Genetic modifiers of Van der Woude syndrome

项目摘要 降低的表达能力和可变的表达能力是常见的，但了解甚少，大多数 单基因疾病遗传修饰是可能的因素，有助于这种表型变异和模糊 单基因疾病和复杂疾病的传统区别。在这里，我们建议研究最 常见的口面裂综合征（货车der Woude综合征，VWS）和非综合征性口面裂（OFC）， 其在表型和遗传病因学上都有交叉，作为理解减少的遗传率的模型， 可变表现力。VWS发生在35，000人中的1人，占所有OFC的2%。的特征 VWS包括OFC和/或下唇凹陷，但15%的VWS患者存在孤立的OFC， 他们与非综合征OFC患者无法区分。基因IRF 6或GRHL 3的突变导致VWS， 但目前约有20%的VWS患者缺乏分子诊断。此外，还有一些 已知突变和患者表型的基因型-表型相关性。相比之下， 非综合征型OFC已经确定了一些风险因素，其中一些我们已经证明会增加 特定类型的OFC或作为OFC亚型的修饰剂。我们已经收集了最大的VWS 家庭在世界上和全基因组序列数据，从900多个非综合征OFC三人组。我们建议 在两个队列中使用全基因组测序和SNP基因分型来识别剩余的基因突变 对于VWS，确定这些基因/区域与非综合征OFC之间的关系，并确定罕见的 以及VWS和OFC表型的常见修饰剂。这些分析将进一步深入了解 VWS和OFC的遗传结构，并将作为探索其他孟德尔遗传之间联系的模型。 具有复杂特征的表型疾病。

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.