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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：
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
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：
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

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.

项目总结