Unraveling the genetic architecture of cochleovestibular malformations

揭示耳蜗前庭畸形的遗传结构

• 批准号: 10672304
• 负责人: Isabelle Veerle Suzanne Schrauwen
• 金额: $ 41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672304
• 关键词: Affect; African; Anatomy; Belgium; Bilateral; Candidate Disease Gene; Cells; Child; Child Development; Cities; Clinical; Cochlea; Collaborations; Collection; Complex; Counseling; Country; DNA; Data; Data Set; Databases; Defect; Developed Countries; Development; Diagnosis; Diagnostic; Disease; Ear; Ethnic Origin; Ethnic Population; Etiology; Event; Family; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Height; Hispanic; Hispanic Populations; Hospitals; Human; Image; Imaging Techniques; In Situ Hybridization; Individual; Intervention; Knowledge; Labyrinth; Magnetic Resonance Imaging; Methods; Mexico; Modeling; Molecular; Molecular Diagnosis; Molecular Diagnostic Testing; Nerve; Neural Crest; New York City; Newborn Infant; Not Hispanic or Latino; Otolaryngologist; Parents; Pathogenicity; Patients; Phenotype; Population; Population Heterogeneity; Productivity; RNA analysis; Race; Repetitive Sequence; Research; Resolution; Resources; Sensorineural Hearing Loss; Sensory; Site; South Asian; Temporal bone structure; Therapeutic; Therapeutic Intervention; United States; Variant; Washington; Work; X-Ray Computed Tomography; autosome; bone imaging; causal variant; cohort; congenital hearing loss; cost effective; craniofacial; dark matter; de novo mutation; demographics; diagnostic screening; diagnostic tool; ethnic diversity; ethnic health disparity; exome; exome sequencing; experimental study; genetic architecture; genetic variant; genome sequencing; genomic data; genomic variation; health disparity; hearing impairment; improved; inner ear development; innovation; insight; malformation; molecular diagnostics; negative affect; novel; novel therapeutic intervention; outcome prediction; participant enrollment; personalized medicine; phenotypic data; preference; proband; racial diversity; racial health disparity; racial population; recruit; repository; screening; sound; therapeutic development; transcriptome sequencing

SUMMARY Hearing impairment is a common and disabling sensory defect which in a subset of individuals can be due to an abnormal cochleovestibular anatomy. Cochleovestibular (CV) and cochleovestibular nerve (CVN) anomalies can significantly impact a child’s development and currently pose challenges in treatment and management. Little research has been done to understand the etiology of these malformations, especially those that are non- syndromic and severe, such as cochlear aplasia. There is a crucial need to better understand the underlying molecular mechanisms of these conditions to aid in diagnosis, intervention and management. In addition, health disparities exist in the molecular diagnosis and treatment of hearing impairment (HI) in Hispanics, as the molecular etiology of HI has been scarcely studied in this ethnic group. It is imperative to study the etiology of CV/CVN anomalies in diverse racial/ethnic populations to understand which genes/variants are a frequent cause of this disorder in each population. Molecular diagnostics and treatment can therefore be tailored based on population-specific information. We hypothesize that a significant subset of severe non-syndromic CV/CVN anomalies has a genetic etiology, which may differ between populations, and knowledge of this information will improve our understanding of inner ear development. Our preliminary research suggests that rare genetic variants, including de novo variants, are implicated in the development of severe CV/CVN anomalies. Our proposal leverages genomics data and temporal bone imaging data to unravel the molecular basis of non-syndromic CV/CVN malformations. To achieve this, we will 1) recruit and establish a large genomic database of racially/ethnically diverse families with CV/CVN malformations which have been phenotyped in detail. 2) Next, we will determine the genetic spectrum of underlying variation implicated in CV/CVN malformations in both Hispanic and non-Hispanic individuals. 3) Last, using recruited and existing cohorts of individuals with CV/CVN malformations and prelingual sensorineural hearing impairment, we will identify novel causal genes implicated in CV/CVN malformations and assess their expression during early craniofacial and inner ear development. We have assembled a team that has the collective expertise to achieve these aims as well as a prior track record of productive collaboration. This work will elucidate the genetic architecture of severe non-syndromic CV/CVN malformations diverse ethnic/racial populations and improve our basic knowledge of human inner ear development and the mechanisms leading to abnormal development. This knowledge can then be used to improve molecular diagnostics, guide therapeutic intervention and management, predict outcomes, and develop novel therapeutic approaches benefiting individuals of diverse ethnicity/racial background.

概括 听力障碍是在一部分个人中常见且残疾的哨兵缺陷白色可能是由于 耳目植物解剖学异常。 显着影响的发展，目前在治疗和管理中构成挑战。 已经进行了研究以理解ESE畸形的病因，尤其是那些非畸形的病因 综合征和严重的人工耳蜗，至关重要的是要更好地了解基础 这些条件的分子机制有助于诊断，间隔和管理。 在西班牙裔中的分子诊断和治疗听力障碍（HI）中存在差异， 在这个种族中，几乎没有研究HI的分子病因。 CV/CV/CVN异常在不同的种族/种族种群中，以了解哪些基因/变体是经常出现的原因 在每个人群中的这种疾病。 特定于人群的信息。 我们假设严重的非综合症CV/CVN异常的显着子集具有遗传病因， 人群之间可能有所不同，并且对这一知识的了解使我们的理解 耳朵发展。我们的初步研究表明 与严重的CV/CVN异常相关。 颞骨成像数据以阐明非综合CV/CVN畸形的分子基础 这，我们将1）招募并建立一个具有CV/CVN的种族/种族多样家庭的大型基因组数据库 已详细概述的畸形2）接下来，我们将确定 基本变化与西班牙裔和西班牙裔人物中的CV/CVN畸形有关。 使用CV/CVN畸形和初步感觉的招募和现有人群 听力障碍，我们将确定与CV/CVN畸形有关的新型因果基因评估他们的 早期颅面和内耳发育期间的表达。 我们组建了一个具有集体专业知识的团队，以及先前的往绩记录 这项工作将阐明严重的非综合症CVN的遗传结构 畸形多种种族/种族种群，并提高我们对人内耳的基本知识 发展和导致异常发展的机制。 改善分子诊断，指导治疗干预和管理，预测结果并发展 新颖的治疗方法使各种种族/种族背景的人受益。