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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：
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
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/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

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.

总结