To Test or Not To Test: Clinical Issues in Genetic Sequencing

The sequencing of the human genome, completed in 2003, opened the doors to providing genetic information for research, and, most recently, made it available directly to the public. Availability of highly precise and efficient sequencers (such as the ones from Illumina) resulted in minituarization of the genetic information, making it available and affordable to look for single-nucleotide polymorphisms, or SNPs, and their association with various diseases. However, as illustrated by the story of the 23and Me, the path to making such information available on-demand is complicated by regulatory and ethical dilemmas. The role of genetic information in clinical decision making is uncertain.

Recently, the New England Journal of Medicine reported on the results of an opinion poll in a case of a hypothetical patient seeking genetic sequencing because of a strong family history of malignancy. The majority of the responders favored genetic testing (60%), with mixed responses as to the extent of such testing to be performed. The authors called for genetic consultations to be carried out by trained geneticists. However, in real-life clinical practice, the statistical and population information provided by such genetic consultations is simply not enough.

As a cardiologist focused on bringing the practice of functional medicine into traditional cardiology domain, I rely on several genetic tests for a variety of reasons. The decisions to test are highly individualized, and have to be made based on patient’s history, objective findings and preferences. In one case, a patient with a distant history of atrial fibrillation sought advice. After normal physical exam and normal echocardiogram, we opted to run a genetic test that may help to determine his risk of atrial fibrillation and stroke. His one and only episode of atrial fibrillation occurred previously while he was treated for hypothyroidism, and has not recurred. Thus, genetic results would be of value in determining if indeed an elevated risk of atrial fibrillation existed independently of hypothyroidism, a reversible condition that could cause atrial fibrillation when untreated.  Detection of a carrier state associated with an elevated risk of atrial fibrillation and stroke would  result in more aggressive surveillance, and, possibly, earlier  treatment.

The decisions get more complicated when genetic testing that identifies a predisposition or likelihood of a disease must be carried out in a context of early disease diagnostic testing. The genetic predisposition as well as early disease may be modified by environmental and lifestyle influences. A patient this week reported that her father died of a massive myocardial infarct in his 40s. How should we proceed? In addition to history, physical exam, electrocardiogram, echocardiogram and possibly a stress test, we can consider imaging for subclinical atherosclerosis, such as obtaining a coronary calcium score. Addition of genetic testing to gauge probability of early myocardial infarction and vascular disease independently of traditional risk factors may be of value if the calcium score is greater than zero. In such circumstances, once sub-clinical disease is identified, a patient who carries a genetic variant forecasting an increased risk of heart disease and its complications may benefit from more aggressive attempt at disease stabilization and risk factor reduction, with supplements, medications, and lifestyle changes. In contrast, for patients with a score of zero (identifying a situation with no discernible vascular disease), detection of a carrier state associated with an increased risk may prompt more aggressive screening, and even result in over-testing.

The applicability of genetic testing is limited by patient acceptance and insurance reimbursement. Many patients view genetic testing as delivering an irreversible verdict, a final “say” about disease and illness. Yet, in most instances, genetic testing presents an opportunity for a change, focused and early intervention, and a possibility for a lifelong commitment to prevention.