本项目旨在应用申请人在临床遗传咨询中发现的26个宝贵的致聋基因新生（de-novo）突变核心家系-包含了“父-母-先证者”详实的临床数据与样本资料，进行突变遗传来源及传递方式研究。对于这类患者家庭在临床咨询中迫切需要解答的科学问题是：如何解读这种突变？父母亲本是否存在一种未被检测到的低度突变嵌合状态？是否存在遗传再发风险？本研究将采用遗传标记位点检测确定核心家系的生物学关系，在此基础上针对de-novo突变涉及到的16个耳聋基因小序列变化的25个核心家系进行高通量深度测序，针对突变为1个5.175Mbp大片段基因拷贝数量变异核心家系进行全基因组测序，根据获得的总碱基数量计算等位基因比值，分析耳聋de-novo突变患者及其父母亲本嵌合突变的可能性，寻找突变遗传来源及可能传递方式的证据。研究结果将对聋病遗传咨询中de-novo突变的再发风险评估和遗传性的准确解读提供重要的理论依据。

De novo mutations are recognized both as an important source of genetic variation and as a prominent cause of sporadic disease in humans. However, the contribution of de novo mutations to hearing loss is most likely under-recognized and whether the extent of mosaicism for the mutations remains unclear. Mutations with low levels of mosaicism are often below the threshold of sensitivity and specificity for conventional gene sequencing methods. Failure to identify low levels of mosaic mutations may lead to the misinterpretation of genetic testing results. In particular, an inherited case may be misinterpreted as sporadic due to low level mosaicism in a carrier parent. In this project, we will perform a systematic evaluation of de novo mutations identified by 26 parent-offspring trios based next-generation sequencing with deep sequence coverage and whole-genome sequencing. The identification of mosaicism will be important in assessing recurrence risk and genetic counseling.