Rapid development of genome sequencing technology has led to dramatic increases in the discovery of the genetic causes of many rare disorders and has transformed our ability to diagnose and treat genetic conditions. In particular, whole exome sequencing (WES) has proven to be a highly successful diagnostic modality in patients with conditions having a high degree of genetic heterogeneity. As part of the Clinical Sequencing Exploratory Research (CSER) consortium, UNC's project, ?North Carolina Clinical Genomic Evaluation by Next-gen Exome Sequencing? (NCGENES) addressed several key issues in the clinical application of exome sequencing, including the diagnostic yield when applying WES in diverse clinical scenarios, optimal approaches to dealing with secondary findings, the informed consent process, and responses of patients and families to genomic information. Due in part to the success of the CSER program, WES has become widely clinically available. However, before it can be widely implemented payers will need to be convinced to routinely cover the use of WES; thus, critical questions must be addressed regarding its clinical utility. The current renewal, NCGENES 2, will provide this necessary evidence base by bringing together a highly inter-disciplinary team to conduct a randomized clinical trial to study healthcare outcomes and communication among patients, family members, clinicians, and laboratorians. Moreover, NCGENES 2 will address these issues in traditionally disadvantaged populations to ensure that the benefits of genomic medicine will accrue to the broadest possible segment of the population.
Each aim of NCGENES 2 will address specific outcomes that are highly relevant to the real-world implementation of clinical exome sequencing: 1) technical and analytic outcomes, 2) patient-centered outcomes, 3) clinical outcomes, and 4) societal outcomes, including economic implications. Ultimately, NCGENES 2 will generate the necessary evidence to support the use of WES as a standard tool in the management of patients with genetic disorders and enable its implementation in populations that experience health disparities.

Public Health Relevance

Genomic sequencing has the potential to allow patients with heterogeneous genetic disorders to receive a prompt and specific molecular diagnosis, allowing physicians, patients and families to benefit from early management, treatment and prevention. In this proposal we will generate the evidence necessary for a variety of stakeholders (patients, physicians, and payers) to determine when the use of this technology will result in an overall benefit.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HG006487-06
Application #
9537665
Study Section
Special Emphasis Panel (ZHG1)
Program Officer
Madden, Ebony B
Project Start
2011-12-05
Project End
2021-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Skinner, Debra; Roche, Myra I; Weck, Karen E et al. (2018) ""Possibly positive or certainly uncertain?"": participants' responses to uncertain diagnostic results from exome sequencing. Genet Med 20:313-319
Ormond, Kelly E; Hallquist, Miranda L G; Buchanan, Adam H et al. (2018) Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background. Genet Med :
Strande, Natasha T; Brnich, Sarah E; Roman, Tamara S et al. (2018) Navigating the nuances of clinical sequence variant interpretation in Mendelian disease. Genet Med 20:918-926
Hart, M Ragan; Biesecker, Barbara B; Blout, Carrie L et al. (2018) Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study. Genet Med :
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
Sanghvi, Rashesh V; Buhay, Christian J; Powell, Bradford C et al. (2018) Characterizing reduced coverage regions through comparison of exome and genome sequencing data across 10 centers. Genet Med 20:855-866

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