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

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。传统遗传 用特定的基因测试，甚至是基因面板的测试，只在一小部分病例中具有诊断性。近期 下一代测序(NGS)的技术进步已经导致了测序和解释的能力 整个外显子相对较快，使25%-30%或更多的发育障碍病例得到诊断 当其他基因测试没有产生结果的时候。 尽管整个外显子组测序(WES)对提高诊断水平有着很大的希望 临床结果，在确定如何最好地应用和利用序列数据方面仍然存在挑战。履行 WES的承诺还需要调查ELSI(伦理、法律、社会)问题，因为一些人对此持怀疑态度 研究将使他们受益的社区；最终决定获得和 公平使用WES；以及需要与家庭和跨医疗保健系统共享临床遗传结果 以便能够更好地预测和管理社区环境中的罕见情况。 我们在加州大学旧金山分校提出了一个产前和儿科基因组测序(P3EGS)计划来检查 WES的诊断和临床应用。P3EGS将招募和研究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。在同意和收集 标准化的表型数据，这些家庭将接受WES作为临床护理的一部分。为了实现多样性， 患者确定和招募将在加州大学旧金山分校的四个地点进行，这些地点为范围广泛的以下人员提供服务： 代表少数群体(目标为75%)，涵盖整个社会经济领域，包括未得到充分服务的群体。 我们的具体目标将：1)检查WES的临床效用，包括评估各种 1100名未确诊个体(300名产前，800名儿童)的健康相关和生殖结果 0-17)；2)解决将基因组测序结果提供给 通过(2.1)混合方法纵向实证研究祖先和经济上不同的人群 临床相互作用和经验，(2.2)保险覆盖范围、价格和 多基因检测的报销，以及(2.3)创建道德咨询委员会，以应对新出现的 问题和建立可信的利益攸关方参与；以及3)试点用户友好的基于网络的 将基因组数据和临床数据整合为共享证据基础的患者/提供商应用程序，以支持 结果沟通、解释和临床决策；应用程序将基于 加州大学旧金山分校创建并成功实施了“Bioscreen”模式。

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. Traditional genetic testing with specific gene tests, or even gene panels, is diagnostic in only a small percentage of cases. 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 when other genetic tests have not yielded a result. Although whole exome sequencing (WES) holds great promise for improved diagnosis leading 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. We propose a Program in Prenatal and Pediatric Genomic Sequencing (P3EGS) at UCSF to examine the diagnostic and clinical utility of WES. P3EGS will recruit and study 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. Following consent and collection of standardized phenotypic data, the families will undergo WES as part of clinical care. To achieve diversity, patient ascertainment and recruitment will occur at four UCSF sites that serve a broad range of under- represented minorities (target of 75%) and span the full socio-economic spectrum, including the underserved. Our specific aims will: 1) examine the clinical utility of WES, including assessment of a variety of health-related and reproductive outcomes, in 1100 undiagnosed individuals (300 prenatal, 800 children ages 0-17); 2) address ethical, social and economic issues in the delivery of genomic sequencing results to ancestrally and economically diverse populations through (2.1) a mixed methods, longitudinal empirical study of clinical interactions and experiences, (2.2) an economic analysis of insurance coverage, price and reimbursement of multigene tests, and (2.3) creation of an Ethics Advisory Board to respond to emerging issues and establishment of authentic stakeholder engagement; and 3) pilot a user-friendly web-based patient/provider application integrating genomic and clinical data as a shared evidence base to support result communication, interpretation and clinical decision making; the application will be based on the “Bioscreen” model created and successfully implemented at UCSF.