GENETIC ETIOLOGY OF NONSYNOMIC CLEFT PALATE

唇裂和腭裂是常见的出生缺陷，影响1-2/1000活产儿。很明显，遗传因素对其病因有很大影响。大多数口腔颌面裂是非综合征性的孤立效应，可分为两种不同的表型：(1)唇裂伴或不伴腭裂(CL/P)和2)单纯腭裂(CPO)。两者都是复杂的遗传特征，这限制了识别疾病基因或基因的能力。以往对非综合征性唇裂遗传病因的研究依赖于候选基因方法，大多数研究集中在CL/P上。本项目和未来项目的总体目标是通过采用新的连锁策略来研究受影响的亲属对和扩展的家系，以确定与非综合征性CPO相关的疾病基因和基因。这些尚未应用于CPO的方法非常强大，因为不需要关于所涉及的生物过程或遗传模式的先验知识。该项目的具体目标是确定上海中国地区150个有多名成员的慢性阻塞性肺病患者家庭。另外100名CPO患者将与他们的父母一起被确定用于连锁不平衡分析。这项研究将与上海闸北眼科医院的刘友娥博士和匹兹堡腭裂中心的Mary Marazita博士合作进行，这两人自匹兹堡大学腭裂-颅面中心的腭裂诊所以来一直在合作，通过合作研究人员的努力已经招募了45个家庭。这个项目的范围将是使用连锁和连锁不平衡分析来评估CPO的候选基因。在上海，中国的人口相对同质，这是一种独特的品质，增加了绘制疾病基因座图的能力，也有助于向物理图谱和基因鉴定的过渡。这项研究的优势在于可以在多个地点确定相对大量的受影响的亲属对，从而增加了研究检测即使是适度影响的基因座的总体能力。将通过像这样的项目，其中与世界各地的研究人员建立合作，应用遗传策略的组合，将确定CPO的疾病位点。最终，这将进一步加深对正常和异常颅面发育的了解，从而可以开发预防CPO的治疗方法。

Cleft lip and cleft palate are common birth defects affecting 1-2/1000 live births. It is apparent that genetic factors contribute significantly to their etiology. Most orofacial clefts are non- syndromic, isolated effects, which can be separated into two different phenotypes: (1) cleft lip with or without cleft palate (CL/P) and 2) cleft palate only (CPO). Both are genetically complex traits, which has limited the ability to identify disease loci or genes. Previous effects to determine the genetic etiology for non-syndromic clefts have relied on candidate gene approaches with most studies focused on CL/P. The overall objective of this and future projects is to identify disease loci and genes involved in non-syndromic CPO by employing new linkage strategies to study affected relative pairs and extended pedigrees. These approaches, which have yet been applied to CPO, are very powerful in that no prior knowledge about the involved biological processes or inheritance pattern is needed. The specific aim of this project is to ascertain 150 families with multiple members affected with CPO from the Shanghai region of China. An additional 100 CPO patients will be ascertained along with their parents for use in linkage disequilibrium analyses. This will be performed in collaboration with Dr. You-e Liu of the Zhabei Eye Hospital, Shanghai and Dr. Mary Marazita of the Cleft Palate Center, Pittsburgh, who have collaborated since Cleft Palate Clinic at the University of Pittsburgh Cleft Palate-Craniofacial Center to add to the 45 families already recruited through the efforts of there collaborative investigators. The scope of this project will be to evaluate candidate genes for CPO using both linkage and linkage disequilibrium analyses. The population of Shanghai, China is relatively homogeneous, which a unique quality that increases the power to map a disease loci and also facilitate the transition to physical mapping and gene identification. The strength of this study is the relatively large numbers of affected relative pairs that can be ascertained at multiple sites, thus increasing the overall power for the study to detect loci of even modest effect. It will be through projects such as this one, in which collaborations with researchers world wide have been established to apply a combination of genetic strategies, that disease loci for CPO will be identified. Ultimately, this will further the knowledge of normal and abnormal craniofacial development, such that therapies to prevent CPO can be developed.