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。每500名新生儿中就有1人被诊断出患有此病， 影响了一半的八十多岁老人。虽然因果关系是多因素的，但在发达国家， 听力损失是遗传性和非综合征性的，即与其他表型无关。 在上一个授予期间，我们实施并整合了全面的基因检测， 这是评估聋人和重听人的基石。美国医学院 遗传学已经认识到这种方法的优点，并在2014年纳入了全面的基因检测 在他们最新的治疗指南中评估耳聋。在迄今为止规模最大的研究中， 为了证实这一结论，我们在1119名患者中发现了440名（39%）听力损失的潜在遗传原因 按顺序纳入无排除标准选择的患者。致病性变异存在于49 基因，包括错义变异（49%），拷贝数变化（18%），插入缺失（18%），无义 变异（8%），剪接位点改变（6%）和启动子变异（<1%），使全面的遗传 在听力图检查后，对听力损失的诊断进行单一最佳测试。 在这次竞争性更新中，我们将通过完成以下目标来巩固这些成就： ·具体目标1：优化遗传性听力损失分析中的表型-基因型整合 通过细化使用分层表面聚类和音频轮廓表面分析来确定 哪些类型的遗传性听力损失与临床上有意义的亚群相关 ·具体目标2：验证和整合基于物理学的蛋白质建模作为耳聋研究中的工具。 变异数据库，用于预测变异效应以及分子和患者表型 ·具体目标3：鉴定通过以下预测的特定致孕基因的遗传修饰剂： 分层表面聚类并通过基于物理的势能自由能建模进行验证 这笔赠款的成功完成将改善听力损失者的临床护理， 增强表型组-基因组整合，并使变异解释更加稳健。知识 从这一建议中获得的信息也将为重点确定以下方面的精细研究奠定基础： 遗传修饰剂-积极和消极的-与复杂的表型，如噪音， 与年龄相关的听力损失。

Project Summary Hearing loss is the most common sensory deficit in humans. It is diagnosed in 1 in 500 newborns and affects half of all octogenarians. 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, we implemented and integrated comprehensive genetic testing as a cornerstone in the evaluation of the deaf and hard-of-hearing person. The American College of Medical Genetics has recognized the merit of this approach, and in 2014 included comprehensive genetic testing for the evaluation of deafness in their newest treatment guidelines. In the largest study to date to corroborate this decision, we found an underlying genetic cause for hearing loss in 440 (39%) of 1119 sequentially accrued patients chosen without exclusion criteria. Pathogenic variants were present in 49 genes and included missense variants (49%), copy number changes (18%), indels (18%), nonsense variants (8%), splice-site alterations (6%) and promoter variants (<1%), making comprehensive genetic testing the single best test to order in the diagnosis of hearing loss after an audiogram. In this competitive renewal, we will build on these accomplishments by completing the following aims: • Specific Aim 1: To optimize phenotype-genotype integration in the analysis of hereditary hearing loss by refining the use of hierarchical surface clustering and audioprofile surface analysis to determine which types of genetic hearing loss are associated with clinically meaningful sub-clusters • Specific Aim 2: To validate and integrate physics-based protein modeling as a tool within the Deafness Variation Database to predict variant effect and the molecular and patient phenotype • Specific Aim 3: To identify genetic modifiers of specific deafness-causing genes predicted by hierarchical surface clustering and validated by physics-based potential free-energy modeling The successful completion of this grant will improve the clinical care of persons with hearing loss by enhancing phenome-genome integration and by making variant interpretation more robust. Knowledge gained from this proposal will also lay the foundation for refined studies focused on the identification of genetic modifiers – both positive and negative – associated with complex phenotypes such as noise- induced and age-related hearing loss.