Washington University School of Medicine Undiagnosed Diseases Network Clinical Site

项目摘要 临床全基因组测序（cWGS）越来越多地被用作危重婴儿的诊断工具 和儿童在新生儿和儿科重症监护病房（NICU，PICU）进行的多项临床试验 在危重婴儿和儿童中，cWGS的诊断成功率约为30-40%。然而，在这方面， 由于危重婴儿和儿童的遗传疾病可能会降低生殖健康， 可能富含以前与人类疾病无关的新基因， 临床再分析此外，使用cWGS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（UTR）的表达仍然有限。因此，大多数重症婴儿 以及在重症监护室接受过仔细表型分析的疑似遗传病患儿 住院治疗在cWGS之后仍然未被诊断。确认新的“候选”基因的致病性 或意义不确定的变体（VUS）仅限于在能力有限的研究中招募， 可访问性。 我们建议系统地审查，同意，并登记危重婴儿和儿童从 圣路易斯儿童医院的重症监护室将非诊断性cWGS纳入UDN，以增加 将从未诊断疾病网络（UDN）研究中受益的参与者的吞吐量和多样性 重新分析和使用额外的工具（例如，转录组分析，长读段DNA基因组测序， 体外功能研究、模式生物体筛选），由UDN提供，第三方未涵盖 付款人。此外，我们将优先招收重症婴儿和代表性不足的儿童， 少数民族和服务不足的社区为UDN注册。 为了提高华盛顿大学圣路易斯分校（WUSTL）UDN第2阶段参与者的诊断成功率 对于非诊断性临床和基因组评估，我们建议进行RNA-Seq转录组学分析， 长读段DNA基因组测序，以及深度内含子或 非翻译区（5和3' UTR）。

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.