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.

总结 听力障碍是一种常见的和致残的感觉缺陷，在一个子集的个人可能是由于 异常的耳蜗前庭解剖。耳蜗前庭神经（CV）和耳蜗前庭神经（CVN）异常可 严重影响儿童的发展，目前在治疗和管理方面构成挑战。小 研究已经完成，以了解这些畸形的病因，特别是那些非- 综合征和重度，如耳蜗发育不全。我们迫切需要更好地了解 这些条件的分子机制，以帮助诊断，干预和管理。此外，健康 在西班牙裔听力损伤（HI）的分子诊断和治疗方面存在差异， HI的分子病因学在这一种族群体中几乎没有研究。研究其病因是非常必要的。 不同种族/民族人群中的CV/CVN异常，以了解哪些基因/变异是常见原因 这种疾病在每个人群中的分布情况。因此，分子诊断和治疗可以根据以下方面进行调整： 具体人口信息。 我们假设严重的非综合征性CV/CVN异常的一个重要子集具有遗传病因， 这些信息可能在不同人群之间存在差异，了解这些信息将有助于我们更好地了解人类的内心世界。 耳发育我们的初步研究表明，罕见的遗传变异，包括新生变异， 与严重CV/CVN异常的发生有关。我们的提案利用了基因组学数据， 颞骨成像数据，以揭示非综合征型CV/CVN畸形的分子基础。实现 为此，我们将1）招募并建立一个大型的CV/CVN种族/民族多样性家庭的基因组数据库 已经详细分型的畸形。2)接下来，我们将确定 西班牙裔和非西班牙裔个体中CV/CVN畸形的潜在变异。3)最后， 使用招募的和现有的CV/CVN畸形和舌前感觉神经性 听力障碍，我们将识别与CV/CVN畸形有关的新因果基因并评估其 在早期颅面和内耳发育过程中表达。 我们已经组建了一个团队，拥有实现这些目标的集体专业知识以及先前的业绩记录 富有成效的合作。这项工作将阐明严重的非综合征型CV/CVN的遗传结构 畸形的不同种族/种族人群，并提高我们对人类内耳的基本知识 发展和机制导致异常发展。这些知识可以用来 改善分子诊断，指导治疗干预和管理，预测结果，并开发 有益于不同种族/种族背景的个体的新的治疗方法。