Optimizing Genetic Testing for Deafness for Clinical Diagnostics

项目摘要 听力损失是人类最常见的感觉缺陷。它影响了超过3.6亿人 在世界范围内，广泛影响他们的生活质量。虽然因果关系是多因素的，但在发达国家， 大部分听力损失是遗传性的和非综合征性的，即与其他表型无关。 在上一个授予期间（12/01/16-11/20/21），我们专注于三个具体目标：1）优化 遗传性耳聋的表型-基因型整合分析 AudioGene中的聚类和audioprofile表面分析; 2）探索基于物理的蛋白质建模， 耳聋变异数据库中的工具;以及3）为了确定特定耳聋的遗传修饰剂是否 通过层次表面聚类可以预测致病基因 在这次竞争性更新中，我们的首要目标是进一步改善患有以下疾病的人的临床护理 听力损失，并为这一人群的基因特异性精准医学提供更坚实的基础。 我们将通过解决以下具体目标所反映的当前知识差距来实现这些目标： 具体目标1.完成非综合征形式的基因特异性自然史研究（NHS）， 使用AudioGene和OtoSCOPE整合表型和基因型数据的听力损失 假设：非综合征性听力损失的自然史是基因特异性的，可以通过以下方式定义： 整合听力损失表型（表型组）与相关基因型（基因组）， 非综合征性听力损失的类型 第二章具体目标通过使其具有基因特异性， 实施深度学习和基于物理的蛋白质建模的组合， 变异体分类 假设：虽然存在变异分类的一般指南，但疾病- 特异性，甚至在疾病内，基因特异性，将有助于变异注释。特别是， 可以通过应用深度学习和基于物理的 建模以预测与错义变体相关的自由能变化。 第三章具体目标确定选定类型的非综合征性听力损失的遗传修饰剂 假设：遗传修饰剂的存在得到了种族基因特异性差异的支持- 基于群体研究，并且可以使用听力损失的鼠模型进行验证。 这些具体目标的成功完成将完善我们对听觉生物学的理解 和耳聋，改善听力损失患者的临床护理，为基因治疗提供坚实的基础， 为听力受损者提供精准医疗，促进临床试验的设计，以测试新的治疗方法 治疗基因特异性类型的听力损失，并可能为耳聋的基因治疗确定新的靶点。

Project Summary Hearing loss is the most common sensory deficit in humans. It affects more than 360 million people worldwide and broadly impacts their quality of life. Although causality is multifactorial, in developed countries a large fraction of hearing loss is genetic and non-syndromic, i.e. not associated with other phenotypes. During the prior granting period (12/01/16-11/20/21), we focused on three specific aims: 1) To optimize phenotype-genotype integration in the analysis of hereditary hearing loss by implementing hierarchical surface clustering and audioprofile surface analysis in AudioGene; 2) To explore physics-based protein modeling as a tool within the Deafness Variation Database; and 3) To determine whether genetic modifiers of specific deafness-causing genes can be predicted by hierarchical surface clustering In this competitive renewal, our overarching goals are to further improve the clinical care of persons with hearing loss and to provide a more robust foundation for gene-specific precision medicine for this population. We will achieve these goals by addressing current knowledge gaps as reflected in the following specific aims:  Specific Aim 1. To complete gene-specific natural history studies (NHS) of non-syndromic forms of hearing loss by integrating phenotypic and genotypic data using AudioGene and OtoSCOPE Hypothesis: The natural history of non-syndromic hearing loss is gene specific and can be defined by integrating the hearing loss phenotype (phenome) with the associated genotype (genome) for the various types of non-syndromic hearing loss.  Specific Aim 2. To refine ACMG guidelines for hearing loss by making them gene specific and by implementing a combination of deep learning and physics-based protein modeling to improve variant classification Hypothesis: While general guidelines exist for variant classification, guidelines that are disease- specific and even within a disease, gene specific, will facilitate variant annotation. In particular, variant calling for missense variants can be refined by applying deep learning and physics-based modeling to predict free-energy changes associated with missense variants.  Specific Aim 3. To identify genetic modifiers of select types of non-syndromic hearing loss Hypothesis: The presence of genetic modifiers is supported by gene-specific differences in ethnically- based population studies and can be validated using murine models of hearing loss. The successful completion of these specific aims will refine our understanding of the biology of hearing and deafness, improve the clinical care of persons with hearing loss, provide a strong foundation for gene- based precision medicine for the hearing impaired, facilitate the design of clinical trials to test novel therapies to treat gene-specific types of hearing loss, and potentially identify new targets for gene therapy for deafness.