Planning Grant for Genome-Wide Association Study of Craniofacial Microsomia

描述(由申请人提供)： CFM涉及面部骨骼和软组织的不对称发育不足，每3500名新生儿中就有1名发生CFM。CFM通常影响下巴和耳朵，除了其美学效果外，还会损害基本功能，如听力、言语、呼吸和咀嚼。由于呼吸道受损，它可能会危及生命。为了恢复颅面形态和功能，常常需要进行多种复杂的外科手术。男性或多胎、母亲患有糖尿病、西班牙裔、宫内暴露于异维A酸或沙利度胺是唯一已知的CFM危险因素。CFM的遗传学基础得到以下方面的支持：有染色体异常的病例报告；常染色体隐性或显性遗传的家族性病例；一个家系中有全基因组与14q32连锁的证据；四倍的家族性相对风险；以及通过动物基因突变诱导的CFM表型。据我们所知，还没有关于CFM儿童的大规模队列研究，在这些研究中，他们的表型、治疗和可能的宫内暴露已经被系统地表征。简而言之，关于CFM的研究很少。我们建议通过招募这样一组CFM病例以及父母和无关的控制人员来解决这些差距，以便进行比较。我们正在响应NIH RFA-OD-09-003，挑战领域08，基因组学，主题08-DE-101：“未被研究的口腔和颅面部疾病和疾病全基因组研究的规划补助金。”我们提出了一项计划拨款，它将在两年内导致R01提案，为CFM的多中心全基因组关联研究(GWAS)提供资金，以纳入500-1000名CFM患者。我们当前计划拨款的具体目标是：1)在五个研究地点招募100名CFM儿童及其父母和无关对照，并对病例进行广泛的表型鉴定；2)开发一个数据基础设施来管理数据收集和参与者跟踪的方方面面，培训每个研究地点的人员使用该数据库；3)对每个数据收集组成部分进行多中心可靠性研究，包括CFM病例定义和参与者问卷；4)再招募10-25个大型颅面中心参加GWAS；5)纳入本规划阶段的信息，以最终完成GWAS研究设计，选择一个基因分型平台，并进行样本量估计。在美国，大约有15,000-30,000名儿童和35,000-50,000名成人患有CFM；他们和他们的家人最终可能从我们的研究结果中受益。这项工作还将阐明正常和异常的颌骨和耳朵发育的生物学。我们制定严格的病例定义和招募大量病例参与者的具体目标将启动目前对这种相对常见的头面部疾病的有限研究。除了计划中的GWAS，队列还将使对非遗传病因、CFM的自然病史和治疗结果的研究成为可能。我们建议与五个头面部中心开展研究合作，以标准化收集100名头面部矮小儿童的表型和基因数据。我们在两年规划拨款期间开发的研究基础设施将为研究人员收集大量头面部矮小症患者的数据奠定必要的基础。这也将使进一步研究头面部疾病患者的病因学和卫生保健结果成为可能。

DESCRIPTION (provided by applicant): CFM involves the asymmetric underdevelopment of facial skeletal bones and soft tissue and occurs in over 1 in 3500 births. Typically affecting the jaw and ear, CFM impairs basic functions such as hearing, speech, respiration, and chewing, in addition to its aesthetic effects. It can be life-threatening due to airway compromise. Multiple complex surgical procedures are often necessary to restore craniofacial form and function. Being male or a multiple birth, having a mother with diabetes, Hispanic ethnicity, and in utero exposure to isotretinoin or thalidomide are the only known risk factors for CFM. A genetic basis for CFM is supported by: case reports with chromosomal anomalies; familial cases suggesting autosomal recessive or dominant inheritance; evidence of genomewide linkage to 14q32 in one pedigree; fourfold familial relative risks; and CFM phenocopies induced through genetic mutations in animals. To our knowledge, there have been no studies of large cohorts of children with CFM in which their phenotypes, treatments, and possible in utero exposures have been systematically characterized. Put simply, there has been very little research about CFM. We propose to address these gaps by recruiting such a cohort of CFM cases as well as parents and unrelated controls for comparison purposes. We are responding to NIH RFA-OD- 09-003, the challenge area 08, Genomics, topic 08-DE-101: "Planning Grants for Genome-wide Studies of Understudied Oral and Craniofacial Diseases and Disorders." We propose a planning grant that will lead, in two years, to an R01 proposal to fund a multi-center genome-wide association study (GWAS) of CFM to include 500-1000 individuals with CFM. Our specific aims for the current planning grant are to: 1) recruit 100 children with CFM, along with their parents and unrelated controls, across five study sites, and perform extensive phenotyping of cases; 2) develop a data infrastructure to manage all aspects of data collection and participant tracking, training personnel at each site to use this database; 3) conduct multi-center reliability studies regarding each data collection component, including CFM case definition and participant questionnaires; 4) recruit an additional 10- 25 large craniofacial centers to participate in the GWAS; 5) incorporate information from this planning phase to finalize the GWAS study design, select a genotyping platform, and perform sample size estimation. There are approximately 15,000-30,000 children and 35,000-50,000 adults living with CFM in the United States; they and their families could eventually benefit from the results of our research. This work will also elucidate the biology of normal and abnormal jaw and ear development. Our specific goals of developing a rigorous case definition and recruiting a very large number of case participants will jump-start the currently scanty research into this relatively common craniofacial condition. In addition to the planned GWAS, the cohort will enable research into nongenetic etiologies, natural history of CFM, and treatment outcomes. We propose to develop a research collaboration with five craniofacial centers to standardize phenotypic and genetic data collection in 100 children with craniofacial microsomia. The research infrastructure that we develop during this two-year planning grant will lay the foundation required to enable researchers to collect data on a large number of individuals with craniofacial microsomia. It will also enable further research on the etiology and health care outcomes in patients with craniofacial disorders.