Implementing genomic medicine in clinical care of deaf patients

在耳聋患者的临床护理中实施基因组医学

• 批准号: 8496435
• 负责人: XUE Z LIU
• 金额: $ 61.32万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-08 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496435
• 关键词: Accounting; Affect; Age; Algorithms; Auditory; Bioinformatics; Biological; Biology; Birth; Caring; China; Clinic; Clinical; Clinical Management; Computerized Medical Record; Data; Databases; Defect; Diagnostic; Dideoxy Chain Termination DNA Sequencing; Disease; Environment; Epidemiologic Studies; Epidemiology; Ethnic Origin; Evaluation; Family; Frequencies; Gene Frequency; Gene Mutation; Genes; Genetic; Genetic Annotation; Genetic Counseling; Genetic Polymorphism; Genetic Variation; Genetic screening method; Genomics; Genotype; Health; Hearing; Hearing Impaired Persons; Hereditary Disease; Human; Individual; Infant; Inherited; Institutes; Knowledge; Laboratories; Lead; Link; Literature; Maps; Medical; Medicine; Meleagris gallopavo; Methods; Molecular; Molecular Epidemiology; Molecular Genetics; Mutation; Patient Care; Patients; Pattern; Pilot Projects; Population; Population Control; Process; Proteins; Reporting; Research Personnel; Resources; Source; System; Testing; Time; United States; Validation; Variant; base; clinical Diagnosis; clinical care; clinically relevant; clinically significant; cohort; deafness; ethnic difference; evidence base; exome sequencing; follow-up; genetic pedigree; hearing impairment; improved; knowledge translation; meetings; next generation sequencing; novel; patient population; proband; programs; public health relevance; research clinical testing; screening; segregation; therapeutic development

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.

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有遗传和环境基础，但据估计，听力损失的遗传原因占出生时表达病例的68%，占4岁时表达病例的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，遗传原因永远无法确定。沿着许多导致NSHL的基因的鉴定以及“靶富集”方法和下一代测序（NGS）的最新技术进步，现在使得遗传性耳聋的分子流行病学研究和遗传性疾病的剩余基因的新一波发现成为可能。然而，将这些知识转化为病人护理的工作却滞后了。目前，很少有可用的数据库有有用的循证信息有关的临床有效性和遗传信息的耳聋患者管理的临床效用。迫切需要将个体患者的全面基因组信息带入“真实的世界”临床环境。我们从美国、中国和土耳其的三个独特来源中收集了一组独特的多重家族，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遗传学项目，包括分子遗传学实验室和遗传性听力损失诊所。重要的是，如我们的初步研究所示，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，在我们的初步研究中排除了40%先证者中的HL已知原因，并使用全外显子组测序在这些小型多重家族中成功鉴定了三个新基因。在这个翻译建议中，我们将根据这些初步数据完成三个具体目标。一曰：通过在来自不同种族人群的大队列先证者中完成导致NSHL的所有基因的突变筛查，确定已知NSHL基因中致突变突变的分子流行病学。第二章：目的：在已知耳聋基因均为阴性的多基因家系中，寻找新的非综合征性耳聋基因。3.建立基因组耳聋数据库（GDD）和个性化序列图谱（PSP），用于耳聋患者的护理。