Genomic basis of phenotypic variability of complex disorders

复杂性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，并与各种 复杂的疾病，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具有更高的患病风险，但它们不一定足以导致 疾病。这意味着需要考虑可能解释表型变异的其他遗传因素。 我们的长期兴趣是了解基因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患有 16p12.1缺失，并从模型的功能研究中了解变异的生物学机制 系统。我们的三个具体目标是：(1)对100个家系进行全基因组测序， 包括估计的325名个人(75个三重家庭和25个四重家庭)，至少有一个受影响的个人 携带16p12.1缺失，以识别拷贝数变异体(CNV)、单核苷酸变异体(SNV)和 使用变异检测算法组合的插入-缺失(INDELs)；(2)确定遗传变异的优先顺序 对于疾病和功能关联，对16p12.1缺失的家系进行定量表型分析，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 用高灵敏的定量方法测定16p12.1基因的黑腹沙鼠和非洲爪哇的同源基因，以及 用两个基因座模型评估选定的十个候选修饰基因的效果。这项建议将有助于 鉴定与导致特定表型的16p12.1基因相互作用的生物有效变体， 这将有助于更准确地诊断特定亚型的发育障碍，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.