Unraveling the genetic architecture of cochleovestibular malformations

摘要 听力障碍是一种常见的致残性感觉缺陷，在一部分人中可能是由于 耳蜗前庭解剖异常。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。一点儿 已经进行了研究以了解这些畸形的病因，特别是那些非 综合征和重症，如耳蜗性再生障碍性贫血。迫切需要更好地理解潜在的 这些疾病的分子机制有助于诊断、干预和治疗。此外，健康 在拉美裔听力障碍(HI)的分子诊断和治疗方面存在差异，因为 在这个民族中，对HI的分子病因学研究很少。因此，对其病因的研究势在必行。 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基于 特定于人口的信息。 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， 这在不同的人群中可能是不同的，了解这些信息将提高我们对内心的理解 耳朵发育。我们的初步研究表明，罕见的遗传变异，包括从头开始的变异，是 与严重的CV/CVN异常的发生有关。我们的计划利用了基因组学数据和 颞骨成像数据，以揭示非综合征性CV/CVN畸形的分子基础。要实现 为此，我们将1)招募和建立一个大型基因组数据库，其中包括种族/民族多样化的CV/CVN家庭 已经进行了详细表型的畸形。2)接下来，我们将确定 潜在变异与西班牙裔和非西班牙裔个体的CV/CVN畸形有关。3)最后， 使用招募的和现有的CV/CVN畸形和语前感觉神经病患者队列 听力障碍，我们将识别与CV/CVN畸形有关的新的致病基因，并评估它们的 在颅面和内耳发育的早期表达。 我们已经组建了一支团队，他们拥有实现这些目标的集体专业知识以及先前的记录 卓有成效的协作。这项工作将阐明严重非综合征CV/CVN的遗传结构 畸形使种族/种族人群多样化，并提高我们对人类内耳的基本知识 发展和导致异常发展的机制。这些知识然后可以用来 改进分子诊断，指导治疗干预和管理，预测结果，发展 新的治疗方法使不同族裔/种族背景的人受益。

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.