Phenotypic and Genomic Characterization of Microtia in the Andean Population

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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.