Characterizing disease-causing variants using personal genomes with large recurrent deletions
使用具有大量重复缺失的个人基因组来表征致病变异
基本信息
- 批准号:10442357
- 负责人:
- 金额:$ 46.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:17q121q21AllelesClinicalCopy Number PolymorphismCounselingDNA Sequence RearrangementDataDatabasesDiabetes MellitusDiagnosisDiseaseDisease OutcomeEnhancersGenesGeneticGenetic DeterminismGenetic DiseasesGenomeGenomicsGenotypeGoalsHeadHumanKnowledgeMedicalMendelian disorderModelingMolecularPatient RecruitmentsPatientsPenetrancePhenotypePublic HealthRecurrenceResearchResourcesRoleTestingValidationVariantWorkbaseclinical diagnosticsclinically significantcohortdisease phenotypeearly onsetgenetic variantgenome sequencinggenomic locushuman diseasehuman subjectindividual patientinduced pluripotent stem cellinnovationpersonalized medicineprecision genomic medicinewhole genome
项目摘要
Abstract
A major challenge in the field of genomic precision medicine is the observation that genotype does not always
predict phenotype in Mendelian disorders. This phenotype variation is thought to be caused in part by common
variants and variants with subtle effects, but the potential deterministic roles of such modifier alleles have not
been rigorously or systematically studied in clinical settings. Toward the long-term goal of deciphering the
genetic basis of incomplete penetrance and variable expressivity in human monogenic diseases, this proposal
aims to study patients with recurrent genomic disorders in whom identical genomic rearrangements manifest
disease phenotypes in an incompletely penetrant manner. The overall objective of this proposed project is to
formulate a generalizable approach using cohorts of patients with recurrent large genomic deletions that can
identify and characterize clinically significant disease-modifying variants. The central hypothesis is that patients
with recurrent large genomic deletions offer an effective genomic background to identify disease-modifying
alleles that serve as reliable predictors of disease outcome in individual patients. This central hypothesis will be
tested by defining the genetic determinants of specific phenotype presentations at two genomic loci: early
onset diabetes at 17q12 and abnormal head size at 1q21.1. Large-scale patient resources will be gathered
based on molecular information made available by clinical diagnostics. Recruited patients will be analyzed at
the molecular level by whole genome sequencing. Phenotype–genotype correlation analysis will be performed
to identify candidate modifier alleles under different disease-modifying models based on preliminary data from
each disease locus. Functional validation of selected disease-modifying alleles will be performed using patient-
derived induced pluripotent stem cells. The innovation of this study lies in the assembly of rare personal
genomes with identical copy number variants from clinical diagnostic databases to enable a human subject
“enhancer screen.” The proposed research is significant because it is expected to identify clinically important
alleles in recurrent deletion loci whose presence or absence can be used for precise diagnosis, counseling and
management for patients with genetic disorders. The research strategy utilized herein could be generalized to
other phenotypes or genomic loci, and the general mechanisms discovered will be directly applicable to
understanding incomplete penetrance and variable expressivity in human diseases.
摘要
基因组精准医学领域的一个主要挑战是观察到基因型并不总是
预测孟德尔疾病的表型。这种表型变异被认为部分是由常见的
变异体和变异体具有微妙的影响,但这种修饰等位基因的潜在决定性作用还没有
在临床环境中进行了严格或系统的研究。为了实现破译
人类单基因疾病的不完全遗传和可变表达的遗传基础,
旨在研究复发性基因组疾病患者,
疾病表型以不完全渗透的方式。本拟议项目的总体目标是
使用复发性大基因组缺失的患者队列制定一种可推广的方法,可以
鉴定和表征临床上显著疾病修饰变体。核心假设是,
与复发性大基因组缺失提供了一个有效的基因组背景,以确定疾病修饰
作为个体患者疾病结果的可靠预测因子的等位基因。这一核心假设将是
通过在两个基因组位点定义特定表型呈现的遗传决定因素进行测试:
在17 q12出现糖尿病,在1q21.1出现头部大小异常。将聚集大规模患者资源
基于临床诊断提供的分子信息。招募的患者将在
通过全基因组测序来进行分子水平的研究。将进行表型-基因型相关性分析
基于来自以下的初步数据,在不同的疾病修饰模型下鉴定候选修饰基因等位基因:
每一个疾病的轨迹。选择的疾病修饰等位基因的功能验证将使用患者-
诱导多能干细胞。本研究的创新之处在于,
来自临床诊断数据库的具有相同拷贝数变体的基因组,
“增强屏”这项拟议中的研究意义重大,因为它有望确定临床上重要的
复发性缺失基因座中的等位基因,其存在或不存在可用于精确诊断、咨询和
遗传性疾病患者的管理。本文所采用的研究策略可以推广到
其他表型或基因组位点,以及发现的一般机制将直接适用于
理解人类疾病中的不完全表达和可变表达。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Pengfei Liu其他文献
Pengfei Liu的其他文献
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- 批准号:
10662930 - 财政年份:2023
- 资助金额:
$ 46.99万 - 项目类别:
Characterizing disease-causing variants using personal genomes with large recurrent deletions
使用具有大量重复缺失的个人基因组来表征致病变异
- 批准号:
10646236 - 财政年份:2021
- 资助金额:
$ 46.99万 - 项目类别:
Characterizing disease-causing variants using personal genomes with large recurrent deletions
使用具有大量重复缺失的个人基因组来表征致病变异
- 批准号:
10047813 - 财政年份:2021
- 资助金额:
$ 46.99万 - 项目类别:
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