Synthesizing cardiovascular genetic test results into a unified diagnosis for the patient

Eye on Innovation

For over two decades, Mayo Clinic has been at the forefront of cardiovascular (CV) genetic testing. The current test menu features 24 different panels that span over 300 genes linked to inherited cardiovascular disorders, many of which are rare and challenging to diagnose. Such disorders can involve multiple genes (genotypic heterogeneity) or may present similarly to other disorders with distinct genetic causes (phenotypic overlap).

Whereas many labs operate in a “silo” — meaning they take a genetic specimen, test it, and then return a result with limited input — Mayo Clinic takes a much more expansive approach.

“We put a lot of care and time into looking at the phenotype information that we're sent,” says Joseph Maleszewski, M.D., a consultant in Mayo’s Division of Anatomic Pathology and a professor of laboratory medicine and pathology. “And if the client sends us documentation, or if we're fortunate enough to receive tissue to look at, we synthesize that information to create a unifying diagnosis for the patient and their treating team. We're able to do that because we have a unique multidisciplinary model that allows us to push the envelope on each case in terms of technology and interpretation.”

At Mayo Clinic, a team of technicians, genetic counselors, Ph.D. geneticists, and physicians works to ensure that the laboratory results fit with the clinical picture and that everything is pieced together.

Dr. Maleszewski continues, “When tests are sent to another institution, sometimes results can seem disparate or irrelevant — we work hard to ensure that doesn’t happen. That's more important now, because we have many folks accessing and using genetic testing who aren't necessarily experts in genetic testing, who may not know what its shortcomings are versus what it can do.” 

With this extra bit of “handholding” to help clients interpret test results, the team can provide a better product, which means better care for the patient.

Linnea Baudhuin, Ph.D., is a consultant in Mayo Clinic’s Laboratory of Genetics and Genomics and also a professor of laboratory medicine and pathology. “Unlike most other laboratories that do this type of testing, we're integrated with this large academic medical center that's world-renowned,” she says. “So we have so many different opportunities to reach out to clinical experts. And our base of genetic counselors is phenomenal on so many levels.”

Genetic counselors at Mayo help with the ordering of tests, and post-test discussions with ordering providers. They help with the analysis of the genetic data, interpretation of the results, and how they relate to the clinical picture of the patient.

Dr. Baudhuin continues, “The depth of knowledge our genetic counselors have is truly remarkable because, given the volumes that we trade in here, they're able to subspecialize in a unique way. Just knowing how brilliant they are helps us to have this climate of mutual trust where we're confident in each other's abilities to provide excellent patient care.”

Innovative gene panels for sudden cardiac death

In addition to the 24 gene panels, Mayo has the ability to analyze postmortem tissue samples from individuals who have experienced sudden cardiac death, a tragic phenomenon that can have hereditary origins. The Mayo team has created four panels that analyze genes that may have contributed to the decedent's sudden death (Mayo test IDs: PMARG; PMCAG; PMCMG; and PMAOG).

“The postmortem panels are an important part of our innovation,” says Dr. Baudhuin. “As far as I know, we're the only lab in the country, possibly the world, that performs genetic testing for postmortem purposes on a specific sample type. And these are often the only sample types available from deceased individuals. The samples are prepared for analysis as formalin-fixed paraffin-embedded tissue (FFPE).”

Sudden cardiac death accounts for about 60% of all sudden deaths. “It's really important for us to be able to test individuals who have passed away unexpectedly to determine if there was a genetic cause,” Dr. Baudhuin says. “Because it can provide an answer to the families and then it can lead to relevant clinical care for at-risk family members.”

Dr. Maleszewski was instrumental in developing this testing. “Imagine a young basketball player out there who passes away while playing,” he offers. “Generally, a genetic etiology for that type of sudden event is sought. And oftentimes there's lots of different genes involved, and when we perform genetic testing on that athlete’s sample it’s not uncommon to identify variants that we're just unsure about. So by looking at the decedent’s tissues and other family members to evaluate for similar clinical signs and symptoms, we can render more definitive interpretations and provide better guidance.”

