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

BMC Medicine

Robert C. Green¹  Christopher Abel²  Michele Kettles²  Steven B. Bleyl³  Scott M. Weissman⁴  Edward D. Esplin⁵  Eden V. Haverfield⁵  Swaroop Aradhya⁵  Kathryn E. Hatchell⁵  Sienna J. Aguilar⁵  Robert L. Nussbaum⁶  Bryce A. Mendelsohn⁷  Stephanie Hines⁸  Sarah Macklin-Mantia⁸  Paldeep S. Atwal⁹  Teresa Kruisselbrink^1,10  Jessica Y. J. Gu^1,11  Lea Velsher^1,11  Peter J. Hulick^1,12  Ora K. Gordon^1,13  Kelly E. Ormond^1,14  Andrea Hanson-Kahn^1,14  Steven Tucker^1,15  Caron W.-M. Sak^1,15  Anne Slavotinek^1,16 

[1] Brigham and Women’s Hospital, Boston, MA, USA;The Broad Institute, Boston, MA, USA;Ariadne Labs, Boston, MA, USA;Harvard Medical School, Boston, MA, USA;Cooper Clinic, Dallas, TX, USA;Genome Medical, San Francisco, CA, USA;Genome Medical, San Francisco, CA, USA;Chicago Genetic Consultants, Northbrook, IL, USA;Invitae, 1400 16th Street, 94103, San Francisco, CA, USA;Invitae, 1400 16th Street, 94103, San Francisco, CA, USA;Volunteer Faculty, University of California San Francisco, San Francisco, CA, USA;Kaiser Permanente, Oakland, CA, USA;Mayo Clinic, Jacksonville, FL, USA;Mayo Clinic, Jacksonville, FL, USA;Atwal Clinic, Jacksonville, FL, USA;PWNHealth, New York, NY, USA;Mayo Clinic, Rochester, MN, USA;Medcan, Toronto, Ontario, Canada;NorthShore University HealthSystem, Chicago, IL, USA;Providence Research Network, St John Cancer Institute, Los Angeles, CA, USA;University of California, Los Angeles, CA, USA;Stanford University School of Medicine, Stanford, CA, USA;Tucker Medical, Singapore, Singapore;University of California San Francisco, San Francisco, CA, USA;

关键词: Cardiovascular disorders;    Clinical genetics;    Hereditary cancer syndromes;    Monogenic disorders;    Population screening;    Proactive genetic screening;   

DOI  :  10.1186/s12916-021-01999-2

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsEligible 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.ResultsAmong 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility.ConclusionsThis is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

【 授权许可】

CC BY