Genetic modifiers of Van der Woude syndrome

范德沃德综合征的遗传修饰

基本信息

批准号：
10452657
负责人：
ELIZABETH JANE LESLIE
金额：
$ 50.69万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452657
关键词：
Accounting Affect Bilateral Caring Cleft Lip Collection Complex Correlation Studies DNA Sequence Alteration Data Deletion Mutation Dental Development Diagnosis Disease Etiology Family First Degree Relative General Population Genes Genetic Genetic Counseling Genetic Predisposition to Disease Genotype Goals Human Individual Link Lip structure Mendelian disorder Methods Modeling Molecular Diagnosis Mus Mutation Operative Surgical Procedures Outcome Patients Penetrance Phenotype Point Mutation Prognosis Recurrence Research Resources Risk Risk Factors SNP genotyping Speech Structural Congenital Anomalies Syndrome Testing Translating Van der Woude syndrome Variant causal variant cleft lip and palate clinical diagnosis cohort complement resource craniofacial craniofacial development family structure genetic analysis genetic architecture genome sequencing genome wide association study improved insight mutation screening orofacial cleft rare variant risk variant trait whole genome

项目摘要

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.

项目概要外显率降低和表现力变化是大多数人的常见特征，但人们对此知之甚少。单基因疾病。遗传修饰剂是导致这种表型变异和模糊的可能因素单基因疾病和复杂疾病之间的传统区别。在这里，我们建议大家学习最常见口面裂综合征（Van der Woude 综合征，VWS）和非综合征性口面裂（OFC），它在表型和遗传病因学上都有交叉，作为理解外显率降低和可变的表现力。 VWS 的发生率为 35,000 人中的 1 人，占所有 OFC 的 2%。的特点 VWS 包括 OFC 和/或下唇凹陷，但 15% 的 VWS 患者存在孤立性 OFC，这使得他们与非综合征性 OFC 患者没有区别。 IRF6 或 GRHL3 基因突变会导致 VWS，但目前大约 20% 的 VWS 患者缺乏分子诊断。此外，还有少数已知突变和患者表型的基因型-表型相关性。相比之下，GWAS 非综合征性 OFC 已确定了许多风险因素，我们已证明其中一些因素会增加患特定类型的 OFC 或充当 OFC 子类型的修饰符。我们收集了最大的 VWS 集合世界各地的家庭以及来自 900 多个非综合征性 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/区域与非综合征性 OFC 之间的关系，并识别罕见的以及 VWS 和 OFC 表型的常见修饰因子。这些分析将提供进一步的见解 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共同表型的疾病。