Without any answers on why an athlete passed suddenly, family members may be relegated to lifelong screening (e.g., annual echocardiograms or EKGs) that looks for clinical signs of a disease. While this may not seem like a big deal, there can be a daunting element of stress the family members must carry around.

Hence, Dr. Maleszewski is passionate in his work to help find answers for the families of these fallen athletes. In fact, he has worked extensively with the National Collegiate Athletic Association (NCAA) and physicians from around the world interested in sudden athletic death to better investigate sudden death among athletes. He was also part of a just-completed 20-year study of these cases. The results, published in the scientific journal Circulation, were recently picked up by Forbes and NBC News

“There's always this sort of Damoclean scenario, or this specter, that's following that family member around saying, ‘Maybe one day it's going to be you,”’ he says. “So by looking at that sample from an individual who had a catastrophic sudden death event and fully characterizing it, understanding it, this allows us to be able to screen those family members in a way that gives them a more conclusive answer to: Are you at risk for a similar fate? Are your other kids at risk? Are the cousins at risk?  

“And that's huge. That can be an enormous burden that's lifted. So if we can better screen for these risk factors that are associated with these diseases, that may portend a tragic or a bad result. Being armed with that extra knowledge is power. It’s power for the family and power for the subsequent generations.”

Gene panel quality varies from lab to lab

The importance of well-thought-out gene panels cannot be overstressed at Mayo Clinic because, through their studies, the genetics team has seen lots of heterogeneity among outside labs — as in how they include genes in their panels and how they interpret their results.

Mayo Clinic Laboratories offers 24 different panels that span over 300 genes linked to inherited cardiovascular disorders.

“A lot of this has to do with not understanding the genes very well,” says Dr. Baudhuin. “So what we've tried to do is to have gene panels that have been designed to be clinically useful and clinically valid. Our panels don't include many genes that aren’t well associated with the conditions, whereas some other laboratories might include those genes. We’ve recognized the importance of having a lot of knowledge about the genes and clinical conditions we’re testing in order to provide the best results we can for the patient.” 

Genes that are not known to be highly associated with specific conditions are called “genes of uncertain significance (GUS).” With a GUS, it’s unclear whether or not the gene is a contributor to the patient’s health condition.

“The concern with including genes, or variants, of uncertain significance is that they can lead to messy reports with confusing results,” continues Dr. Baudhuin. “So if you find a variant in a gene of uncertain significance and you report it out, this is problematic because often the physicians and the patients don't know what to do with that information. You're giving them this result that is very confusing and not helpful.”

In the realm of known genes, Mayo does genetic testing for inherited cardiovascular conditions within four major categories: cardiomyopathies, arrhythmias, aortopathies, and dyslipidemias. Most of the inherited disorders within these categories are rarer in incidence, e.g., Marfan syndrome, obstructive hypertrophic cardiomyopathy, long QT syndrome, and Brugada syndrome.

Over time, cardiovascular genetic testing at Mayo has continued to expand in breadth and depth, especially after the advent of next-generation sequencing (NGS) technology, which allows for more efficient and comprehensive genetic analyses.

Dr. Maleszewski sums it up this way: “I think we've come to recognize, over the last 20 years, that genetic testing is not only critical to the management of the patient and their family, it's also not a panacea. It's not something that provides all the answers,” he says. “And I think, as people have become more aware of the prevalence of genetic disease and how prevalent it is in the population, more folks are ordering it. But there's a need to ensure that the findings we are getting, when we look at the genes, are comporting with the overall clinical picture. Here at Mayo, I like to think we do that way better than most.”

More from Eye on Innovation


Chris Bahnsen

Chris J. Bahnsen covers emerging research and discovery for Mayo Clinic Laboratories. His writing has also appeared in The New York Times, Los Angeles Times, and Smithsonian Air & Space. He divides his time between Southern California and Northwest Ohio.