Genomic Diagnostics in Cornelia de Lange Syndrome, Related Diagnosis and Structural Birth Defects

项目总结 人类形态发生障碍是人类遭受痛苦的一个主要原因 个人和他们的家人。约3%的足月有先天性畸形。 出生，死产的10%，以及多达50%的早期妊娠自然流产。而当 大多数，如果不是全部的话，人类结构性出生缺陷都有显著的遗传成分， 在孤立的结构性出生缺陷中识别遗传扰动已经变得复杂 其根本原因的复杂性质，可能涉及监管中断 可以以时间和组织特有的方式发挥作用的元素，多基因，表观遗传和 基因与环境的相互作用。我们梳理出导致出生缺陷的遗传因素的方法 一直是为了找出综合症出生缺陷的根本原因，这些缺陷通常是孟德尔式的 在自然界，因此更容易进行基因因果鉴定。一次 经鉴定，出生缺陷综合症形式的这些遗传原因可以被用来 了解这些星座中孤立的出生缺陷的遗传贡献 综合症。我们建议使用Cornelia de Lange综合征(CDLS)，这是一种显性的多系统 由一系列结构性出生缺陷组成的发育障碍 身体系统和显著的发育和认知障碍就是一个很好的例子 接近。我们和其他人已经证明，凝集素和相关通路的变化 在受到干扰时会导致CDLS和相关诊断，而且更广泛地说 称为“粘连病症”或“转录调节障碍(DTRs)”。在这份提案中，我们 概述分析基因组序列和RNA测序数据的初步计划 400名患有临床确诊的CDL或相关疾病的先证者和家庭成员的队列 通过靶向基因测序进行分子分析的下一代诊断 测序(NGS)小组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来解释他们的临床特征。 这项工作将导致对人类胚胎发育至关重要的基因的识别， 为转录调控提供新的见解，并帮助确定遗传原因和 在这组诊断中，星座中可以看到孤立出生缺陷的候选基因。多数 关键的发育基因也是癌症基因，而已知的导致CDL的基因是NO 例外情况。CDLS不是一种癌症易感综合征，所以了解突变 当这些基因存在于生殖系时，导致结构性出生缺陷的机制 并在体细胞突变时导致癌症是这项研究的一个基本方面。

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.