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 这些基因中的机制，导致结构性出生缺陷时，存在于生殖系 并导致癌症是这项研究的一个基本方面。