Phenotypic and Genomic Characterization of Microtia in the Andean Population

安第斯人群小耳症的表型和基因组特征

• 批准号: 8163953
• 负责人: Daniela Varela Luquetti
• 金额: $ 10.11万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8163953
• 关键词: Acute; Affect; Alcohols; Award; BMP5 gene; Birth; Bolivia; Candidate Disease Gene; Career Transition Award; Caring; Child; Clinical; Clinical Management; Colombia; Congenital Abnormality; Country; DNA; DNA Resequencing; Data; Databases; Development; Disease; Ear; Ecuador; Environmental Exposure; Environmental Risk Factor; Etiology; External Ear; FGF8 gene; Family; Frequencies; Future; Genes; Genetic; Genetic Risk; Genomics; Goals; High Prevalence; Hispanics; Human Development; Individual; Intake; International; Knowledge; Laboratories; Labyrinth; Lead; Life; Manuscripts; Medical; Mentors; Methods; Molecular Genetics; Mutation; Operative Surgical Procedures; Outcome; Pathogenesis; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Population; Positioning Attribute; Prevalence; Prevention; Psychological Impact; Public Health; Registries; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Sampling; Severities; South America; South American; Testing; Time; Training; Variant; Work; base; career; case control; clinical phenotype; cost; exome; external ear auricle; genetic risk factor; hearing impairment; improved; malformation; middle ear; non-genetic; prospective; reconstruction; skills

DESCRIPTION (provided by applicant): Microtia is a congenital anomaly of the auricle ranging from mild structural abnormalities to complete absence of the ear. The clinical impact of this condition relates to the management of hearing loss, present in the majority of the cases, and the multi-step ear reconstruction. There is a fundamental gap in understanding the etiology of microtia; to date no extensive studies have been performed either on the molecular genetic basis or environmental factors related to its occurrence. More important, although there is strong evidence for a genetic component in the pathogenesis of microtia, only one study, which resequenced two candidate genes, has been conducted. The short-term goal of this research is to study the phenotypic, genetic, and environmental risk factors for microtia in children from the Andean region, more specifically from Ecuador, Bolivia and Colombia. This population was selected because previous studies and strong preliminary data, demonstrate that these countries have a birth prevalence that is higher than previously reported worldwide. The central hypothesis is that candidate genes and non-genetic risk factors associated with microtia will be identified in this population. In the mentored phase of this career transition award the candidate will 1) conduct SNP discovery in five candidate genes in samples from Bolivian individuals with isolated microtia, and 2) conduct a case-control analysis on microtia risk factor involving over 2,000 isolated microtia cases using information collected in a South American birth registry database. In addition, under the direction of three career research mentors, she will complete advanced coursework, receive laboratory training in genomics, submit manuscripts, and seek an independent research position. During the independent phase of the award she will prospectively ascertain and perform extensive phenotypic characterization on 145 subjects with isolated microtia from Bolivia, Colombia and Ecuador. First, she will identify subphenotypes in individuals with isolated microtia assessing the severity of outer ear malformation as well as the presence and pattern of hearing impairment and inner and middle ear anomalies. Second, she will characterize ancestry in the same subjects using ancestry informative markers to investigate the role of ancestry in the higher prevalence in the Andean region. Third, she will conduct the first whole-exome sequencing in individuals with isolated microtia to discover new candidate genes involved in its pathogenesis. The rationale that underlies the proposed research is that a better understanding of the etiology and phenotype of microtia will lead to improve clinical management and prevention in the future. The long-term goal of the candidate's proposed research is to identify and understand how genetic and environmental factors contribute to abnormal human development. Completion of these aims will provide the candidate with the necessary training and preliminary data for her future research into the genetic and non-genetic risk factors of microtia and other birth defects in larger international studies. PUBLIC HEALTH RELEVANCE: The aim of this career transition award proposal is to study microtia, a congenital ear malformation that is associated with hearing loss in approximately 90% of the affected individuals. We propose to study the genetic and environmental risk factors involved in microtia in the Andean Region, in South America, where the frequency of this malformation is three to four times higher than in other countries. This research is relevant to public health because the discovery of causes for microtia occurrence is ultimately expected to increase understanding of the pathogenesis and risk prediction of developmental abnormalities of the ear.

描述（由申请人提供）：小耳畸形是一种先天性耳廓异常，范围从轻度结构异常到完全无耳。这种情况的临床影响与大多数病例中存在的听力损失的管理和多步骤耳重建有关。有一个根本的差距，在了解小耳畸形的病因，迄今为止，没有广泛的研究已经进行了分子遗传基础或环境因素与其发生。更重要的是，虽然有强有力的证据表明遗传因素在小耳畸形的发病机制中起作用，但只有一项研究对两个候选基因进行了重新测序。本研究的短期目标是研究来自安第斯地区，更具体地说，来自厄瓜多尔，玻利维亚和哥伦比亚的儿童小耳畸形的表型，遗传和环境风险因素。之所以选择这一人群，是因为先前的研究和有力的初步数据表明，这些国家的出生率高于世界各地先前报告的出生率。中心假设是，候选基因和非遗传性风险因素与小耳畸形将在这一人群中确定。在该职业过渡奖的指导阶段，候选人将1）在玻利维亚孤立性小耳症患者的样本中进行五个候选基因的SNP发现，2）使用南美出生登记数据库中收集的信息对涉及2,000多例孤立性小耳症病例的小耳症风险因素进行病例对照分析。此外，在三位职业研究导师的指导下，她将完成高级课程，接受基因组学实验室培训，提交手稿，并寻求独立的研究职位。在该奖项的独立阶段，她将前瞻性地确定并对来自玻利维亚、哥伦比亚和厄瓜多尔的145名孤立性小耳畸形受试者进行广泛的表型表征。首先，她将确定孤立性小耳畸形个体的亚表型，评估外耳畸形的严重程度以及听力障碍和内耳和中耳异常的存在和模式。第二，她将使用祖先信息标记来描述相同受试者的祖先，以调查安第斯地区祖先在较高患病率中的作用。第三，她将在患有孤立性小耳畸形的个体中进行首次全外显子组测序，以发现参与其发病机制的新候选基因。提出这项研究的基本原理是，更好地了解小耳畸形的病因和表型将有助于改善未来的临床管理和预防。候选人提出的研究的长期目标是确定和了解遗传和环境因素如何导致人类发育异常。完成这些目标将为候选人提供必要的培训和初步数据，以便她将来在更大的国际研究中研究小耳症和其他出生缺陷的遗传和非遗传风险因素。 公共卫生相关性：这个职业转型奖的目的是研究小耳畸形，一种先天性耳畸形，与听力损失有关，约90%的受影响的人。我们建议在南美洲安第斯地区研究小耳畸形的遗传和环境风险因素，这种畸形的频率比其他国家高出三到四倍。这项研究与公共卫生有关，因为发现小耳症发生的原因最终有望增加对耳发育异常的发病机制和风险预测的理解。