You Suspect a Cardiogenetic Condition in Your Patient; What Next?
In the first article of this series we explored why genetic testing for certain cardiogenetic conditions is so important – one of several reasons is that it can save lives! In the second article, we discussed the wide range of cardiac conditions that can be inherited, and the signs and symptoms as well as family history that healthcare providers should be on the lookout for. Now that we know what to look for and why this is so important, our last article in this series explores the steps to take after identifying a patient suspected of having a cardiogenetic condition.
Once a provider has identified a patient based on their personal or family medical history (click to see the list of symptoms to be aware of), a referral for genetic counseling is appropriate. Several professional societies recommend that individuals with potential cardiogenetic conditions be evaluated by a center specializing in inherited cardiovascular disease. 1,2 Genetic counselors, geneticists, and cardiologists focused on inherited disease are key players in the genetic testing process, as genetic counseling should take place both before and after testing. Genetic testing may be appropriate for and/or affect many members of a family, therefore clinicians should consider not only the patient at hand, but their entire family as well.
Cardiogenetic conditions are complex, and the landscape of available genetic tests changes frequently. There are many panel-based tests available, meaning that a group of genes related to a certain condition, such as arrhythmia or cardiomyopathy, is examined as a set for genetic changes that could be causative of the condition. The genes can be examined in the lab by gene sequencing, analysis of genetic duplications or deletions, and/or by the examination of single nucleotide polymorphisms (SNPs). The selection of the appropriate genetic test for a patient and the interpretation of the genetic test results are both highly specialized skills due to the complex nature of the conditions themselves and the variety of tests available. 3
As an overview, genetic test results generally fall into one of three categories:
- Positive: a known pathogenic variant is identified
- Negative: no pathogenic variants are found
- Variant(s) of uncertain significance (VUS): a genetic change is identified, but whether it causes disease is currently unknown.
Cardiac gene variants are plentiful, and it is possible for patients to have multiple variants identified by a genetic test. It is important to note that genetic testing should first be performed on an individual who has disease. If a pathogenic variant is identified, in certain cases (but not all) the patient should be followed closely and managed as if they are affected by the condition, even if they currently display no symptoms. An example of a pathogenic variant known to cause Long QT syndrome is a deletion in the gene KCNQ1, called 3-BP DEL, PHE339DEL. 4 Patients with this pathogenic variant are at risk for cardiac events and sudden death. Management for this syndrome typically includes beta-blocker medications and possibly implantable cardioverter-defibrillators (ICDs). The avoidance of drugs that can cause further prolongation of the QT interval, competitive sports and activities associated with intense physical activity, and/or emotional stress is very important for these patients. 5 Close surveillance by an expert cardiovascular team, and genetic counseling and testing for family members of the patient is recommended.
If no pathogenic variants are identified by a test, it does not necessarily mean that the patient and family do not have a genetic cause for their disease. It could mean that the family’s particular pathogenic variant was not tested for, or science has yet to discover their causative variant. Careful clinical evaluation of family members remains the primary basis for a diagnosis of inherited heart disease, even when genetic test results are negative.
Normal variation exists in the human genome, and this often leads to the most challenging genetic test result to be returned by a multi-gene panel: a variant of uncertain significance (VUS). In these cases, the patient does have a genetic variant within a disease-related gene, but science has not definitively established that the variant is causative of disease. This type of variant may be studied by researchers if the family is available to participate with the goal of classifying such a variant as pathogenic or benign. An example of such a VUS occurred in a family with inherited hypertrophic cardiomyopathy (HCM). Genetic testing in the patient (proband) revealed a VUS in the MYH7 gene. The treating clinicians performed a robust segregation analysis, as there were multiple affected family members and obligate carriers available to study. Based on this segregation data, the laboratory eventually reclassified this particular variant as pathogenic. This case highlights the importance of two-way communication between clinicians and genetic testing laboratories, which can move the science forward. 6 It also highlights the importance of patients and their family members participating in research, and routinely checking in with their healthcare providers over time to determine if the identified VUS has been reclassified.
Genetic testing for potentially inherited cardiac conditions can be life-saving for at-risk family members. There is a wide range of cardiac conditions that can be genetic, and it is incumbent upon clinicians to be vigilant for the signs and symptoms of these potentially inherited diseases. Once identified, patients at risk for inherited cardiac disease are best handled by expert cardiovascular centers that can provide genetic counseling for the whole family, both before and after testing. There are also independent organizations that can provide remote (telegenetic) counseling in the field of cardiogenetics, such as Metis Genetics. This resource can enable family members who are located geographically far away from each other to receive the same vital information regarding their personal genetic makeup and be managed appropriately. Test results are often not straightforward. Genetic counselors and others working in an interdisciplinary team should be involved in their interpretation and patient management. The field of cardiogenetics continues to evolve, along with many other areas in genetics, and it holds great promise for saving and improving the quality of patients’ lives affected by heart conditions.
Please visit the following resources for more information:
Genetic testing registry: www.ncbi.nlm.nih.gov/gtr
National Society of Genetic Counselors: www.nsgc.org
Find a Genetic Counselor: www.findageneticcounselor.com
Genetic Alliance: www.geneticalliance.org
Genetics Home Reference: http://ghr.nlm.nih.gov
Genetic Evaluation of Cardiomyopathy - A Heart Failure Society of America Practice Guideline. Hershberger RE et al. J Card Fail. 2018 May;24(5):281-302.
Ackerman MJ, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm. 2011;8(8):1308-39.
Kristina Habermann, MS, CGC, MBA
Kristina is a board-certified genetic counselor and a long-time enthusiast of the use of genetics to improve patients’ health and lives. She has practiced as a genetic counselor and worked in Sales and Marketing educating clinicians and patients about the risks and benefits of genetic testing; ranging from prenatal to cancer to pharmacogenetic testing in psychiatry. She particularly enjoys writing about genetics and genetic counseling and is currently the Assistant Program Director of the Genetic Counseling Graduate Program at LIU Post.