听神经病是目前国际上研究听觉信息处理障碍机制的标志性疾病。本课题组历经20余年的系统研究与随访，发现中国遗传性听神经病患者的多种临床亚型及其由OTOF，AIFM1等基因突变致病的临床意义。但听神经病的各种临床表型与基因型的相互关系如何？分子定位分型诊断的遗传学基础如何？基于CRISPR/Cas9基因编辑的基因治疗能否有效恢复听神经病模型鼠的听觉传导和信息整合功能？这些问题一直是诠释和干预听神经病的核心问题。因此，本项目将对490例珍贵的听神经病患者进行全基因组学研究，深度绘制我国听神经病的致病基因图谱，针对OTOF和AIFM1基因热点突变建立人类iPS细胞库，应用CRISPR/Cas9技术对听神经病小鼠模型进行基因编辑治疗，从听力学、编辑效率（Indel率）、脱靶率（Off-target）等角度评估基因治疗有效性及安全性，从而迈入对听神经病精准分子分型和靶向基因治疗新阶段。

Auditory neuropathy (AN) is a landmark disease in the study of auditory information processing mechanism in the whole world. After 20 years systematic research and follow-up study, our group has found a variety of clinical subtypes of AN and the clinical significance of OTOF and AIFM1 genes mutations in Chinese patients with AN. However, what about the relationship between multiple clinical phenotypes and genotypes of AN? What is the genetic basis for molecular localization diagnosis? Can CRISPR/ Cas9 based gene therapy effectively restore the auditory conduction and information integration function of mice model with AN? These are the key issues of interpretation and intervention of AN. Thus, this project will carry out whole genomics study on 490 patients with AN and deeply map the pathogenic gene mutation spectrum of AN, establish human iPS cell bank of OTOF and AIFM1 gene hotspot mutations, apply CRISPR/ Cas9 technology to conduct gene editing therapy on mouse models with AN, assess the efficiency and security of gene therapy by audiology, Indel rate, Off-target rate evaluation, stepping into the new era of precise molecular classification and targeted gene therapy on AN.