Genetic sequencing is far more accessible than it was 10 to 15 years ago. This capability makes it possible to screen for genetic types of cardiovascular disease (CVD) before patients develop symptoms.
But many questions must be answered before we know that a genotype-first approach is truly viable and valuable.
C. Anwar A. Chahal, MD
The Genotype-First Approach Investigators group, which I contribute to, is now pursuing these questions. Our recent paper uses CVD as a catalyst for this conversation — and makes it clear that the future for genetic screening isn’t certain. Instead, it is loaded with both promise and peril: It may be right for certain conditions and save lives, including preventing sudden death and heart failure. But to do that, we must get it right and avoid imposing unnecessary financial and psychosocial hardship on patients.
It’s important for cardiologists to understand the potential benefits and risks of a genotype-first approach so they can make informed choices for their patients, and, perhaps, contribute to research and guidelines shaping this strategy.
Some Types of CVD May Be Ripe for Wider Screening
The American College of Medical Genetics and Genomics recognizes 94 genes that cause treatable disease, half of which are associated with types of CVD. Many of these types are caused by mutations in a single gene, such as the LMNA gene, which causes dilated and arrhythmogenic cardiomyopathy and heart block requiring pacing.
Widespread screening for monogenic types of CVD may be worthwhile because of the effect size of the genes behind them. One tiny mutation can have massive clinical consequences — for example, causing a child to collapse on the playing field with no warning. If we knew everyone’s risk for these outcomes when they were born, we could help people enjoy longer and healthier lives.
3 Questions Guide Future Research
To find out if widespread genetic screening has clear clinical benefit, we must answer three questions.
Is a Given Gene Associated With Disease?
In some cases, like LMNA, we already know the answer to this question. But in many cases, we don’t.
Multiple projects are underway to catalog the disease associations of genes and variants as they are discovered. I am a member of the Hereditary Cardiovascular Disease Gene Curation Expert Panel with ClinGen, which follows a systematic approach and shares its findings for anyone to query. The panel is chaired by my colleague Dr. Jodie Ingles and includes a wide group of experts, including clinical cardiologists, scientists, geneticists and genetic counselors. I invite all providers to use the panel’s work to stay abreast of the latest research in CVD-associated genes. You can also contribute to our efforts by curating or contributing data.
Which Variants of the Gene Are Consequential?
Answering this question is the “holy grail” for us right now. A single gene can have hundreds of variants. For genetic screening to yield answers we can act on, we have to know which variants lead to disease and which are benign.
Fortunately, technology advancements enable new ways of finding out. For example, an ion channel associated with electrical rhythm problems in the heart may have dozens of variants. Instead of creating dozens of mouse models, researchers can create thousands of cells and place electrodes directly into them to measure the change in electrical current. If they see a change, the variant is more likely to be disease causing.
Does the Variant Express Disease?
A person may carry a disease-causing genetic variant and never express disease. And here lies the peril in taking a genotype-first approach: Someone known to have a CVD-associated gene could be denied or overcharged for life insurance, excluded from a high-risk career like the military or piloting, or prohibited from playing sports — even if their actual risk of developing disease is low or unknown.
Addressing this peril will take immense research, combining both genetic and clinical data: Who developed which symptoms? How severe were they? What genetic, health and demographic factors correlate?
When we know these answers, then we can achieve our ultimate goal of finding patients who are truly at risk and avoid foisting personal consequences onto those who are not.
What Genetic Testing Means for Cardiologists Today
While we explore these broader questions, physicians and patients are already reckoning with genetic information. Direct-to-consumer genetic tests and biobank projects like NIH All of Us are increasingly popular. They’re extremely valuable as well — through the Gene Health Project at WellSpan Health, we have screened more than 30,000 patients for CDC Tier 1 diseases, leading to more than 400 potentially life-saving diagnoses.
What do you do when your patient gets a positive result from one of these tests? For CVD, at least, there is a plan. I joined a team of multidisciplinary experts from around the world in drafting a statement from the American Heart Association that includes a pathway for patients found to carry a CVD-causing gene.
As the medical community learns more about the promise and peril of a genotype-first approach, it’s important to keep an open mind. Look at this approach the way we look at any medical advancement: Does it help our patients? How do we know?
Only through honest, collaborative study will we learn what role our genes should play in screening and prevention.
To learn more about the genotype-first approach to CVD or refer a patient, contact Dr. Chahal at 717-356-4660 or icvd@wellspan.org.