Genetic modifiers of Van der Woude syndrome

项目总结 外显率降低和表现力可变是大多数的常见特征，但了解较少 单基因疾病。遗传修饰者可能是导致这种表型变异和模糊的因素 单基因疾病和复杂疾病之间的传统区别。在这里，我们建议研究最多的 常见的口裂综合征(范德伍德综合征，VWS)和非综合征性口裂(OFCs)， 它们在表型和遗传病因学上都是相交的，作为一种模型来理解外显率降低和 可变的表现力。大众汽车的发生率为每35,000人中就有1人，占所有离岸金融中心的2%。的特点 大众包括OFC和/或下唇窝，但15%的VWS患者存在孤立的OFC，使 与非综合征型OFC患者无明显区别。基因IRF6或GRHL3的突变会导致VWS， 但目前约有20%的VWS患者缺乏分子诊断。更重要的是，几乎没有 已知突变和患者表型的基因-表型相关性。与之形成对比的是， 非综合征性离岸金融中心已经确定了一些风险因素，其中一些我们已经显示出风险增加 特定类型的OFC或充当OFC子类型的修饰语。我们已经组装了最大的VWS集合 世界上的家系和900多个非综合征OFC三人组的全基因组序列数据。我们建议 在两个队列中使用全基因组测序和SNP基因分型来确定剩余的基因突变 对于VWS，确定这些基因/区域与非综合征OFCs之间的关系，并确定罕见的 以及VWS和OFC表型的常见修饰物。这些分析将为我们提供对 VWS和OFCS的遗传结构，并将作为探索其他孟德尔人之间联系的模型 具有复杂特征的表型相同的疾病。

PROJECT SUMMARY Reduced penetrance and variable expressivity are common, but poorly understood, features of most monogenic diseases. Genetic modifiers are possible factors to contribute to this phenotypic variability and blur the traditional distinction between monogenic and complex disease. Here, we propose to study the most common orofacial cleft syndrome (Van der Woude syndrome, VWS) and nonsyndromic orofacial clefts (OFCs), which intersect both in phenotype and in genetic etiology, as a model to understand reduced penetrance and variable expressivity. VWS occurs in 1 in 35,000 individuals and accounts for 2% of all OFCs. The features of VWS include an OFC and/or lower lip pits, but 15% of VWS patients present with an isolated OFC, making them indistinguishable from nonsyndromic OFC patients. Mutations in the genes IRF6 or GRHL3 cause VWS, but approximately 20% of VWS patients currently lack a molecular diagnosis. Furthermore, there are few genotype-phenotype correlations for known mutations and patient phenotypes. By contrast, GWAS of nonsyndromic OFCs have identified a number of risk factors, some of which we have shown increase risk for specific types of OFCs or act as modifiers of OFC subtypes. We have assembled the largest collection of VWS families in the world and whole genome sequence data from over 900 nonsyndromic OFC trios. We propose to use whole genome sequencing and SNP genotyping in both cohorts to identify the remaining genetic mutations for VWS, determine the relationship between those genes/regions with nonsyndromic OFCs, and identify rare and common modifiers of VWS and OFC phenotypes. These analyses will provide further insight into the genetic architecture of VWS and OFCs and will serve as a model for exploring links between other Mendelian disorders that share phenotypes with complex traits.