Genomic basis of phenotypic variability of complex disorders

复杂疾病表型变异的基因组学基础 摘要 最近的研究表明，一类罕见的CNV通常是遗传的，也与各种疾病有关。 包括智力残疾、先天性心脏病、肥胖、癫痫、自闭症和 精神分裂症虽然这些CNV赋予更高的疾病风险，但它们不一定足以引起 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。 我们的长期利益是了解遗传变异的组合如何导致特定的临床 结果。所提出的具体目标将有助于我们识别个体中所有形式的遗传变异， 16p12.1缺失，并从模型中的功能研究中了解变异性的生物学机制 系统.我们的三个具体目标是：（1）进行100个家庭的全基因组测序（WGS）， 包括估计325个个体（75个三人组和25个四人组家庭），至少有一个受影响的个体 携带16p12.1缺失，以鉴定拷贝数变体（CNV）、单核苷酸变体（SNV），和 使用变异检测算法的组合进行插入-缺失（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， 将遗传数据与表型数据整合，以鉴定有助于遗传变异的特定模式。 （3）在模型系统中进行功能研究，以测试果蝇的剂量敏感性 使用高灵敏度定量方法，测定黑腹非洲爪蟾和非洲爪蟾16p12.1基因的直系同源物，和 通过两个基因座模型评估所选择的十个候选修饰基因的作用。该提案将有助于 鉴定与16p12.1基因相互作用的生物学上有效的变异体，所述变异体促成特定表型， 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。

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.