定致病基因对群体发病风险的贡献度。结合生物学通路、细胞定位、蛋白作用网络和组织表达特异性等多种分析，预测易感基因编码蛋白结构和功能，进一步阐明基因型和表型关系。该策略具有所需样本量小，简便快捷，可重复性强的优点；将为耳部畸形的遗传咨询、早期诊断和临床早期干预、以及靶向治疗奠定遗传学基础，具有重要的经济价值和社会意义。

Approximately 5% of the population has some sort of congenital ear malformation which affect position, shape and even function of the ear. The cupped or constricted ear deformity occurs as a result of hooding of the superior helix of the ear which account for 10% among all kinds of ear malformation. Different from other ear deformities, cupped ear is characterized by bilateral occurrence and potential genetic predisposition. Literatures showed that most of the studies focused on the surgical treatment rather than the etiology, inculding it genetic mechanism, specificity and susceptibility gene of the disease. In this study, we aim to identify the susceptibility gene using targeted next-generation sequencing combined with the linkage region based on the cupped ear families which follow Mendelian genetic mode. The candidate mutations or genes obtained from next-generation sequencing will be further subjected to Sanger sequencing with additional pedigrees and sporadic cases/controls. Relationship between genotype and phenotype will be further elucidated by the prediction of susceptibility gene and its ecoding protein through analyzing the biological pathways, cellular localization, protein interaction networks and tissue specificity. Next-generation sequencing is a powerful new technology which is frequently used in mapping the causal genes for common and rare diseases. Its high efficiency has been proved nowadays. The identification of the susceptibility gene for congenital cupped ear will not only improve the understanding of the genetic mechanism, but also facilitate relevant genetic counseling and early diagnosis, targeted intervention, and has an important social value as well.