Unraveling the genetic architecture of cochleovestibular malformations

揭示耳蜗前庭畸形的遗传结构

基本信息

批准号：
10522114
负责人：
Isabelle Veerle Suzanne Schrauwen
金额：
$ 42.62万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10522114
关键词：
Affect African Anatomy Belgium Bilateral Candidate Disease Gene Cells Child Child Development Cities Clinical Cochlea Cochlear Nerve Collaborations Collection Complex Counseling Country DNA Data Data Set Databases Defect Developed Countries Development Diagnosis Diagnostic Disease Ear Enrollment Epithelial Ethnic Origin Ethnic group Etiology Event Family Future Gene Expression Genes Genetic Genetic Predisposition to Disease Genomics Hispanic Hispanic Populations Hospitals Human 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 RNA analysis 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 base 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 neurosensory novel novel therapeutic intervention outcome prediction personalized medicine phenotypic data preference proband racial and ethnic racial diversity racial population recruit repository screening sound therapeutic development transcriptome sequencing

Affect African Anatomy Belgium Bilateral Candidate Disease Gene Cells Child Child Development Cities Clinical Cochlea Cochlear Nerve Collaborations Collection Complex Counseling Country DNA Data Data Set Databases Defect Developed Countries Development Diagnosis Diagnostic Disease Ear Enrollment Epithelial Ethnic Origin Ethnic group Etiology Event Family Future Gene Expression Genes Genetic Genetic Predisposition to Disease Genomics Hispanic Hispanic Populations Hospitals Human 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 RNA analysis 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 base 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 neurosensory novel novel therapeutic intervention outcome prediction personalized medicine phenotypic data preference proband racial and ethnic racial diversity racial population recruit repository screening sound therapeutic development transcriptome sequencing

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项目摘要

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.

概括听力障碍是一种常见且残疾的感觉缺陷，在一部分中，这可能是由于异常的耳目植物解剖结构。耳目骨鱼（CV）和耳目植物神经（CVN）异常可以显着影响孩子的成长，目前在治疗和管理方面构成挑战。小的进行了研究以了解这些畸形的病因，尤其是那些非畸形的畸形综合征和严重，例如人工耳蜗。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，干预和管理。此外，健康在西班牙裔的分子诊断和听力障碍（HI）的分子诊断和治疗中存在差异，在这个种族中，几乎没有研究HI的分子病因。必须研究在潜水员种族/种族种群中，CV/CVN异常，以了解哪些基因/变体通常是原因每个人群中的这种疾病。因此，分子诊断和治疗可以根据特定于人群的信息。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，对这些信息的了解将改善我们对内心的理解耳朵发育。我们的初步研究表明，包括从头变异在内的罕见遗传变异是实施在严重的CV/CVN异常中实施。我们的建议利用基因组学数据和临时骨成像数据以揭示非综合性CV/CVN畸形的分子基础。实现这，我们将1）招募并建立一个大约具有CV/CVN家庭的大型基因组数据库已详细表型的畸形。 2）接下来，我们将确定在西班牙裔和非西班牙裔个体中，在CV/CVN畸形中实施的基本变化。 3）最后，使用CV/CVN畸形和初步感官的招募和现有人群听力障碍，我们将确定在CV/CVN畸形中实施的新的因果基因并评估其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，以实现这些目标以及先前的往绩记录生产性合作。这项工作将阐明严重非综合症CV/CVN的遗传结构畸形潜水员种族/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。然后可以将这些知识用于改善分子诊断，指导治疗干预和管理，预测结果并发展新颖的热方法使潜水员种族/种族背景的个人受益。