Implementing genomic medicine in clinical care of deaf patients

翻译后摘要：这一持续的建议将转化为基础研究，利用高通量基因组学的方法， 非综合征性听力损失（NSHL）的常规诊断和治疗工具， 儿童和成人的听力障碍类型。我们开发了一个基因组变异检测平台 MiamiOtogenomics -由MiamiCapitalArray/MiamiOtoGenes面板/外显子组（WES）/基因组（WGS）和 开发了一个基因型和表型数据库- MiamiGeneHeal。如初步数据所示，我们已经 我从一个大型国际队列（迈阿密耳遗传学）中收集了大约3,000个具有表型数据的DNA样本 家庭与NSHL。此外，我们还成功地排除了200多个家系中所有已知的HL基因， 鉴定了超过18个潜在的新候选基因，建立了人类HL的动物模型，并产生了人类HL。 来自遗传性耳聋患者的iPSC。我们将在这些成就和初步数据的基础上， 完成以下具体目标：1.为NSHL应用创新的基于基因组学的MiamiOtogenomics管道; 2. 确定影响进行基因组检测的决定的因素; 3.启动临床前治疗实验 作为HL潜在治疗的概念验证。该提案的基础将利用特殊的基因组学 迈阿密大学的合作者的能力，以基因组为基础，以少数民族为重点，诊断和治疗 管道HL。该应用程序的首要目的是将实验室中的发现转移到患者护理中。这 这项研究将把基因组分析转化为临床听力筛查，以阐明HL的确切分子病因， 这将使更准确的诊断，更好的护理质量，更有效的遗传咨询，以及改善 医疗保健的成本效益。此外，我们希望能为基因型-表型研究和 建立一个评估长期临床结果的强大框架。这项研究将有助于我们 对HL的基本认识。最后，我们在敲入小鼠中进行的创新临床前治疗实验， 使用CRISPR的人类iPSC模型将有可能发现HL的新治疗方法。本研究将为两个重要的 精准医疗在美国人群中的临床方面，特别是在美国少数民族中：临床上的普遍接受度 实践和临床应用。我们将开展一项规模最大、最完整的临床/基因组/功能/新型 迄今为止对NSHL的治疗研究。我们先前的结果，跨学科团队的专业知识和我们的既定研究 基础设施和人口准入支持我们目标的可行性。

Abstract: This continuing proposal will translate basic research utilizing high-throughput genomic approaches and functional genomics into routine diagnostic and therapeutic tools for non-syndromic hearing loss (NSHL), the most common type of hearing impairment in children and adults. We have developed a genomic variant detection platform MiamiOtogenomics - composed of MiamiCapitalArray/MiamiOtoGenes panels/exome (WES)/genome (WGS) and developed a genotype and phenotype database – MiamiGeneHeal. As shown in the preliminary data, we have already collected approximately 3,000 DNA samples with phenotypic data from a large international cohort (Miami Otogenetic Repository) of families with NSHL. Moreover, we have excluded all known HL genes in over 200 families, successfully identified more than 18 potential new candidate genes, created animal models for human HL, and have generated human iPSCs from patients with genetic deafness. We will build on these accomplishments and preliminary data by proposing to complete the following specific aims: 1. Apply an innovative genomics-based MiamiOtogenomics pipeline for NSHL; 2. Identify factors influencing the decision to pursue and act on genomic testing; 3. Initiate preclinical therapeutic experiments as a proof-of-concept for potential treatments for HL. The foundation of the proposal will leverage the exceptional genomics capacity of collaborators at the University of Miami into a genomic-based, minority-focused, diagnostic and treatment pipeline for HL. The overarching purpose of this application is to transit discoveries made in laboratory to patient care. This study will translate genomic analysis into clinical hearing screening to elucidate the exact molecular etiology for HL, which will enable more accurate diagnoses, better quality of care, more effective genetic counseling, as well as improved cost-effectiveness in medical care. In addition, we expect to contribute significantly to genotype-phenotype studies and to establish a robust framework for assessing long-term clinical outcomes. Moreover, this study will contribute to our fundamental understanding of HL. Finally, our innovative preclinical therapeutic experiments in our knockin mouse and human iPSC models using CRISPR will potentially discover new treatments for HL. This study will inform two important clinical aspects of precision medicine in USA populations, especially in USA minorities: general acceptance in clinical practice and clinical utility. We will perform one of the largest and most integrated clinical/genomic/functional/novel therapeutic studies on NSHL to date. Our prior results, the interdisciplinary team's expertise and our established study infrastructure and population access support feasibility of our Aims.