Genomic Diagnostics in Cornelia de Lange Syndrome, Related Diagnosis and Structural Birth Defects
Cornelia de Lange 综合征的基因组诊断、相关诊断和结构性出生缺陷
基本信息
- 批准号:9808671
- 负责人:
- 金额:$ 17.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-09 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAddressAffectAlgorithmsBruck-de Lange syndromeCandidate Disease GeneChIP-seqChromosome StructuresClinicalCodeComplexCongenital AbnormalityConsensusCopy Number PolymorphismCounselingDNADataDevelopmental GeneDiagnosisDiagnosticDiseaseElementsEmbryonic DevelopmentEpigenetic ProcessEtiologyEventFamilyFamily memberFirst Pregnancy TrimesterGenesGeneticGenetic TranscriptionGenomeGenomic DNAGenomicsGerm LinesGrowthHealthHumanImpaired cognitionIndividualLeadLibrariesMalignant NeoplasmsMessenger RNAMissionMolecular AnalysisMolecular DiagnosisMorphogenesisMutateMutationNatureNucleotidesOncogenesOutcomeOutcomes ResearchPathogenicityPathway interactionsPhenotypePredispositionPublic HealthRNA SplicingRegulatory ElementResearchSamplingSiteStructural Congenital AnomaliesStructureSyndromeTerm BirthTherapeuticTissuesTranscriptional RegulationUnited States National Institutes of HealthUntranslated RNAVariantWorkbasebody systemcohesincohortcongenital anomalydevelopmental diseaseepigenomicsexome sequencingfusion genegene environment interactiongene functiongenome sequencingimprovedinsertion/deletion mutationinsightlymphoblastoid cell linenext generation sequencingnovelprobandprogramsstillbirthtranscriptome sequencingwhole genome
项目摘要
PROJECT SUMMARY
Disorders of human morphogenesis are a major cause of human suffering for the affected
individuals and their families. Congenital anomalies are identified in approximately 3% of term
births, 10% of stillbirths, and in as many as 50% of first trimester spontaneous abortuses. While
most, if not all, human structural birth defects have a significant genetic component,
identification of genetic perturbations in isolated structural birth defects has been complicated by
the complex nature of their underlying etiologies, likely involving disruption of regulatory
elements that can act in a temporal and tissue specific manner, multi-gene, epigenetic and
gene-environment interactions. Our approach to tease out genetic contributions to birth defects
has been to identify the underlying causes of syndromic birth defects which are often Mendelian
in nature and therefore lend themselves more readily to genetic causal identification. Once
identified, these genetic causes of syndromic forms of birth defects can be leveraged to
understand the genetic contributions to isolated birth defects seen in constellation in these
syndromes. We propose to use Cornelia de Lange Syndrome (CdLS), a dominant multisystem
developmental disorder consisting of a constellation of structural birth defects involving most
body systems and significant growth and cognitive impairment as a prime example of this
approach. We and others have shown that alterations in the cohesin and associated pathways
are causative of CdLS and related diagnoses when disrupted and have more broadly been
termed “cohesinopathies” or “disorders of transcriptional regulation (DTRs)”. In this proposal we
outline an initial plan to analyze genome sequence and RNA sequencing data on a unique
cohort of 400 probands and family members with clinically confirmed CdLS or a related
diagnosis in whom molecular analysis by targeted gene sequencing, next generation
sequencing (NGS) panels or exome sequencing have been negative, but are strongly
suspected of having an underlying genetic alteration to explain their clinical features.
This work will lead to the identification of genes critical in human embryonic development,
provide novel insights into transcriptional regulation and help to identify genetic causes and
candidate genes for isolated birth defects seen in constellation in this group of diagnoses. Most
critical developmental genes are also cancer genes and the genes known to cause CdLS are no
exception. CdLS is not a cancer predisposition syndrome so understanding the mutational
mechanisms in these genes that lead to structural birth defects when present in the germ line
and result in cancer when mutated somatically is a fundamental aspect of this research.
