Amy Daly

Cardiovascular genetic testing: complexity refined

Amy Daly, MS, LCGC, Invitae Genetic Counselor

Cardiovascular genetics has a history of changing how we think about genetic tests and results. We once counted on autosomal dominant disorders behaving a certain way, and many of us thought the rules of Mendelian genetics would easily translate into the growing world of cardiovascular genetics. But over the years we learned that things are far more complicated.

In our search for answers, we moved to testing more and more genes for variants with cardiovascular implications. As a result, test results have become frequently complex. In some cases, large panels reveal more than one pathogenic variant in the same person, or the same pathogenic variant causes incredibly different clinical presentations in family members. Often, panels uncover a host of variants of uncertain significance. In testing more people and their family members, we are also learning the penetrance of many cardiovascular disorders is unknown or not as high as we may have thought.

As we grapple with what these complex results mean for individual patients, some in the community are beginning to question whether large cardiovascular panels are always the right choice.

I have been lucky to have the opportunity to see how cardiovascular genetic testing has developed from both the clinic and the lab. If I were back in the clinic today, one of the most important questions I would ask is why we are packing so many genes into panels. On average, the clinical sensitivity of all the panels from various labs may be fairly comparable, assuming the labs use similar test methods. A panel of 150 genes is likely to have a similar clinical sensitivity to a panel of 75 genes because only a subset of these genes account for the vast majority of what we understand about cardiovascular disorders.

A benefit of testing so many genes is that we’re more likely to catch variants in genes associated with various phenocopies, from those disorders that are truly hard to distinguish to genes associated with rare, severe, syndromic conditions with a cardiovascular component. This may be ideal for clinicians with extensive experience in cardiac genetics who can easily scan through a list of variants of uncertain significance and intuitively know which ones are likely clinically irrelevant. It’s a little more daunting for clinicians evaluating such reports from a general genetics perspective or within a cardiology practice that does relatively little genetic testing. Aside from the pitfalls of taking a wrong turn acting on variants of uncertain significance, it can be challenging for any of us to figure out what to do next with this information.

As Invitae expands our genetic testing offering for cardiovascular indications, I know in some ways we are not different from all the other labs that preceded us. We’ve built large, comprehensive panels with lists of genes ranging from likely to unlikely to provide an answer. What sets us apart is how much control we hand to the clinician. You can pick from pre-packaged gene lists, you can add additional gene panels for overlapping disorders, you can add genes that have limited evidence for an association with that particular indication. Or you can create your own panel from scratch, perhaps selecting your highest suspicion genes and then, if you don’t find the answers you need with those, re-requisitioning to a comprehensive panel later on. I suspect the majority of clinicians will default to large panels, because it’s hard not to when they’re available. But for those who want to pump the breaks on these super panels, I’m glad you will have the option to do so. I look forward to seeing what the cardiology community decides is most important.

I am optimistic that more genetic testing options will help many more patients. We put quite a lot of thought into how we arranged our new pre-curated panels, with the goal of helping clinicians find the combination of genes that has the best chance of uncovering an answer. And if our panels do not match up for everyone, I hope the customizability will allow us to learn from our clients and adapt our panels to your interests and requests.