Almost all of us know that October is breast cancer awareness month. Many of us also know that BRCA 1/2, the BReast CAncer genes, can increase a person’s chances of developing breast cancer. In fact, BRCA 1/2 is so well known that patients with a positive family history often seek genetic screening for it on their own accord. As a medical professional, I am awed by this level of awareness. Yet, at the same time, I am left feeling dissatisfied, and you’re probably wondering why.
Well, when was the last time a patient came to you asking for a TTR or BAG3 genetic test? Most likely, never, because the strong genetic link to heart disease is not as widely recognized — even among us physicians. But like breast cancer, genetic dysfunction also underlies many forms of heart disease and should be more widely considered in the clinic.
To address this lack in clinical practice, in 2018, the Heart Failure Society of America issued a practice guideline recommending that a comprehensive family history be taken for all patients with cardiomyopathy and that genetic testing be performed if there is the suggestion of affected relatives. In 2020, the American Heart Association (AHA) issued a statement encouraging genetic testing for patients diagnosed with or suspected of having any inherited cardiovascular disorders or at high risk based on the presence of family member with a known genetic variant. Both groups provide direction for physician implementation of testing and follow-up in their practice. Our implementation of these recommendations is crucial, considering the prevalence of genetically-driven cardiac diseases, and the need for expert care in diagnosis, counseling, and treatment of these patients.
For instance, about 1 in 100,000 people in the U.S. have the mutations that give rise to TTR cardiac amyloidosis per the latest estimate. Additionally, up to 50 percent of dilated cardiomyopathy (DCM) cases are estimated to have a familial link. And to date, researchers have identified over 50 genes that can induce DCM when mutated, including genes encoding nuclear membrane protein lamin A (LMNA), muscle cell structural protein titin (TTN) and muscle cell multifunctional regulator BCL2–associated athanogene (BAG3). This doesn’t even take into account the genetic variants that cause cardiac arrhythmias secondary to channelopathies.
Despite these high numbers, we cardiologists often look to genetic screening last in our diagnostic workup. But without genetic screening, we can’t always see the whole picture in our cardiomyopathy patients. Once we’ve excluded coronary disease as an etiology, available diagnostic tools such as echocardiography and magnetic resonance imaging provide great insight into the symptoms and consequences of these conditions but not the specific underlying causes. Epidemiology studies support this notion. For example, in 2011, one study found that more than half of previously unexplained cardiac deaths in young people resulted from genetically-linked arrhythmia, as determined through postmortem genetic testing. Thus, our ability to advise patients and their families, and in some cases, take preemptive measures such as defibrillator implantation, is limited.
So how do we get to the root of these genetically linked cardiac issues? Inquiring about family health history is an important and inexpensive start — acknowledging that a comprehensive history can be difficult for the time-pressed clinician. In addition to asking about a history of heart failure or cardiomyopathy, we should encourage patients to speak to their families about whether they have relatives who died suddenly or had a “heart attack” or “stroke” before age 50. Family lore alone regarding the history of premature death may not always represent a medical arterial thrombotic event. Even seemingly unrelated causes of death such as falling asleep at the wheel or unusual drowning may indicated an undiagnosed inherited heart disease, such as cardiomyopathy.
But, for more definitive answers, we should turn to genetic testing to best advise patients and their families. To ease the process, most genetic testing companies have created “cardiomyopathy panels” that clearly outline each step in the process for patients and providers to follow. And though the cost has historically been a concern, genetic tests at many of these companies are covered by insurance with an average out-of-pocket cost of <$100. The price for the uninsured can be slightly higher at ~$250 for self-pay.
But the most crucial thing we need to do is to start talking about it. We need to increase the dialogue amongst physicians and with our patients. We need to ensure that the world knows that certain genes lead to cardiac diseases. We need to amplify this awareness and continue researching ways to diagnose and treat these disorders more effectively.
Overall, we need to address the lack of awareness around the genes that cause cardiac diseases. Hopefully, one day, BAG3 and TTN will be spoken about and understood in the way that BRCA is. Until then, we must continue to identify patients who may benefit from cardiac genetic screening and the precision gene therapies in development to address them.
Marc Semigran is a cardiologist and chief medical officer of a biotechnology company developing cardiac gene therapy.
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