项目摘要
人类形态发生障碍是造成患者痛苦的一个主要原因
个人及其家庭。先天性异常被确定在约3%的任期
分娩,10%的死产,以及多达50%的头三个月自然流产。而
大多数(如果不是全部的话)人类结构性出生缺陷具有显著的遗传成分,
在孤立的结构性出生缺陷中识别遗传扰动已经变得复杂,
其潜在病因的复杂性,可能涉及监管中断
可以以时间和组织特异性方式起作用的元件、多基因、表观遗传和
基因与环境的相互作用我们的方法梳理出遗传因素对出生缺陷的贡献
一直是为了找出综合征性出生缺陷的根本原因,这些缺陷通常是孟德尔式的
因此更容易进行遗传因果鉴定。一旦
一旦确定,这些综合征形式的出生缺陷的遗传原因就可以被利用,
了解这些星座中孤立出生缺陷的遗传贡献,
综合征我们建议使用科尔内利亚德兰格综合征(CdLS),一个显性多系统
由一系列结构性出生缺陷组成的发育障碍,涉及大多数
身体系统和显着的增长和认知障碍作为一个主要的例子,
approach.我们和其他人已经表明,在粘附素和相关途径的改变,
当被破坏时,是CdLS和相关诊断的原因,
称为“粘着蛋白病”或“转录调节障碍(DTR)"。在本提案中,我们
概述了分析基因组序列和RNA测序数据的初步计划,
400名先证者和家族成员的队列,临床证实为CdLS或相关
通过靶向基因测序进行分子分析,下一代
测序(NGS)面板或外显子组测序一直是阴性的,但强烈
怀疑有潜在的基因改变,以解释他们的临床特征。
这项工作将导致人类胚胎发育关键基因的鉴定,
为转录调控提供新的见解,并帮助确定遗传原因,
在这组诊断中的星座中看到的孤立出生缺陷的候选基因。最
关键的发育基因也是癌症基因,已知引起CdLS的基因是不存在的。
例外. CdLS不是一种癌症易感综合征,因此了解突变
这些基因存在于种系中时会导致结构性出生缺陷的机制
并导致癌症是这项研究的一个基本方面。
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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IAN D. KRANTZ其他文献
IAN D. KRANTZ的其他文献
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{{ truncateString('IAN D. KRANTZ', 18)}}的其他基金
Advancing Child Health: Preparing the Next Generation of Pediatric Researchers
促进儿童健康:培养下一代儿科研究人员
- 批准号:
10613355 - 财政年份:2020
- 资助金额:
$ 17.6万 - 项目类别:
Advancing Child Health: Preparing the Next Generation of Pediatric Researchers.
促进儿童健康:培养下一代儿科研究人员。
- 批准号:
8830125 - 财政年份:2015
- 资助金额:
$ 17.6万 - 项目类别:
Advancing Child Health: Preparing the Next Generation of Pediatric Researchers.
促进儿童健康:培养下一代儿科研究人员。
- 批准号:
9280625 - 财政年份:2015
- 资助金额:
$ 17.6万 - 项目类别:
NIPBL, Cohesin and Related Structural Birth Defects
NIPBL、粘连蛋白和相关结构性出生缺陷
- 批准号:
7931201 - 财政年份:2009
- 资助金额:
$ 17.6万 - 项目类别:
A role for the CdLS gene NIPBL in HP1 gene silencing
CdLS 基因 NIPBL 在 HP1 基因沉默中的作用
- 批准号:
7356463 - 财政年份:2007
- 资助金额:
$ 17.6万 - 项目类别:
Molecular Analysis of Human Subtelomeric Rearrangements
人类亚端粒重排的分子分析
- 批准号:
7354822 - 财政年份:2007
- 资助金额:
$ 17.6万 - 项目类别:
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