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障碍。它影响了超过3.6亿人 在世界范围内和广泛地影响他们的生活质量。尽管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和非综合征性的，即与其他表型无关。 在之前的授权期(12/01/16-11/20/21)，我们专注于三个具体目标：1)优化 表型-基因整合在遗传性耳聋分析中的应用 Audiogene中的聚类和音频轮廓表面分析；2)探索基于物理的蛋白质建模作为一种 在耳聋变异数据库中的工具；以及3)以确定特定的遗传修饰物 通过分层表面聚类可以预测导致耳聋的基因 在这次竞争性的更新中，我们的首要目标是进一步改善对患有疾病的患者的临床护理 并为这一人群的基因特异性精准医学提供更坚实的基础。 我们将通过解决目前的知识差距来实现这些目标，具体目标如下： 的具体目标1.完成非综合征形式的基因特异性自然史研究 利用Audiogene和耳镜整合表型和基因数据的听力损失 假设：非综合征性听力损失的自然病史是基因特有的，可以通过以下方式定义 将听力损失表型(表型组)与相关的基因(基因组)整合 各种类型的非综合征性听力损失。 特定目标2.完善ACMG听力损失指南，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相结合的方法来改进 变式分类 假设：虽然存在变种分类的一般指南，但属于疾病的指南- 特定的，甚至在疾病中，基因特定的，将有助于变异注释。特别是， 调用错义变体的变体可以通过应用深度学习和基于物理的 用于预测与错义变体相关的自由能变化的建模。 特定目标3.确定选定类型的非综合征性听力损失的遗传修饰因素 假说：基因修饰物的存在是由基因特定的种族差异支持的。 基于人群研究，并可以用小鼠听力损失模型进行验证。 这些特定目标的成功完成将加深我们对听觉生物学的理解 提高聋人的临床护理水平，为基因治疗提供坚实的基础。 基于听力障碍的精确医学，促进临床试验的设计，以测试新的疗法 治疗特定基因类型的听力损失，并有可能确定耳聋基因治疗的新靶点。

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.