The American Heart Association offers new guidance on interpreting and acting on genetic results for inherited cardiovascular diseases—adding a caveat that variants of uncertain significance (VUS) continue to pose challenges for physicians and genetic testing labs. Any discovery of a pathogenic or likely pathogenic variant should lead to familial cascade testing.
“Although genetic testing has seen explosive growth in the past few years, both in the clinical setting and with direct-to-consumer testing, genetic testing for heart disease should be reserved for specific patients,” said Kiran Musunuru, MD, PhD, MPH, chair of the writing group for the scientific statement, in a news release. This includes patients with a confirmed or suspected diagnosis of a heritable cardiovascular disease or those at high risk due to a prior disease-causing variant in their family.
Cardiomyopathies, thoracic aortic aneurysms and dissections, arrhythmic disorders, and familial hypercholesterolemia or highly elevated low-density lipoprotein cholesterol levels are cardiovascular conditions that might have an inherited component.
The statement includes two important algorithms. One describes a method for evaluating patients with confirmed or suspected diagnosis of inherited cardiovascular disease. The other addresses evaluating patients with secondary or incidental genetic findings.
“If the testing reveals ≥1 variants in a gene or genes definitively linked to disease, the variants need to be interpreted with respect to their likelihood to cause disease,” the authors noted. Interpretations can vary among respective labs and providers, and also change over time.
Providers are generally advised to treat pathogenic and likely pathogenic variants as positive results, and benign and likely benign variants as negative results. A pathogenic or likely pathogenic finding should lead to cascade genetic testing of family members. That said, VUS have no clear definition on the spectrum of benign versus pathogenic. “In some cases, they might indicate a better or worse prognosis but are not considered directly actionable for predictive testing in at-risk family members,” noted the writers of the statement.
VUS classification and reclassification is subject to many variables—new data might change a VUS designation from pathogenic to likely pathogenic or change the result of a genetic test. New research might also unveil novel genes associated with a patient’s disease, which would lead to a retest. VUS vary by populations: More genes have been classified in European ancestry populations, for example, so patients with this background are less likely to have VUS. As a result, physicians have found it challenging to counsel patients on treatment, given that the role of VUS in disease risk is so unclear.
“Another issue is that we have not yet clarified the full spectrum of genes that are responsible for various inherited cardiovascular diseases—we are still very much in discovery mode, with ongoing research efforts,” said Musunuru, a professor of cardiovascular medicine and genetics at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. “Genetic testing methods are evolving, and reliable classification of variants identified in genetic testing will remain a preeminent challenge for the practice of clinical genetics.”
To help streamline genetic testing results, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology have published a framework that classifies variants into benign, likely benign, uncertain significance, likely pathogenic, and pathogenic categories. The Clinical Genome Resource Consortium has also been trying to modify the framework for specific genes “in part on the basis of data submitted on individual gene variants and their relationships to disease by genetic testing laboratories, clinicians, and researchers to the ClinVar database,” according to the statement authors.