Dissection of the VCFS phenotype--Palatal anomalies

血管紧张素转换酶综合征(VCFS)是一种与大多数患者的22q11号染色体缺失相关的多发性畸形综合征。VCFS表型包括广泛的特征，但最常见的特征是腭裂、先天性心脏病、认知障碍和典型的面部外观。患有VCFS的患者通常只表现出这些特征的一个子集，并且任何给定特征的特定性质可能因个体而异。例如，在大约50%的VCFS患者中可以观察到腭部异常，包括显性腭裂、粘膜下裂、悬雍垂裂和腭咽闭合功能障碍。最初的假设是，染色体22q11缺失大小的差异可以解释观察到的VCFS表型的差异。然而，缺失大小尚未被证明是一个强大的表型预测因子，这表明其他因素--如遗传背景和/或暴露史的个体差异--肯定有助于观察到的VCFs表型的变异性。确定影响VCFS表型的具体因素的研究将需要从数百名患者中广泛、系统地收集数据。我们特别准备进行这种性质的研究，因为必要的数据将通过拟议的计划项目获得。拟议的项目将利用这些数据来确定影响VCFS患者腭部表型的因素。一种综合的方法，结合来自VCFS患者的分子和临床数据，将被用来识别这些因素。这些分析将大大增加我们对影响VCFS患者腭部表型的因素的了解，并将为类似分析该综合征的其他表型特征奠定基础。

Velocardiofacial syndrome (VCFS) is a multiple malformation syndrome that is associated with a deletion of chromosome 22q11 in the majority of patients. The VCFS phenotype includes a broad range of features, but is most commonly characterized by the tetrad of palatal anomalies, congenital heart defects, cognitive impairment and a typical facial appearance. Individuals with VCFS usually exhibit only a subsets of these features, and the specific nature of any given feature may differ between individuals. For example, palatal anomalies are observed in approximately 50% of patients with VCFS and include overt cleft palate, submucous cleft palate, bifid uvula and velopharyngeal dysfunction. It was originally hypothesized that differences in the size of the chromosome 22q11 deletion would explain the observed variability in the VCFS phenotype. However, deletion size has not proven to be a strong phenotypic predictor, indicating that other factors-such as individual differences in genetic background and/or exposure history-must contribute to the observed variability in the VCFS phenotyped. Studies to identify specific factors that influence the VCFS phenotype will require extensive, systematically collected data from several hundred patients. We are uniquely poised to conduct studies of this nature, since the requisite data will be available through the proposed program project. The proposed project will capitalize on these data to identify the factors that influence the palatal phenotype in patients with VCFS. A comprehensive approach, integrating molecular and clinical data from patients with VCFS, will be employed to identify these factors. The proposed analyses will greatly increase our understanding of the factors that influence the palatal phenotype in patients with VCFS, and will lay the foundation for similar analyses of other phenotypic features of this syndrome.