Genomic basis of phenotypic variability of complex disorders

项目摘要 复杂疾病表型变异的基因组学基础 广泛的表型变异使我们对复杂疾病的理解变得复杂。我们研究了520- 染色体16p12.1上的KBP缺失作为剖析复杂疾病的遗传基础的范例。 最初在儿童中发现的发育迟缓，在>95%的情况下， 来自具有轻度神经精神病学特征的父母，赋予疾病的不同易感性， 同一个家族中的携带者我们发现携带者儿童更有可能携带另一个大的CNV或罕见的CNV。 与携带者父母相比，在基因组其他地方的有害突变（“二次打击”），表明 这种缺失使基因组对一系列神经发育结果敏感， 是由遗传背景的变异决定的。我们的长期目标是了解 与16p12.1缺失一致的二次命中变体的组合导致不同的临床结果。在 在上一个资助期，我们分析了150个家庭的基因组和数量表型， 16p12.1缺失，并测试了16p12.1基因的同源物的个体以及214对相互作用， 果蝇和非洲爪蟾模型。我们发现罕见变异的模式与 临床特征的严重程度取决于神经精神疾病的家族史， 父母的交配模式。此外，在果蝇中敲除单个16p12.1同源物， 和X. laevis导致明显的发育缺陷，这些同系物与 患者特异性二次命中以调节神经元和细胞缺陷。在这里，我们建议精细绘制遗传图谱 和家族因素，评估更深层次的细胞类型特异性影响，并确定可推广的 复杂疾病表型变异的原则，通过以下具体目标：目标1： 对另外250个携带16p12.1的家庭进行全基因组测序和详细的表型分析。 删除，并利用增加的样本量，以确定单一和组合的基因和 变异类别以及多基因对家庭变异的风险，包括跨 目的2：评估不同先证者表型谱、家族 1，281名无关的16p12.1缺失携带者的病史、疾病确定和重复人群， 并将结果与2,200名患有其他罕见CNV（如16p11.2和15q13.3缺失）的个体进行比较， 识别不同CNV和确定的共同或独特的二次命中模式;目标3： 进行功能研究，以评估16p12.1基因与神经元细胞类型内二次命中的相互作用 在果蝇和定量神经测定在斑马鱼模型。最终，我们的研究会得到改善 遗传诊断、咨询和复杂疾病治疗策略的发展策略。

Project Summary Genomic basis of phenotypic variability of complex disorders Extensive phenotypic variability has complicated our understanding of complex disorders. We study the 520- kbp deletion on chromosome 16p12.1 as a paradigm to dissect the genetic basis of complex disorders. Originally identified in children manifesting developmental delay, the deletion is inherited in >95% of cases from a parent with mild neuropsychiatric features, conferring differential susceptibilities to disease among carriers in the same family. We found that carrier children were more likely to carry another large CNV or rare deleterious mutation (“second-hit”) elsewhere in the genome compared to their carrier parents, indicating that the deletion sensitizes the genome for a range of neurodevelopmental outcomes, and the ultimate phenotype is determined by variants in the genetic background. Our long-term goal is to understand how specific combinations of second-hit variants, in concert with the 16p12.1 deletion, lead to distinct clinical outcomes. In the previous funding period, we analyzed the genomes and quantitative phenotypes of 150 families with the 16p12.1 deletion, and tested individual as well as 214 pairwise interactions of homologs of 16p12.1 genes in Drosophila melanogaster and Xenopus laevis models. We found that patterns of rare variants correlated with the severity of clinical features, which were contingent upon family history of neuropsychiatric disease and assortative mating profiles of parents. Furthermore, knockdown of individual 16p12.1 homologs in Drosophila and X. laevis resulted in distinct developmental defects and these homologs interacted synergistically with patient-specific second-hits to modulate neuronal and cellular defects. Here, we propose to fine-map genetic and familial factors in larger cohorts, assess deeper cell type-specific effects, and identify generalizable principles for phenotypic variability of complex disorders, through the following Specific Aims: Aim 1: Perform whole genome sequencing and detailed phenotyping on an additional 250 families carrying the 16p12.1 deletion, and leverage the increased sample size to identify effects of single and combinations of genes and variant classes as well as polygenic risks towards variability in families, including anticipation across generations; Aim 2: Assess patterns of second-hits across different proband phenotypic profiles, family histories, disease ascertainments, and unselected populations of 1,281 unrelated 16p12.1 deletion carriers, and compare results with 2,200 individuals with other rare CNVs, such as 16p11.2 and 15q13.3 deletions, to identify patterns of second-hits that are common or unique to different CNVs and ascertainments; Aim 3: Perform functional studies to assess interactions of 16p12.1 genes with second-hits within neuronal cell types in Drosophila and quantitative neurological assays in Danio rerio models. Ultimately, our study will improve strategies for genetic diagnosis, counseling, and development of therapeutic strategies for complex disorders.