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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.

项目总结