Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study

作者：Eden Haverfield, Edward D. Esplin, Sienna Aguilar, Kathryn E. Hatchell, Kelly E. Ormond, Andrea Hanson‐Kahn, Paldeep S. Atwal, Sarah K. Macklin‐Mantia, Stephanie L. Hines, Caron W.-M. Sak, Steven Tucker, Steven B. Bleyl, Peter J. Hulick, Ora Gordon, Lea Velsher, Jessica Gu, Scott M. Weissman, Teresa Kruisselbrink, Christopher Abel, Michele Kettles, Anne Slavotinek, Bryce A. Mendelsohn, Robert C. Green, Swaroop Aradhya, Robert L. Nussbaum · 发表于：BMC Medicine · 年份：2021 · DOI：10.1186/s12916-021-01999-2 · 被引用次数：37 · 研究领域：Genomics and Rare Diseases、BRCA gene mutations in cancer、Genetic Associations and Epidemiology

BACKGROUND: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. METHODS: Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction. RESULTS: Among 10,478 unrelated adults screened, 1619 (15.5%) had resul...