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：
10205025
负责人：
ELIZABETH JANE LESLIE
金额：
$ 55.65万
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/10205025
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 Structure 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

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 Structure 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

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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.

项目摘要降低的渗透率和可变表达性很常见，但理解不佳，大多数特征单基因疾病。遗传修饰符是导致这种表型变异性和模糊的可能因素单基因和复杂疾病之间的传统区别。在这里，我们建议最多研究常见的口面裂综合征（Van der Woude综合征，VWS）和非综合型口面裂（OFCS），OFCS）在表型和遗传病因学中都相交的是一种了解降低的外观和可变表达性。大众在35,000个人中有1个出现，占所有OFC的2％。功能大众包括OFC和/或较低的唇部坑，但有15％的大众患者出现了孤立的OFC，使它们与非核OFC患者没有区别。基因IRF6或GRHL3中的突变导致大众，但是目前约有20％的大众大众患者缺乏分子诊断。此外，很少已知突变和患者表型的基因型 - 表型相关性。相比之下，GWA 非综合症OFC已经确定了许多风险因素，其中一些风险因素已显示出增加的风险 OFC的特定类型或充当OFC亚型的修饰符。我们组装了最大的大众集合来自900多种非元素ofc Trios的全世界家庭和整个基因组序列数据。我们建议在两个队列中使用整个基因组测序和SNP基因分型鉴定剩余的基因突变对于大众，确定这些基因/区域与非综合症OFC之间的关系，并确定罕见大众和OFC表型的常见修饰符。这些分析将进一步了解大众和OFC的遗传体系结构，将作为探索其他门德利人之间联系的模型具有复杂特征的表型的疾病。