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.

Project Narrative 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) has been studying 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 are also addressing ethical, social and economic issues in the delivery of genomic sequencing results to diverse populations, such as under-represented minorities and the medically underserved.