GENETIC ETIOLOGY OF NONSYNOMIC CLEFT PALATE

唇腭裂是常见的先天性缺陷，影响1 / 2/1000的活产婴儿。显然，遗传因素对其病因有重要影响。大多数唇腭裂是非综合征性的孤立性影响，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）。两者都是遗传上复杂的特征，这限制了识别疾病位点或基因的能力。以前确定非综合征性唇裂的遗传病因的效果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研究受影响的亲属对和扩展家系，确定与非综合征性CPO有关的疾病位点和基因。这些已经应用于CPO的方法非常强大，因为不需要事先了解所涉及的生物过程或遗传模式。该项目的具体目标是确定来自中国上海地区的150个有多人患有小儿麻痹症的家庭。另外100名CPO患者将与他们的父母一起确定，用于连锁不平衡分析。此次手术将与上海闸北眼科医院的刘友叶医生和匹兹堡腭裂中心的Mary Marazita医生合作进行，他们自匹兹堡大学腭裂-颅面中心的腭裂诊所以来一直在合作，通过他们的合作调查员的努力，已经招募了45个家庭。本项目的范围将是利用连锁和连锁不平衡分析来评估CPO的候选基因。中国上海的人口是相对同质的，这是一种独特的品质，增加了绘制疾病位点的能力，也促进了向物理作图和基因鉴定的过渡。本研究的优势在于可以在多个位点确定相对大量的受影响的相对对，从而增加了研究检测即使是适度影响的位点的总体能力。将通过诸如此类的项目，与世界各地的研究人员建立合作关系，以应用遗传策略的组合，从而确定CPO的疾病位点。最终，这将进一步了解正常和异常颅面发育，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.