Genomic basis of phenotypic variability of complex disorders

复杂疾病表型变异的基因组基础

基本信息

批准号：
10618346
负责人：
Santhosh Girirajan
金额：
$ 55.25万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
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/10618346
关键词：
16p11.2 17p11.2 Affect Award Behavior Behavioral Biological Biological Assay Biological Models Brain Child Chromosome Mapping 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 Homologous Gene Individual Inherited Intellectual functioning disability Lead Machine Learning Maps Modeling Mutation Nature Nervous System Neurodevelopmental Disorder Neurologic Neurons Nucleic Acid Regulatory Sequences Outcome Parents Partner in relationship Pathway interactions Patients Pattern Phenotype Population Population Control Predisposition Quantitative Evaluations Recording of previous events Reporting Risk Sample Size Schizophrenia Sensory Severities Smith Magenis syndrome Source Structure 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 sequencing genomic data improved insight knock-down neuroblast neuropsychiatric disorder neuropsychiatry novel pleiotropism predictive tools proband public health relevance rare variant schizophrenia risk statistical learning therapeutic development transmission process whole genome

项目摘要

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.

项目摘要复杂疾病的表型变异的基因组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520- 16p12.1染色体上的KBP缺失是剖析复杂疾病的遗传基础的范式。最初在儿童表现出发育延迟的儿童中识别，删除均在> 95％的情况下继承来自具有轻度神经精神特征的父母，会议差异敏感性到疾病同一家庭的载体。我们发现，载体儿童更有可能携带另一个大型CNV或稀有与他们的承运人父母相比，基因组其他地方的有害突变（“第二次打击”）删除感知一系列神经发育结果的基因组和最终表型由遗传背景中的变体决定。我们的长期目标是了解如何具体与16p12.1缺失的一致性，第二次打击变体的组合导致了不同的临床结果。在上一个资金期，我们分析了150个家庭的基因组和定量表型 16p12.1删除，测试的个体以及214个16p12.1基因同源物的成对相互作用果蝇Melanogaster和Xenopus laevis模型。我们发现稀有变体的模式与临床特征的严重程度，这取决于神经精神疾病的家族史和父母的分类配置文件。此外，果蝇中的单个16p12.1同源物的敲低 X. laevis产生了不同的发育缺陷，这些同源物与特定于患者的第二次命中，以调节神经元和细胞缺陷。在这里，我们建议对仿制和较大队列中的家庭因素，评估更深的细胞类型特异性效应，并确定可普遍的效果复杂疾病的表型变异的原理，通过以下特定目的：目标1：执行对另外250个携带16p12.1的家庭进行的整个基因组测序和详细表型删除并利用增加的样本量来确定基因和组合的影响变体类别以及对家庭变异性的多基因风险，包括期望世代； AIM 2：评估不同概率和表型概况的第二次命中模式，家族历史，疾病确定和未选择的人群为1,281个无关16p12.1缺失载体，并将结果与2200个具有其他稀有CNV的人（例如16p11.2和15q13.3）的人进行比较，确定不同CNV和确定的常见或独特的第二次命中模式；目标3：进行功能研究以评估16p12.1基因在神经元细胞类型中具有第二次命中的基因的相互作用在Danio Rerio模型中的果蝇和定量神经系统测定中。最终，我们的研究将有所改善复杂疾病理论策略的遗传诊断，咨询和发展策略。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.

DOI：
10.1038/s41436-018-0266-3
发表时间：
2019-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
0
作者：
Pizzo L;Jensen M;Polyak A;Rosenfeld JA;Mannik K;Krishnan A;McCready E;Pichon O;Le Caignec C;Van Dijck A;Pope K;Voorhoeve E;Yoon J;Stankiewicz P;Cheung SW;Pazuchanics D;Huber E;Kumar V;Kember RL;Mari F;Curró A;Castiglia L;Galesi O;Avola E;Mattina T;Fichera M;Mandarà L;Vincent M;Nizon M;Mercier S;Bénéteau C;Blesson S;Martin-Coignard D;Mosca-Boidron AL;Caberg JH;Bucan M;Zeesman S;Nowaczyk MJM;Lefebvre M;Faivre L;Callier P;Skinner C;Keren B;Perrine C;Prontera P;Marle N;Renieri A;Reymond A;Kooy RF;Isidor B;Schwartz C;Romano C;Sistermans E;Amor DJ;Andrieux J;Girirajan S
通讯作者：
Girirajan S

The gene dose makes the disease.

DOI：
10.1016/j.cell.2022.07.005
发表时间：
2022-08-04
期刊：
CELL
影响因子：
64.5
作者：
Smolen, Corrine;Girirajan, Santhosh
通讯作者：
Girirajan, Santhosh

Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion.

DOI：
10.1186/s13073-021-00982-z
发表时间：
2021-10-18
期刊：
Genome medicine
影响因子：
12.3
作者：
Jensen M;Tyryshkina A;Pizzo L;Smolen C;Das M;Huber E;Krishnan A;Girirajan S
通讯作者：
Girirajan S

The chromatin remodeler ISWI acts during Drosophila development to regulate adult sleep.

DOI：
10.1126/sciadv.abe2597
发表时间：
2021-03
期刊：
Science advances
影响因子：
13.6
作者：
Gong NN;Dilley LC;Williams CE;Moscato EH;Szuperak M;Wang Q;Jensen M;Girirajan S;Tan TY;Deardorff MA;Li D;Song Y;Kayser MS
通讯作者：
Kayser MS

Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development.

致病性拷贝数变异基因的果蝇模型显示发育过程中的整体和非神经元缺陷。

DOI：
10.1371/journal.pgen.1008792
发表时间：
2020
期刊：
PLoS genetics
影响因子：
4.5
作者：
Yusuff,Tanzeen;Jensen,Matthew;Yennawar,Sneha;Pizzo,Lucilla;Karthikeyan,Siddharth;Gould,DagnyJ;Sarker,Avik;Gedvilaite,Erika;Matsui,Yurika;Iyer,Janani;Lai,Zhi-Chun;Girirajan,Santhosh
通讯作者：
Girirajan,Santhosh