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Genomic basis of phenotypic variability of complex disorders

复杂疾病表型变异的基因组基础

基本信息

批准号：
9220180
负责人：
Santhosh Girirajan
金额：
$ 60.65万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9220180
关键词：
17p11.2 7q11.23 Affect Algorithms Autistic Disorder Biological Biological Assay Biological Models Candidate Disease Gene Chromosomal translocation Chromosomes Clinical Complex Copy Number Polymorphism Data Detection Development Disease Drosophila melanogaster Economic Burden Engineering Epilepsy Etiology Evaluation Event Family Family member Frequencies Gene Deletion Gene Dosage General Population Genes Genetic Genetic Predisposition to Disease Genetic Variation Genome Genomics Health Heart Diseases Human Individual Inherited Intellectual functioning disability Knock-out Lead Live Birth Methods Modeling Mutation Nature Nucleic Acid Regulatory Sequences Nucleotides Obesity Orthologous Gene Outcome Parents Patients Pattern Phenotype Population Records Recruitment Activity Recurrence Reporting Resolution Schizophrenia Series Site Smith Magenis syndrome System Testing Variant Williams Syndrome Work Xenopus Xenopus laevis accurate diagnosis base congenital heart disorder cost developmental disease disorder risk dosage fly follow-up genetic analysis genetic disorder diagnosis genetic variant genome sequencing high risk insertion/deletion mutation interest mouse genome neuropsychiatry novel phenotypic data public health relevance socioeconomics targeted treatment tool trait treatment strategy whole genome

项目摘要

Genomic basis of phenotypic variability of complex disorders Abstract Recent studies have suggested a class of rare CNVs that are often inherited as well as associated with various complex disorders including intellectual disability, congenital cardiac disease, obesity, epilepsy, autism, and schizophrenia. While these CNVs confer a higher risk for disease, they are not necessarily sufficient to cause disease. This implies a need to consider additional genetic factors that may account for phenotypic variability. Our long-term interests are to understand how a combination of genetic variants can lead to specific clinical outcomes. The specific aims proposed will help us to identify all forms of genetic variants in individuals with 16p12.1 deletion and to understand the biological mechanisms for variability from functional studies in model systems. Our three specific aims are to: (1) Perform whole genome sequencing (WGS) of 100 families, including an estimated 325 individuals (75 trios and 25 quad families), with at least one affected individual carrying a 16p12.1 deletion, to identify copy-number variants (CNVs), single nucleotide variants (SNVs), and insertion-deletions (INDELs) using a combination of variant-detection algorithms; (2) Prioritize genetic variants for disease and functional association,, perform quantitative phenotyping of families with 16p12.1 deletion, and integrate genetic data with phenotypic data to identify specific patterns of genetic variants contributing to the observed traits; (3) Perform functional studies in model systems to test dosage-sensitivity of Drosophila melanogaster and Xenopus leavis orthologs of 16p12.1 genes using highly sensitive quantitative methods, and assess the effect of a selected ten candidate modifier genes by two locus models. This proposal will aid in identifying biologically valid variants that interact with 16p12.1 genes contributing towards specific phenotypes, which will help in a more accurate diagnosis of specific subtypes of developmental disorders, and provide impetus for targeted treatment strategies.

复杂疾病表型变异的基因组基础