PHENOTYPE AND GENETICS IN OROFACIAL CLEFT FAMILIES

口腔裂，无裂(夹型)，是健康问题，全世界每500-1000名新生儿中就有一名受到影响。我们小组和其他人最近在确定CL/P的遗传位点方面取得了实质性的进展，证实了CL/P遗传病因的疑似复杂性。随着导致CLIP的遗传因素的出现，鉴定表型是至关重要的 每个基因的特征，以便将新兴的研究成果转化为临床实践。与CLIP相关的表型特征也取得了进展：有证据表明，发育不对称效应可能是CLIP的病因之一，而且在明显未受影响的唇裂患者亲属中，可能存在未被识别的亚临床表型。 这项研究的主要目标是在候选基因、基因组扫描和精细定位标记的连锁和关联研究中利用扩展的表型谱进行CLIP。扩展的CLIP表型谱将更准确地识别在特定裂隙家族中在遗传水平上分离的表型，从而增加我们的基因图谱和关联研究的能力。此外，如果我们能够识别可能携带裂隙基因的未受影响的(即非裂隙)个体(例如，具有亚临床表型表达的个体)，那么这种常见出生缺陷的复发风险计算和遗传咨询将得到极大的改善。因此，我们将研究表型特征 在世界各地的几个人群中，通过CL/P个体和对照，确定了多重亲属(即有2个或更多受影响的家庭)。将被调查的具体特征包括：惯用手、头面部测量、不对称性(基于皮纹和头面部测量)、腭咽闭合能力(通过感知筛选)以及口轮匝肌的解剖。将分析每个单独的特征，以及由两个或更多特征组成的复合特征。候选基因将与其他中心项目合作确定优先顺序；候选基因将利用基因分型核心进行基因分型。基因组扫描标记已经可以用于这些家庭中的大多数。全 标记将用于CLIP和多重家系中每个表型特征的连锁和关联研究，也将被包括在寻找导致风险的基因之间相互作用的分析中。

Orofacial clefts, cleft with without cleft (CLIP), health problem, affecting one in every 500-1000 births worldwide. There has been substantial recent progress by our group and others in identifying genetic loci for CL/P, confirming the suspected complexity in the genetic etiology of CL/P. As the genetic factors contributing to CLIP emerge, it is essential to identify the phenotypic characteristics attributable to each gene n order to translate the emerg ng research results into cinical practice. Progress has also been made regarding phenotypic features associated with CLIP: there is evidence that developmental asymmetry effects may contribute to the etiology of CLIP, and that there may be unrecognized sub-clinical phenotypes in apparently unaffected relatives of individuals with clefts. The primary goal of this study is to utilize an expanded phenotypic spectrum for CLIP in our linkage and association studies of candidate genes, genome-scan and fine-mapping markers. An expanded phenotypic spectrum for CLIP will more accurately identify the phenotype that is segregating at a genetic level in specific cleft families, thereby increasing the power of our gene mapping and association studies. Furthermore, if we can then identify unaffected (i.e. non-cleft) individuals who are likely to be carrying cleft genes (e.g. individuals with sub-clinical phenotypic expression), then recurrence risk calculations and genetic counseling for this common birth defect will be vastly improved. Therefore, we will investigate phenotypic features in multiplex kindreds (i.e. with 2 or more affecteds) ascertained through CL/P individuals, plus controls, in several populations world-wide. The specific features that will be investigated include: handedness, craniofacial measurements, asymmetry (based on dermatoglyphic patterns and craniofacial measurements), velopharyngeal competence (by perceptual screening) and anatomy of the orbicularis oris muscle. Each individual feature will be analyzed, as well as composite traits composed of two or more features. Candidate genes will be prioritized in collaboration with the other Center Projects; candidate genes will be genotyped utilizing the Genotype Core. Genome-scan markers are already available for most of these families. All markers will be used for linkage and association studies of CLIP and each phenotypic feature in the multiplex kindreds, and will also be included in analyses looking for interactions between genes contributing to risk.