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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。

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

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 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

Challenges and considerations for reproducibility of STARR-seq assays.

DOI：
10.1101/gr.277204.122
发表时间：
2023-04
期刊：
GENOME RESEARCH
影响因子：
7
作者：
Das, Maitreya;Hossain, Ayaan;Banerjee, Deepro;Praul, Craig Alan;Girirajan, Santhosh
通讯作者：
Girirajan, Santhosh

Clinical utility gene card for: 16p12.2 microdeletion.

临床实用基因卡为：16p12.2微缺失。