Implementing genomic medicine in clinical care of deaf patients

在聋哑患者的临床护理中实施基因组医学

• 批准号: 8634091
• 负责人: XUE Z LIU
• 金额: $ 61.38万
• 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/8634091
• 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）：至少 30% 的人口在一生中的某个时期会受到听力损失 (HL) 的影响。虽然 HL 既有遗传因素，也有环境因素，但据估计，出生时出现的听力损失病例中有 68% 是由遗传原因造成的，而四岁时出现的听力损失病例中则占 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还不够。基因测试目前仅侧重于测试少数已知基因，因此在许多情况下，遗传原因永远无法确定。导致 NSHL 的众多基因的鉴定以及“目标富集”方法和下一代测序 (NGS) 方面的最新技术进步，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的工作却滞后。目前，很少有可用的数据库拥有关于耳聋患者管理遗传信息的临床有效性和临床实用性的有用的循证信息。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独特的多重家族队列，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，正如我们的初步研究所示，我们已经证明可以在一个平台上同时分析所有耳聋基因，在我们的试点研究中排除了 40% 先证者中 HL 的已知原因，并成功鉴定了这些基因中的 3 个新基因。使用全外显子组测序的小型多重家族。基于此翻译提案中的这些初步数据，我们将完成三个具体目标。图 1：通过对来自不同种族人群的大量先证者中所有导致 NSHL 的基因进行突变筛查，确定已知 NSHL 基因中导致耳聋的突变的分子流行病学。图 2：在通过整个外显子组序列发现所有已知耳聋基因呈阴性的多重家族中，鉴定非综合征性听力损失的新基因。 3：创建基因组耳聋数据库（GDD）和个性化序列图谱（PSP）以护理耳聋患者。