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

• 批准号: 9808671
• 负责人: IAN D. KRANTZ
• 金额: $ 17.6万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9808671
• 关键词: ATAC-seq; Address; Affect; Algorithms; Bruck-de Lange syndrome; Candidate Disease Gene; ChIP-seq; Chromosome Structures; Clinical; Code; Complex; Congenital Abnormality; Consensus; Copy Number Polymorphism; Counseling; DNA; Data; Developmental Gene; Diagnosis; Diagnostic; Disease; Elements; Embryonic Development; Epigenetic Process; Etiology; Event; Family; Family member; First Pregnancy Trimester; Genes; Genetic; Genetic Transcription; Genome; Genomic DNA; Genomics; Germ Lines; Growth; Health; Human; Impaired cognition; Individual; Lead; Libraries; Malignant Neoplasms; Messenger RNA; Mission; Molecular Analysis; Molecular Diagnosis; Morphogenesis; Mutate; Mutation; Nature; Nucleotides; Oncogenes; Outcome; Outcomes Research; Pathogenicity; Pathway interactions; Phenotype; Predisposition; Public Health; RNA Splicing; Regulatory Element; Research; Sampling; Site; Structural Congenital Anomalies; Structure; Syndrome; Term Birth; Therapeutic; Tissues; Transcriptional Regulation; United States National Institutes of Health; Untranslated RNA; Variant; Work; base; body system; cohesin; cohort; congenital anomaly; developmental disease; epigenomics; exome sequencing; fusion gene; gene environment interaction; gene function; genome sequencing; improved; insertion/deletion mutation; insight; lymphoblastoid cell line; next generation sequencing; novel; proband; programs; stillbirth; transcriptome sequencing; whole genome

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 人类形态发生的疾病是受影响的人类痛苦的主要原因 个人及其家人。先天性异常大约在期限的3％中识别 出生，占死产的10％，多达50％的妊娠胎生流产。尽管 大多数（如果不是全部）人类结构性先天缺陷具有重要的遗传成分， 鉴定孤立结构出生缺陷中遗传扰动的鉴定已经复杂化 其潜在病因的复杂性，可能涉及监管的破坏 可以以临时和组织特定方式起作用的元素，多基因，表观遗传和 基因环境相互作用。我们取消对先天缺陷的遗传贡献的方法 一直是确定通常是门德利人的综合症的根本原因 从本质上讲，因此更容易将自己带入遗传因果鉴定。一次 确定，这些综合症形式的遗传原因可以利用 了解这些在这些星座中看到的孤立先天缺陷的遗传贡献 综合征。我们建议使用Cornelia de Lange综合征（CDLS），这是一个主要的多系统 大多数涉及的结构性先天缺陷组成的发育障碍 人体系统以及重大的增长和认知障碍作为这一点的一个典型例子 方法。我们和其他人表明，粘着蛋白和相关途径的改变 在中断时是CDL和相关诊断的原因，并且更广泛地存在 被称为“粘蛋白病”或“转录调节（DTRS）的疾病”。在这个建议中，我们 概述一个初始计划，以分析独特的基因组序列和RNA测序数据 有400个概率和家庭成员的临床确认CDL或相关的家族成员的队列 诊断，其中分子分析通过靶向基因测序，下一代 测序（NGS）面板或外显子组测序是负面的，但很强 怀疑具有潜在的遗传改变来解释其临床特征。 这项工作将导致对人类胚胎发育至关重要的基因的鉴定， 提供对转录调节的新见解，并有助于确定遗传原因和 在这组诊断中，在星座中看到的孤立的先天缺陷的候选基因。最多 关键发育基因也是癌症基因，已知引起CDL的基因无 例外。 CDL不是癌症易感综合征，因此了解突变 这些基因中导致结构出生缺陷的机制存在 当突变时，导致癌症是这项研究的基本方面。