Genomic sequencing to aid diagnosis in pediatric and prenatal practice: Examining clinical utility, ethical implications, payer coverage, and data integration in a diverse population.

项目摘要/摘要 先天性异常和发育障碍影响3%-5%的活产婴儿和儿童。 尽管在产前和产后治疗方面都取得了进展，但基因检测在诊断病因中的作用 在这样的条件下，指导管理层的能力一直有限，这一点令人沮丧。最新技术 下一代测序(NGS)的进步导致了对整个序列进行测序和解释的能力 Exome相对较快，可以在25%-30%或更多的发育障碍病例中得到诊断。 虽然外显子组测序(ES)已经改善了诊断并导致了更好的临床结果，但挑战 继续确定如何最好地应用和利用序列数据。履行WES的承诺还需要 对ELSI(伦理、法律、社会)问题的调查，因为一些社区对研究是否会 使他们受益；最终决定获得和公平使用WES的经济考虑因素；以及 需要与家庭和医疗保健系统共享临床遗传结果，以实现更好的 社区环境中罕见情况的预测和管理。 加州大学旧金山分校的产前和儿科基因组测序计划(P3EGS)一直在审查 WES的诊断和临床应用。我们招募并研究了受影响的个人及其父母， 包括胎儿有确认的结构异常的怀孕和以前有 可能由遗传因素引起的未确诊的发育障碍。我们从四个加州大学旧金山分校招募了患者 广泛服务于代表性不足的少数群体的网站(75%)，并跨越整个社会经济 光谱，包括那些服务不足的人。我们正在按部就班地实现我们招募849例患者(566例儿科)的目标 2例和283例产前病例)，并在2021年5月31日之前对这些病例进行外显子组测序。 然而，我们至少还需要一年的时间来完成对过去80个月左右的6个月的跟踪 12月以来登记的案件，组织数据并将其存入数据库，分析收集的数据，以及 准备手稿(为我们的项目和CSER联盟范围的项目)以供出版。因此， 我们正在申请资金，以保持一个小团队在一起，以完成该项目最令人兴奋的部分：仔细 对数据进行分析，得出关于临床测序的许多方面的合理结论。 具体地说，我们的团队将在三个主要领域分析数据： 1.来自不同人群的产前和儿科病例的外显子组测序数据。 2.对患者进行的人种学研究提供了产前和儿科手臂的外显子组测序 学习。 3.外显子组/基因组测序覆盖面支付方决策的卫生经济学研究。

Project Summary/Abstract Congenital abnormalities and developmental disorders affect 3-5% of live born infants and children. Despite advances in both pre- and post-natal treatment, the utility of genetic testing in diagnosing the etiology underlying such conditions in order to guide management has been frustratingly limited. Recent technological advances in next generation sequencing (NGS) have led to the ability to sequence and interpret the entire exome relatively quickly, allowing a diagnosis in 25-30% or more of cases of developmental disorders. Although exome sequencing (ES) has improved diagnosis and led to better clinical outcomes, challenges remain in determining how best to apply and utilize sequence data. Fulfilling the promise of WES also requires investigation of ELSI (ethical, legal, social) concerns, given skepticism in some communities that research will benefit them; economic considerations that ultimately determine access to and equitable use of WES; and a need to share clinical genetic results with families and across health care systems to enable better prognostication and management of rare conditions in community settings. The Program in Prenatal and Pediatric Genomic Sequencing (P3EGS) at UCSF has been examining the diagnostic and clinical utility of WES. We have recruited and studied affected individuals and their parents, including pregnancies in which the fetus has a confirmed structural anomaly and children with previously undiagnosed developmental disorders that are likely of genetic etiology. We recruited patients from four UCSF sites that serve a broad range of underrepresented minorities (75%) and span the full socio-economic spectrum, including the underserved. We are on-track to meet our goal of enrolling 849 cases (566 pediatric cases and 283 prenatal cases) and performing exome sequencing of these cases by May 31, 2021. However, we will need at least an additional year to complete the 6-month follow-up of the last 80 or so cases enrolled since December, organize and deposit the data into databases, analyze the data collected, and prepare manuscripts (both for our project and for CSER Consortium-wide projects) for publication. Accordingly, we are requesting funding to keep a small team together to finish the most exciting part of the project: carefully analyze the data and draw sound conclusions regarding the many aspects of clinical sequencing. Specifically, our team will analyze the data in three main areas: 1. Exome sequencing data of prenatal and pediatric cases from a diverse population. 2. Ethnographic studies of patients offered exome sequencing from the prenatal and pediatric arms of the study. 3. Health economics study of payer decision making on exome/genome sequencing coverage.