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: 8320884
• 负责人: Daniela Varela Luquetti
• 金额: $ 10.25万
• 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/8320884
• 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.

描述(申请人提供)：小耳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的耳朵缺失。这种情况的临床影响涉及大多数病例中存在的听力损失的处理，以及多步骤耳再造。对小耳畸形的病因认识存在着根本性的差距；迄今为止，还没有对其发生的分子遗传学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耳畸形的发病机制中有遗传成分，但只有一项研究对两个候选基因进行了重新测序。这项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。之所以选择这一群体，是因为之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此前报告的全球范围内的出生流行率。中心假设是，与小耳垂相关的候选基因和非遗传风险因素将在该人群中被识别出来。在这一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样本中发现5个候选基因的SNP，2)使用南美出生登记数据库中收集的信息，对涉及2,000多个孤立性小耳病例的微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，她将完成高级课程工作，接受基因组学实验室培训，提交稿件，并寻求独立的研究职位。在奖项的独立阶段，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名患有孤立小耳的受试者进行广泛的表型表征。首先，她将确定患有孤立小耳的个体的亚型，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。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，她将在患有孤立小耳的个体中进行第一次完整外显子组测序，以发现与其发病机制有关的新的候选基因。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治疗和预防。候选人提出的研究的长期目标是确定和理解遗传和环境因素如何导致人类异常发育。完成这些目标将为候选人提供必要的培训和初步数据，以便她今后在更大的国际研究中研究小耳畸形和其他出生缺陷的遗传和非遗传风险因素。

项目成果

Risk factors and demographics for microtia in South America: a case-control analysis.

• DOI: 10.1002/bdra.23193
• 发表时间: 2013-11
• 期刊: BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
• 作者: Luquetti, Daniela V.;Saltzman, Babette S.;Lopez-Camelo, Jorge;Dutra, Maria da Graca;Castilla, Eduardo E.
• 通讯作者: Castilla, Eduardo E.

Evaluation of ICD-9-CM codes for craniofacial microsomia.

颅面微小症的 ICD-9-CM 代码评估。

• DOI: 10.1002/bdra.23059
• 发表时间: 2012
• 期刊: Birth defects research. Part A, Clinical and molecular teratology
• 作者: Luquetti,DanielaV;Saltzman,BabetteS;Vivaldi,Daniela;Pimenta,LuizA;Hing,AnneV;Cassell,CynthiaH;Starr,JacquelineR;Heike,CarrieL
• 通讯作者: Heike,CarrieL

Preferential associated anomalies in 818 cases of microtia in South America.

• DOI: 10.1002/ajmg.a.35888
• 发表时间: 2013-05
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• 影响因子: 2
• 作者: Luquetti, Daniela V.;Cox, Timothy C.;Lopez-Camelo, Jorge;Dutra, Maria da Graca;Cunningham, Michael L.;Castilla, Eduardo E.
• 通讯作者: Castilla, Eduardo E.