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.

Public Health Relevance

Genome sequencing, which allows physicians to look at many genes concurrently, has been rapidly integrated into the clinical setting but its usefulness remains uncertain. The UCSF Program in Prenatal and Pediatric Genome Sequencing (P3EGS) will study the effectiveness of sequencing as a tool for 1) diagnosing infants and children with serious developmental disorders, and, 2) providing genetic information to parents when a prenatal study reveals a fetus with a structural anomaly. We will also address ethical, social and economic issues in the delivery of genomic sequencing results to diverse populations, such as under represented minorities and the medically underserved.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHG1)
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Hindorff, Lucia
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Phillips, Kathryn A; Trosman, Julia R; Deverka, Patricia A et al. (2018) Insurance coverage for genomic tests. Science 360:278-279
Phillips, Kathryn A (2018) Evolving Payer Coverage Policies on Genomic Sequencing Tests: Beginning of the End or End of the Beginning? JAMA 319:2379-2380
Amendola, Laura M; Berg, Jonathan S; Horowitz, Carol R et al. (2018) The Clinical Sequencing Evidence-Generating Research Consortium: Integrating Genomic Sequencing in Diverse and Medically Underserved Populations. Am J Hum Genet 103:319-327
Douglas, Michael P; Parker, Stephanie L; Trosman, Julia R et al. (2018) Private payer coverage policies for exome sequencing (ES) in pediatric patients: trends over time and analysis of evidence cited. Genet Med :
Phillips, Kathryn A; Deverka, Patricia A; Hooker, Gillian W et al. (2018) Genetic Test Availability And Spending: Where Are We Now? Where Are We Going? Health Aff (Millwood) 37:710-716
Ginsburg, Geoffrey S; Phillips, Kathryn A (2018) Precision Medicine: From Science To Value. Health Aff (Millwood) 37:694-701