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

项目总结/摘要 先天性畸形和发育障碍影响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方面的实用性仍然不足。 令人沮丧的是，为指导管理而对这些条件的基础进行的研究非常有限。最近的技术 下一代测序（NGS）的进步已经导致了测序和解释整个基因组的能力。 外显子相对较快地被识别，允许诊断25-30%或更多的发育障碍病例。 尽管外显子组测序（ES）改善了诊断并带来了更好的临床结果，但挑战仍然存在。 仍然是确定如何最好地应用和利用序列数据。实现WES的承诺还需要 对ELSI（伦理、法律的、社会）问题的调查，考虑到一些社区对研究将 使他们受益;最终决定获得和公平使用水和环境卫生服务的经济考虑;以及 需要与家庭和整个卫生保健系统分享临床遗传结果， 社区环境中罕见疾病的诊断和管理。 加州大学旧金山分校的产前和儿科基因组测序项目（P3 EGS） 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先前有 未确诊的发育障碍，可能是遗传病因。我们从四个加州大学旧金山分校 为广泛的代表性不足的少数民族（75%）提供服务的网站， 频谱，包括服务不足的人群。我们正在努力实现入组849例病例（566例儿童）的目标 例和283例产前病例），并在2021年5月31日前对这些病例进行外显子组测序。 然而，我们将需要至少一个额外的一年，以完成6个月的后续行动的最后80左右， 12月以来入组的病例，将数据整理并存款数据库，分析收集的数据， 准备手稿（包括我们的项目和CSER联盟范围内的项目）以供出版。因此，委员会认为， 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 分析数据并得出关于临床测序的许多方面的合理结论。 具体而言，我们的团队将从三个主要方面分析数据： 1.不同人群产前和儿科病例的外显子组测序数据。 2.对患者进行人种学研究，提供了来自产前和儿科的外显子组测序， study. 3.外显子组/基因组测序覆盖率的支付者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.