Phenotypic and Genomic Characterization of Microtia in the Andean Population

描述（由申请人提供）：耳廓小畸形是一种先天性耳廓畸形，范围从轻微的结构异常到完全没有耳廓。这种情况的临床影响与听力损失的管理有关，存在于大多数病例中，以及多步骤耳部重建。在对小体病病因的理解上存在根本性的空白；迄今为止，还没有对其发生的分子遗传基础或环境因素进行广泛的研究。更重要的是，尽管有强有力的证据表明小体病的发病机制中存在遗传成分，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安第斯地区，特别是厄瓜多尔、玻利维亚和哥伦比亚儿童小个子症的表型、遗传和环境危险因素。之所以选择这一人群，是因为以前的研究和强有力的初步数据表明，这些国家的出生流行率高于以前在世界范围内报道的水平。中心假设是，候选基因和非遗传风险因素相关的小个子症将确定在这一群体。在该职业过渡奖的指导阶段，候选人将1)在玻利维亚分离性小体病个体样本中对5个候选基因进行SNP发现，2)利用南美出生登记数据库收集的信息，对涉及2000多例分离性小体病病例的小体病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，接受基因组学的实验室培训，提交论文，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名分离的小虫进行广泛的表型表征。首先，她将识别个体的亚表型与孤立的小耳畸形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。其次，她将使用祖先信息标记来描述相同受试者的祖先特征，以调查祖先在安第斯地区较高患病率中的作用。第三，她将对分离的小体病个体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。这项研究的基本原理是，更好地了解小个子症的病因和表型将有助于改善临床管理和预防。候选人提出的研究的长期目标是识别和理解遗传和环境因素如何导致人类异常发育。这些目标的完成将为候选人提供必要的培训和初步数据，为她未来在更大的国际研究中对小畸形和其他出生缺陷的遗传和非遗传风险因素进行研究。

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.