Ability of Patients to Distinguish Among Cardiac Genomic Variant Subclassifications

Abstract

Background Clinical genetic testing for heritable cardiovascular disease has become a widely-used tool to aid in the management of patients and their families. A five-category variant classification system is commonly used for genetic test results, but some laboratories further sub-classify variants of uncertain significance (VUS). How and whether patients perceive differences among the variant categories or sub-classifications of VUS is unknown. Methods and Results We tested whether participants perceived differences in genetic variant sub-classifications on outcomes including: risk comprehension, risk perception, worry, perceived uncertainty, and intentions. Order-randomized hypothetical cardiovascular genetic results were given to 289 participants enrolled in a genome sequencing study. Three categories of variants were presented to participants: VUS, Possibly Pathogenic, and Likely Pathogenic. Responses to the first variant presented were analyzed in a between-groups analysis, and responses to all three variants were analyzed in a within-groups analysis. When presented with all three results, participants distinguished among the sub-classifications on all outcomes (p<0.001). When given only a Possibly Pathogenic result, their risk perceptions were similar to those of a VUS, but they were more worried and intended to behave as if they had received a Likely Pathogenic result. Individuals depended more on their affective responses such as worry when they received only one result (p<0.05). Conclusions Participants are better able to distinguish pathogenicity sub-classifications when presented with multiple categories. Individuals who receive a single uncertain result in a cardiovascular disease gene may benefit from interventions to decrease worry, calibrate risk perceptions, and motivate variant-appropriate behaviors.

Large next-generation sequencing gene panels in genetic heart disease: challenges in clinical practice

“…Therefore, pre-test counselling—even in disease-specific gene panels—should not only include information on disease-related VUS, but also on incidental findings (i. e. not directly related with the disease tested for). In our experience, and literature supports this, genetic test results, especially VUS, are not only difficult to understand for a patient, but are also often misinterpreted by non-genetic physicians [ 20 – 22 ]. We therefore also recommend pre-test and post-test counselling to be performed by a physician/counsellor with sufficient knowledge on VUS and variant classification.…”

Informed Consent in the Genomics Era

“…Recent studies suggest patients undergoing genomic sequencing struggle with comprehension (Hellwig et al 2018;Roberts et al 2019). Information overload may contribute to patients' challenges with comprehension, and that problem can be exacerbated when the consent discussion includes secondary findings in addition to the primary purpose of testing (Turbitt et al 2018).…”

Changes in genetic variant results over time in pediatric cardiomyopathy and electrophysiology

“…The complexity of variant interpretation was confirmed by the need for the American College of Medical Genetics (ACMG) standards and guidelines for variant classification issued in 2015 (Richards et al., 2015). Since then, the ACMG guidelines have been subject to ongoing evaluations assessing the efficacy and utility of the guidelines in clinical practice, as well as the ongoing logistical, social, and ethical considerations of variant reporting (Amendola et al., 2016; Bombard et al., 2019; Hellwig et al., 2018; Lin et al., 2017; Patel et al., 2017; Wong et al., 2019).…”