CSER: Genomic Sequencing to Aid Diagnosis in Pediatric and Prenatal Practice: Examining Clinical Utility, Ethical Implications, Payer Coverage, and Data Integration in a Diverse Population

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 underrepresented 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 undiagnosed individuals; 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.

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Inclusion Criteria:
1. Presenting clinical features suggestive of a genetic etiology, including ID, seizures, multiple congenital anomalies, metabolic conditions, and neurodegenerative conditions or idiopathic CP; 80 of these patients will have encephalopathy or multiple congenital anomalies so that they may benefit from rapid exome sequencing in the PICU or NICU.
2. Pregnant women with fetuses with structural birth defects identified by ultrasound.
3. A minimum of one biological parent is available and willing to provide a biospecimen for WES, with a preference for two available parents. At least one parent consenting to WES of the child. For the prenatal cases, at least the mother has to consent to WES of a fetal sample as well as on herself.
4. Pediatric patients must have had at least one prior genetics appointment or evaluation.5. Pediatric and prenatal patients must have had a single nucleotide polymorphism (SNP) array or oligonucleotide array that did not provide a diagnosis.

Exclusion Criteria:
1. Prior WES performed for a clinical or research indication
2. Lack of phenotypic indication of a likely underlying genetic etiology
3. Both biological parents are unavailable.
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