Washington University School of Medicine Undiagnosed Diseases Network Clinical Site

华盛顿大学医学院未确诊疾病网络临床站点

基本信息

批准号：
10872919
负责人：
PATRICIA I DICKSON
金额：
$ 31.1万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-21 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10872919
关键词：
3&apos Untranslated Regions Address Administrative Supplement African American Alternative Splicing Arkansas Asian Americans Blood Candidate Disease Gene Cardiac Cells Child Childhood Cities Clinical Clinical Trials Collaborations Communities Complex Consent Critical Care Critical Illness DNA Data Diagnostic Disease Enrollment Evaluation Fibroblasts Genes Genetic Diseases Genomics Goals Guidelines Hispanic Americans Hospitalization Hospitals Illinois In Vitro Individual Infant Intensive Care Units Laboratories Literature Maps Medical Genetics Mendelian disorder Missouri Modification Native Americans Neonatal Neonatology Participant Pathogenicity Patients Pediatric Hospitals Pediatric Intensive Care Units Pediatric cardiology Phase Phenotype Population Heterogeneity Publishing RNA RNA Splicing Rare Diseases Research Rural Skin Third-Party Payer Transcript Translations Underrepresented Minority Universities Untranslated RNA Untranslated Regions Variant Washington bioinformatics pipeline candidate identification clinical diagnostics clinical phenotype clinical research site clinical sequencing cohort diagnostic tool ethnic diversity exome sequencing genetic disorder diagnosis genome sequencing human disease improved medical schools member minority communities model organism multidisciplinary novel participant enrollment patient population pediatric patients posttranscriptional predictive tools proband reproductive fitness research clinical testing research study screening success systematic review tool transcriptome sequencing transcriptomics underserved community variant detection variant of unknown significance whole genome

项目摘要

PROJECT SUMMARY Clinical whole genome sequencing (cWGS) is increasingly being used as a diagnostic tool for critically ill infants and children. Multiple clinical trials in neonatal and pediatric intensive care units (NICUs, PICUs) have demonstrated a diagnostic success rate of ~30-40% for cWGS among critically ill infants and children. However, because genetic diseases in critically ill infants and children may reduce reproductive fitness, pathogenic variants are likely to be enriched in novel genes not previously associated with human diseases and not detected by clinical reanalysis. In addition, use of pathogenicity prediction tools for noncoding variants identified with cWGS including deep intronic and untranslated regions (UTR) remains limited. Thus, the majority of critically ill infants and children with suspected genetic diseases who have been carefully phenotyped during their ICU hospitalizations remain undiagnosed after cWGS. Confirmation of pathogenicity among novel ‘candidate’ genes or variants of uncertain significance (VUS) is limited to enrollment in research studies with limited capacity and accessibility. We propose systematically reviewing, consenting, and enrolling critically ill infants and children from the intensive care units at St. Louis Children’s Hospital with non-diagnostic cWGS into the UDN to increase the throughput and diversity of participants who will benefit from Undiagnosed Diseases Network (UDN) research reanalysis and from use of additional tools (e.g., transcriptomic analysis, long-read DNA genomic sequencing, in vitro functional studies, model organism screening) offered through the UDN and not covered by third party payers. In addition, we will prioritize enrollment of critically ill infants and children from underrepresented minorities and underserved communities for UDN enrollment. To increase diagnostic success of Washington University in St. Louis (WUSTL) UDN Phase 2 participants with non-diagnostic clinical and genomic evaluations, we propose performing RNA-Seq transcriptomic analyses, long-read DNA genomic sequencing, and functional studies of noncoding variants in deep intronic or untranslated (5 and 3’ UTR) regions.

项目摘要临床整个基因组测序（CWGS）越来越多地用作重症婴儿的诊断工具和孩子。新生儿和小儿重症监护病房（NICUS，PICUS）的多次临床试验具有在重症儿童和儿童中，CWG的诊断成功率约为30-40％。然而，由于重症婴儿和儿童中的遗传疾病可能会降低生殖适应性，所以致病性变异可能会富含以前与人类疾病相关的新基因，而不是被检测到的临床重新分析。此外，使用CWG鉴定的非编码变体的致病性预测工具包括深内含子和非翻译区域（UTR）的包括仍然有限。那，大多数重病婴儿以及怀疑遗传疾病的儿童，他们在ICU期间经过精心表型 CWGS后仍未诊断住院治疗。确认新型“候选”基因之间的致病性或具有不确定意义（VU）的变体仅限于能力有限和可访问性。我们建议系统地审查，同意和入学危害的婴儿和儿童圣路易斯儿童医院的重症监护病房，非诊断CWG进入UDN，以增加将从未诊断的疾病网络（UDN）研究中受益的参与者的吞吐量和多样性重新分析和使用其他工具（例如，转录组分析，长阅读DNA基因组测序，在体外功能研究，模型生物体筛选）通过UDN提供，而不是由第三方覆盖付款人。此外，我们将优先考虑因代表性不足的重病婴儿和儿童的入学率 UDN入学率的少数民族和服务不足的社区。为了增加圣路易斯华盛顿大学（WUSTL）UDN 2阶段参与者的诊断成功通过非诊断的临床和基因组评估，我们提出了进行RNA-SEQ转录组分析，长阅读的DNA基因组测序以及深内含子或不编码变体的功能研究未翻译（5和3'UTR）区域。