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: 10467208
• 负责人: Santhosh Girirajan
• 金额: $ 58.39万
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467208
• 关键词: 16p11.2; 17p11.2; Affect; Award; Behavior; Behavioral; Biological; Biological Assay; Biological Models; Brain; Child; Chromosomes; Clinical; Clinical Data; Cognitive; Cognitive deficits; Complex; Copy Number Polymorphism; Counseling; Data; Defect; Development; Developmental Delay Disorders; Diagnosis; Disease; Disease Outcome; Drosophila genus; Drosophila melanogaster; Epilepsy; Family; Family history of; Frequencies; Funding; Gene Combinations; General Population; Generations; Genes; Genetic; Genetic Anticipation; Genome; Genomics; Genotype; Goals; Individual; Inherited; Intellectual functioning disability; Lead; Maps; Modeling; Mutation; Nature; Nervous system structure; Neurodevelopmental Disorder; Neurologic; Neurons; Nucleic Acid Regulatory Sequences; Outcome; Parents; Partner in relationship; Pathway interactions; Patients; Pattern; Period Analysis; Phenotype; Population; Population Control; Predisposition; Quantitative Evaluations; Recording of previous events; Reporting; Risk; Sample Size; Schizophrenia; Sensory; Severities; Smith Magenis syndrome; Source; Structure; Syndrome; System; Testing; Variant; Work; Xenopus laevis; Zebrafish; autism spectrum disorder; behavioral phenotyping; cell type; cohort; disorder risk; dopaminergic neuron; follow-up; genetic analysis; genetic approach; genetic disorder diagnosis; genetic variant; genome analysis; genome sequencing; genomic data; improved; insight; knock-down; neuroblast; neuropsychiatric disorder; neuropsychiatry; novel; pleiotropism; proband; public health relevance; rare variant; schizophrenia risk; statistical and machine learning; therapeutic development; tool; whole genome

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.

项目摘要 复杂性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- KBP在染色体16p12.1上的缺失，作为剖析复杂疾病遗传基础的范例。 这种缺失最初是在表现出发育迟缓的儿童中发现的，但95%的病例是遗传的 父母有轻微的神经精神特征，对疾病的易感性不同 同一家族中的携带者。我们发现携带者儿童更有可能携带另一种大的CNV或罕见的CNV 与其携带者父母相比，基因组中其他地方的有害突变(“二次命中”)，表明 缺失使基因组对一系列神经发育结果和最终表型敏感 是由遗传背景中的变异决定的。我们的长期目标是了解具体到什么程度 与16p12.1缺失相结合的二次命中变异会导致不同的临床结果。在……里面 在之前的资助期间，我们用 16p12.1缺失，并检测了16p12.1基因的同源物的个体和214个成对交互作用 黑腹果蝇和非洲爪哇模型。我们发现，罕见变异的模式与 临床特征的严重性，这取决于神经精神疾病的家族史和 双亲的配对情况。此外，果蝇个体16p12.1同源基因的敲除 和莱维氏X.laevis导致明显的发育缺陷，这些同源物与 针对患者的二次击打，以调节神经元和细胞缺陷。在这里，我们建议对基因进行精细定位 和家族因素在更大的队列中，评估更深层次的细胞类型特异性影响，并确定可推广的 复杂疾病的表型可变性原则，通过以下具体目标：目标1：执行 另外250个携带16p12.1的家系的全基因组测序和详细表型分析 删除，并利用增加的样本量来确定单个和组合基因和 变异类别以及对家庭变异性的多基因风险，包括预期 世代；目标2：评估不同先证者表型谱、家族的二次命中模式 1,281名无关的16p12.1缺失携带者的病史、疾病确证和未选择的群体， 并将结果与2200名具有其他罕见CNV的个体进行比较，例如16p11.2和15q13.3缺失 确定不同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打击的相互作用 在果蝇中和在Danio rerio模型中的定量神经学分析。最终，我们的研究将得到改进 基因诊断、咨询和复杂疾病治疗策略的发展战略。