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。传统遗传 用特定的基因测试或甚至基因板进行测试，仅在一小部分情况下是诊断性的。最近 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，允许诊断25-30%或更多的发育障碍病例 当其他基因测试没有结果时。 尽管全外显子组测序（WES）在改善诊断方面有很大的希望， 临床结果，挑战仍然存在于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、法律的、社会）问题进行调查，因为有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;需要与家庭和整个卫生保健系统共享临床遗传结果 以便在社区环境中更好地诊断和管理罕见疾病。 我们提出了一个产前和儿科基因组测序计划（P3 EGS）在加州大学旧金山分校，以检查 WES的诊断和临床应用。P3 EGS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先前有 未确诊的发育障碍，可能是遗传病因。在征得同意并收集 标准化的表型数据，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四个UCSF站点进行，这些站点为广泛的 代表少数群体（目标为75%），涵盖所有社会经济阶层，包括得不到充分服务的群体。 我们的具体目标是：1）检查WES的临床效用，包括评估各种 1100名未确诊的个体（300名产前，800名儿童年龄）的健康相关和生殖结果 0-17）; 2）解决基因组测序结果交付中的伦理、社会和经济问题， 通过（2.1）混合方法，纵向实证研究， 临床互动和经验，（2.2）保险范围，价格和 （2.3）设立道德咨询委员会，以应对新出现的 问题和建立真正的利益攸关方参与;和3）试行一个方便用户的网络 患者/提供者应用程序，将基因组和临床数据整合为共享证据库， 结果交流、解释和临床决策;申请将基于 “生物筛选”模型在UCSF创建并成功实施。

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.