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。每500名新生儿中就有1人被诊断出患有这种疾病 影响到一半的八十多岁的人。尽管因果关系是多因素的，但在发达国家， 听力损失是遗传性的和非综合征的，即与其他表型无关。 在之前的授权期内，我们实施和整合了全面的基因测试作为 是评估聋哑人和重听者的基石。美国医学院 遗传学已经认识到这种方法的优点，并在2014年包括了全面的基因测试 在他们最新的治疗指南中对耳聋进行评估。这是迄今为止规模最大的研究 证实了这一结论，我们在1119名中的440名(39%)中发现了听力损失的潜在遗传原因 无排除标准选择按顺序累加的患者。在49例患者中存在致病变异 基因和包括错义变异(49%)、拷贝数变化(18%)、插入片段(18%)、无稽之谈 变异(8%)、剪接位点改变(6%)和启动子变异(1%)，使综合遗传 测试听力图后听力损失诊断中的单项最佳顺序测试。 在这次竞争性更新中，我们将通过实现以下目标在这些成就的基础上再接再厉： ·具体目标1：在遗传性听力损失分析中优化表型-基因整合 通过细化使用分层表面聚类和音频剖面表面分析来确定 哪些类型的遗传性听力损失与临床上有意义的亚群有关 ·具体目标2：验证和整合以物理学为基础的蛋白质建模，将其作为聋人的工具 用于预测变异效应和分子和患者表型的变异数据库 ·具体目标3：确定下列预测的特定致聋基因的遗传修饰因子 基于物理势自由能模型的层次化表面聚类及验证 这笔赠款的成功完成将改善听力损失患者的临床护理 加强表现组-基因组整合，并通过使变体解释更加稳健。知识 从这项建议中获得的成果也将为专注于识别 遗传修饰物--既有积极的，也有消极的--与复杂的表型有关，如噪音-- 诱发的和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.