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Open Access 01-12-2021 | Research article

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

Authors: Eden V. Haverfield, Edward D. Esplin, Sienna J. Aguilar, Kathryn E. Hatchell, Kelly E. Ormond, Andrea Hanson-Kahn, Paldeep S. Atwal, Sarah Macklin-Mantia, Stephanie Hines, Caron W.-M. Sak, Steven Tucker, Steven B. Bleyl, Peter J. Hulick, Ora K. Gordon, Lea Velsher, Jessica Y. J. Gu, Scott M. Weissman, Teresa Kruisselbrink, Christopher Abel, Michele Kettles, Anne Slavotinek, Bryce A. Mendelsohn, Robert C. Green, Swaroop Aradhya, Robert L. Nussbaum

Published in: BMC Medicine | Issue 1/2021

Abstract

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 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.

Conclusions

This 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.

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Title: Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study
Authors: Eden V. Haverfield
Edward D. Esplin
Sienna J. Aguilar
Kathryn E. Hatchell
Kelly E. Ormond
Andrea Hanson-Kahn
Paldeep S. Atwal
Sarah Macklin-Mantia
Stephanie Hines
Caron W.-M. Sak
Steven Tucker
Steven B. Bleyl
Peter J. Hulick
Ora K. Gordon
Lea Velsher
Jessica Y. J. Gu
Scott M. Weissman
Teresa Kruisselbrink
Christopher Abel
Michele Kettles
Anne Slavotinek
Bryce A. Mendelsohn
Robert C. Green
Swaroop Aradhya
Robert L. Nussbaum
Publication date: 01-12-2021
Publisher: BioMed Central
Published in: BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-01999-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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