Inherited cardiovascular disorders were historically identified through a patient’s family history and clinical presentation. With the introduction of genetic testing for several of these disorders, the individual gene or mutation test became a critical component for the identification of the inherited disorder. Now, next-generation sequencing technology has taken genetic testing to a new level, allowing for assessment of multiple genes with one test.
Presenter and Credentials:
Linnea Baudhuin, Ph.D., Associate Professor of Laboratory Medicine and Pathology at Mayo Clinic, Consultant in the Personalized Genomics Laboratory, Clinical Genome Sequencing Laboratory, and Cardiovascular Laboratory. Dr. Baudhuin also holds a joint appointment in the Department of Medical Genetics.
Welcome to Mayo Medical Laboratories Hot Topics. These presentations provide short discussion of current topics and may be helpful to you in your practice.Title
Our speaker for this program is Dr. Linnea Baudhuin, an Associate Professor of Laboratory Medicine and Pathology at Mayo Clinic, as well as a consultant in the Personalized Genomics Laboratory, Clinical Genome Sequencing Laboratory, and Cardiovascular Laboratory. Dr. Baudhuin also holds a joint appointment in the Department of Medical Genetics. Dr. Baudhuin provides an overview of the new multigene next-generation sequencing tests available for the evaluation of inherited cardiovascular disorders.
Thank you for that introduction. I have nothing to disclose.
As you view this presentation, please consider the following important points regarding multi-gene panel testing:
- How is the testing going to be used in your practice?
- When should the tests be used?
- How will results impact patient management?
- How will the results of these tests impact the patient’s family members?
Cardiac Diseases with a Genetic Contribution
There are many different cardiac conditions that have an underlying genetic contribution. Some are straight forward Mendelian disorders whereas others, such as coronary artery disease, have a more complex genetic involvement.
How are Inherited Cardiac Conditions Discovered and Diagnosed in a Patient?
Inherited cardiac conditions can be discovered and diagnosed in a patient based on multiple different factors. These include symptoms, such as shortness of breath, chest pain, and exercise intolerance. Systemic findings may additionally raise the suspicion of a genetic disorder. Incidental findings can also lead to a genetic diagnosis, and patients with a family history of, for example, early cardiac death or high cholesterol, may undergo further evaluation for a possible genetic disorder. In all cases of a suspected genetic disorder, genetic testing is an important tool to help clarify and specify the precise diagnosis.
Benefits of Genetic Testing
Genetic testing is important to confirm the suspected diagnosis, and may be especially useful in cases of borderline clinical findings. Genetic testing can also be beneficial for risk assessment and counseling of the patient and family. Identification of a pathogenic variant can help to identify family members at increased risk for the disorder, as well as those family members who are not at an increased risk. Genetic test results can also help guide clinical management decisions, and I will discuss this in more detail later in my presentation.
Why Phenotype is Insufficient to Make the Diagnosis in Many Cases
Some may wonder why a diagnosis for a genetic disorder cannot be made simply based on patient presentation, or phenotype. Many hereditary cardiovascular disorders have an overlapping clinical presentation and many different genes can be the cause of the same, or similar, clinical presentation. Thus, the phenotype is oftentimes not sufficient to determine exactly which disorder the patient has. Furthermore, many phenotypes can be borderline and it is simply unclear whether the patient has any genetic disorder. This is why more comprehensive genetic testing, in the form of multi-gene panels, is so important.
Next-Generation Sequencing: An Efficient Method for Multi-Gene Panel Testing
In the past, Sanger sequencing has been utilized to comprehensively test small- to medium- sized genes in an efficient manner. However, as we are discovering the involvement of more genes involved in one disorder or overlapping disorders, Sanger has become too cumbersome, inefficient, and costly to analyze multiple genes in a single test. Recently, next-generation sequencing, or NGS, has been brought into the clinic. NGS uses technologies analogous to massively parallel computing and it has the ability to efficiently sequence large genes and multi-gene panels, including the whole exome and even the entire 3 billion base pairs of the human genome. Overall, NGS has been proven to be more efficient and cost effective compared to Sanger sequencing for most multi-gene panels.
Mayo Medical Laboratories: Next-Generation Sequencing Panels for Inherited Cardiovascular Disorders
At Mayo Medical Laboratories, we have recently implemented 8 new multi-gene NGS panels for inherited cardiovascular conditions as shown here. These include tests for various hereditary cardiomyopathies, Noonan syndrome and related disorders, Marfan syndrome and related disorders, and long QT and Brugada syndromes. In the next slides, I will go over these new tests in more detail.
This picture gives a snapshot of our tests for hereditary cardiomyopathies and Noonan Syndrome and related disorders. Here you can see that many genes overlap with these different cardiovascular genetic conditions, again highlighting the importance of NGS technology in being able to give us the ability to comprehensively test for these conditions.
