Implementing genomic medicine in clinical care of deaf patients

描述（由申请人提供）：听力损失（HL）影响至少30%的人口在他们的生活中的某个时候。虽然HL既有遗传基础，也有环境基础，但据估计，听力损失的遗传原因占出生时表达的病例的68%，占4岁时表达的病例的55%。许多HL基因的鉴定极大地改善了耳聋和听力障碍家庭的临床诊断和管理。然而，目前的耳聋基因检测策略是不够的。基因检测目前只专注于检测少数已知基因，因此在许多情况下，遗传原因从未确定。随着“靶富集”方法和下一代测序（NGS）的最新技术进步，对许多导致NSHL的基因的鉴定正在使遗传性耳聋的分子流行病学研究和对遗传疾病剩余基因的新一波发现成为可能。然而，将这些知识转化为患者护理是滞后的。目前，有关遗传信息在耳聋患者管理中的临床有效性和临床应用的有用循证信息数据库很少。迫切需要将个体患者的全面基因组信息带入“真实世界”的临床环境。我们收集了来自美国、中国和土耳其三个独特来源的多家族的独特队列，适用于遗传性耳聋的分子流行病学测定和新基因鉴定。我们已经建立了迈阿密耳发育项目，包括分子遗传实验室和遗传性听力损失诊所。重要的是，正如我们的初步研究所显示的那样，我们已经证明在一个平台上同时分析所有耳聋基因是可能的，在我们的先导研究中排除了40%的HL的已知原因，并成功地在这些小的多重家族中使用全外显子组测序确定了三个新的基因。在这些初步数据的基础上，我们将完成三个具体目标。1：通过对来自不同民族人群的大队列先证完成所有NSHL致病基因的突变筛选，确定已知NSHL基因致聋突变的分子流行病学。目的：在已知聋基因全外显子组序列均为阴性的多家族中，寻找非综合征性听力损失的新基因。3：建立耳聋基因组数据库（GDD）和个性化序列图谱（PSP），用于耳聋患者的护理。

DESCRIPTION (provided by applicant): Hearing loss (HL) affects at least 30% of the population at some time in their lives. While HL has both genetic and environmental underpinnings, the genetic causes of hearing loss are estimated to account for 68% of cases expressed at birth and 55% of those expressed by the age of four. The identification of many genes for HL has dramatically improved the clinical diagnosis and management of deaf and hard-of-hearing families. However, current strategies for genetic testing for deafness are inadequate. Genetic testing currently focuses on testing only a few of the known genes and so in many cases, the genetic cause is never determined. The identification of numerous genes causing NSHL along with recent technological advances in "target-enrichment" methods and next generation sequencing (NGS) is now making possible molecular epidemiological studies of genetic deafness and a new wave of discoveries of the remaining genes for genetic diseases. The translation of this knowledge to patient care is, however, lagging behind. Currently, few available databases have useful evidence-based information concerning the clinical validity and clinical utility of genetic information for deafness patient management. There is an urgent need to bring comprehensive genomic information of individual patients into the "real world" clinical environment. We have collected a unique cohort of multiplex families derived from three unique sources from USA, China and Turkey, suitable for determination of molecular epidemiology of hereditary deafness and for new gene identification. We have established the Miami Otogenetic Program including the Molecular Genetic Laboratory and the Hereditary Hearing Loss Clinic. Importantly, as shown in our preliminary studies, we have shown that it is possible to analyze all deafness genes simultaneously on a single platform, excluded known causes of HL in 40% of the probands in our pilot studies and successfully identified three new genes in these small multiplex families using whole exome sequencing. Building on these preliminary data in this translational proposal we will complete three specific aims. 1: To determine molecular epidemiology of deafness-causing mutations in known NSHL genes by completing mutation screening of all genes causing NSHL in a large cohort of probands from different ethnic populations. 2: To identify new genes for non-syndromic hearing loss in those multiplex families found to be negative for all known deafness genes by whole exome sequence. 3: To create Genomic Deafness Database (GDD) and Personalized Sequence Profile (PSP) for care of deafness patients.