Genomic basis of phenotypic variability of complex disorders

复杂疾病表型变异的基因组基础

• 批准号: 10090479
• 负责人: Santhosh Girirajan
• 金额: $ 52.92万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090479
• 关键词: 17p11.2; 7q11.23; Affect; Algorithms; 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; Obesity; Orthologous Gene; Outcome; Parents; Patients; Pattern; Phenotype; Population; Records; Recurrence; Reporting; Resolution; Schizophrenia; Series; Single Nucleotide Polymorphism; Site; Smith Magenis syndrome; System; Testing; Variant; Williams Syndrome; Work; Xenopus; Xenopus laevis; accurate diagnosis; autism spectrum disorder; 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; recruit; socioeconomics; targeted treatment; tool; trait; treatment strategy; variant detection; whole genome

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 抽象的 最近的研究表明，一类罕见的 CNV 通常是遗传性的，并且与各种疾病相关。 复杂的疾病，包括智力障碍、先天性心脏病、肥胖、癫痫、自闭症和 精神分裂症。虽然这些 CNV 会带来更高的疾病风险，但它们不一定足以导致 疾病。这意味着需要考虑可能导致表型变异的其他遗传因素。 我们的长期兴趣是了解遗传变异的组合如何导致特定的临床 结果。提出的具体目标将帮助我们识别患有以下疾病的个体的所有形式的遗传变异 16p12.1 缺失并通过模型功能研究了解变异性的生物学机制 系统。我们的三个具体目标是：(1) 对 100 个家族进行全基因组测序 (WGS)， 包括估计 325 人（75 个三人家庭和 25 个四人家庭），其中至少有 1 人受到影响 携带 16p12.1 缺失，以识别拷贝数变异 (CNV)、单核苷酸变异 (SNV) 和 使用变异检测算法组合的插入删除 (INDEL)； (2) 优先考虑遗传变异 对于疾病和功能关联，对 16p12.1 缺失的家族进行定量表型分析，以及 将遗传数据与表型数据相结合，以确定导致遗传变异的特定模式 观察到的特征； (3) 在模型系统中进行功能研究以测试果蝇的剂量敏感性 使用高度灵敏的定量方法获得 16p12.1 基因的黑腹果蝇和非洲爪蟾直系同源物，以及 通过两个基因座模型评估选定的十个候选修饰基因的效果。该提案将有助于 识别与 16p12.1 基因相互作用的生物学有效变体，有助于特定表型， 这将有助于更准确地诊断发育障碍的特定亚型，并提供 推动有针对性的治疗策略。