IDENTICAL BY DESCENT MAPPING OF CRANIOFACIAL ANOMALIES

颅面畸形是常见的出生缺陷，尤其是 与口面裂有关很明显遗传因素 对他们的病因有很大的贡献。然而，许多基因 颅面畸形还没有被发现。大多数口面裂 非综合征性孤立缺陷，可分为两种不同的 表型：唇裂伴或不伴腭裂（CL/P）和腭裂 （CPO）。两者都是基因复杂的特征，这限制了 识别疾病位点或基因的能力。努力确定基因， 非综合征性裂缝依赖于候选基因方法。然而，在这方面， 对于非综合征性CL/P或CPO，尚未鉴定出突变。 本项目和未来项目的总体目标是确定疾病 参与非综合征型CL/P和CPO的基因座和基因。这可以 通过采用几种方法完成，包括重点研究 非综合征性裂缝此外，识别综合征性裂缝的基因， 具有简单的孟德尔遗传模式， 非综合征性唇腭裂的病因 该项目的具体目标是确定大型近交系 非综合征性CL/P和CPO患者然而，在此过程中， 很可能是大的，在繁殖的家庭与其他颅面 异常也将被识别。因此，这些家庭也将 招募的近亲繁殖的一个重要后果是，在家庭中， 患有罕见隐性疾病的个体可能遗传了 来自共同祖先的突变基因的两个拷贝;即，等同于 血统.这一事实有助于通过DNA汇集进行基因位点鉴定 纯合性作图的方法。这种方法被用来识别 在只有5个患病成员的家庭中的疾病位点。一旦疾病 基因座被确定，与附近标记的正式连锁分析将被 使用Genehunter程序来确认结果。基因猎人 是专为近亲繁殖家庭设计的此外，在 将筛选候选基因的突变。预计2-3 每年都会招募大家庭。已经是一个大家庭， 额鼻发育不良。 此外，来自非综合征CL/P或CPO的个体 还将招募近交系进行连锁分析。的 可供确定受试者的人口预计将有50个非 综合征CL/P和25例非综合征CPO新生儿， 年 约旦人口的独特之处在于， 占所有婚姻的50%。这个项目提供了一个机会， 快速识别非综合征性CL/P和CPO的疾病位点， 其他颅面异常通过使用一种新的，有效的纯合性 映射策略最后，招募小型近交家庭， 非综合征型CL/P和CPO将为未来的基因组学研究奠定基础 扫描疾病位点

Craniofacial anomalies are common birth defects, especially those associated with orofacial clefts. It is apparent that genetic factors contribute significantly to their etiology. However, genes for many craniofacial anomalies have not been identified. Most orofacial clefts are non-syndromic, isolated defects, which can be separated into two different phenotypes: cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). Both are genetically complex traits, which has limited the ability to identify disease loci or genes. Efforts to identify genes for non-syndromic clefts have relied on candidate gene approaches. However, mutations have not been identified for either non-syndromic CL/P or CPO. The overall objective of this and future projects is to identify disease loci and genes involved in non-syndromic CL/P and CPO. This can be accomplished by employing several approaches, included focused research on non-syndromic clefts. In addition, identifying genes for syndromic clefts, which have simple Mendelian inheritance patterns, may also provide clues to the etiology of non-syndromic clefts. The specific aim of this project is to ascertain large inbred families with non-syndromic CL/P and CPO from Jordan. However, during this process it is likely that large, in bred families with other craniofacial anomalies will also be identified. Therefore, these families will also be recruited. An important ramification of inbreeding is that in a family, individuals with a rare recessive disease are likely to have inherited both copies of the mutated gene from a common ancestor; i.e., identical by descent. This fact facilitates gene locus identification by a DNA pooling approach to homozygosity mapping. This approach has been used to identify disease loci in families with as few as 5 affected members. Once a disease locus is identified, formal linkage analysis with nearby markers will be performed using a program, Genehunter, to confirm the results. Genehunter is specifically designed for inbred families. In addition, nearby candidate genes will be screened for mutations. It is anticipated that 2-3 large families will be recruited per year. Already a large family with frontonasal dysplasia has been identified. In addition, individuals with non-syndromic CL/P or CPO who are from inbred families will also be recruited for linkage analysis. The population available for identifying subjects is projected to have 50 non- syndromic CL/P and 25 non-syndromic CPO newborns from inbred marriage per year. The population of Jordan is unique in that consanguineous marriages comprise over 50% of all marriages. This project presents the opportunity to rapidly identify disease loci for non-syndromic CL/P and CPO as well as other craniofacial anomalies by the use of a novel, efficient homozygosity mapping strategy. Finally, the recruitment of small inbred families with non-syndromic CL/P and CPO will provide a foundation for future genome scans for disease loci.