Hypertrophic Cardiomyopathy (HCM)
Hypertrophic cardiomyopathy (HCM) is a relatively common condition, affecting approximately 1 in 500 individuals. It is characterized by unexplained left ventricular hypertrophy and can be diagnosed by echocardiogram or MRI. Patients with HCM may present with shortness of breath, chest pain, palipitations, presyncope, or syncope. HCM is associated with risk for sudden cardiac death, and is one of the leading causes of sudden cardiac death in young athletes. HCM is usually inherited in an autosomal dominant manner with reduced penetrance and variable expressivity. Treatment includes pharmacologic therapy, invasive septal reduction, pacemaker, and ICDs.
Hypertrophic Cardiomyopathy Genetic Panel
Here is a closer look at our HCMGP panel test, which examines 26 genes. The 2 genes most commonly involved in HCM -- MYBPC3 and MYH7 -- are underlined here. In patients with a family history of HCM, approximately 60% of them will have a mutation in one of these genes. In patients without a family history, the rate falls to about 20 to 30%.
HCM: Benefits of Genetic Testing
The benefits of genetic testing for HCM are multi-fold. First, it can be used to identify presymptomatic family members as well as predict prognosis and guide patient treatment. For example, some mutations have a high risk of sudden cardiac death. In terms of utilizing genetic testing to guide patient treatment, patients with GLA mutations can be given enzyme replacement therapy. Clinical trials may also be available to patients with HCM-associated genetic mutations. Also, genetic testing can help to identify a genetic etiology in athletes with mild hypertrophy. Finally, heart transplant decisions and/or reproductive discussions and choices may benefit from a positive genetic test.
Another type of hereditary cardiomyopathy is dilated cardiomyopathy, which affects approximately 1 in 250 to 1 in 2,000 individuals. It is characterized by dilation and impaired contraction of the left ventricle and can be diagnosed by echocardiogram or MRI. Patients with DCM may present with edema, shortness of breath, fatigue, and arrhythmias. DCM is associated with risk for sudden cardiac death. DCM is usually inherited in an autosomal dominant manner, but can be autosomal recessive or X-linked. Like HCM, DCM demonstrates reduced penetrance and variable expressivity, and treatment includes pharmacologic therapy, pacemaker, ICD, and transplant.
Dilated Cardiomyopathy Genetic Panel
Our DCMGP panel test examines 30 genes. The gene most commonly involved in DCM is TTN which encodes for the large protein, titin. The clinical sensitivity of this test is approximately 30 to 35%.
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
ARVC or arrhythmogenic right ventricular cardiomyopathy affects approximately 1 in 5,000 individuals in the U.S., and about 1 in 2,000 in Italy. It is characterized by progressive fibrofatty replacement of the myocardium and can be diagnosed by echo or MRI and conduction abnormalities. Patients with ARVC may present with palpitations and syncope. ARVC is associated with risk for sudden cardiac death, and like HCM is associated with sudden death in young athletes. ARVC is usually inherited in an autosomal dominant manner with reduced penetrance and variable expressivity. Treatment includes pharmacologic therapy, ICD, and transplant.
ARVC Genetic Panel
Our ARVGP genetic panel examines 9 genes. The gene most commonly involved in ARVC is PKP2. The clinical sensitivity of this test is approximately 50%.
Comprehensive Cardiomyopathy Multi-Gene Panel
We also have a comprehensive cardiomyopathy panel available, which examines 55 genes. This test is most useful for families exhibiting multiple forms of cardiomyopathy clinically, in cases where the specific cardiomyopathy is simply not clear, or it may be secondary to a more focused panel. Because more genes are included on this panel, a caveat to this test is that there is a higher probability of having more ambiguous results or variants of uncertain significance as compared to a more focused panel.
Noonan Syndrome and Related Disorders
Another NGS test that we offer is for Noonan syndrome and related disorders. Noonan syndrome affects approximately 1 in 1,000 to 1 in 2,500 people, although this number may be an underestimate due to the sometimes subtle expression of this disorder. Classic features of Noonan syndrome are listed here and include facial anomalies, short stature, and congenital heart defects, which can include pulmonary valve stenosis, HCM, and atrial and ventricular septal defects. Noonan syndrome has significant clinical and genetic overlap with LEOPARD, cardiofaciocutaneous, and Costello syndromes. Together, this group of disorders is known as the “Ras-opathies” because they involve genes that code for proteins in the Ras signaling pathway. These disorders are autosomal dominant with variable expressivity. Treatment includes surveillance and surgical repair of cardiac defects.
Noonan Syndrome and Related Disorders Associated Testing
Our test for Noonan syndrome and related disorders analyzes 11 genes, which are involved in Noonan, LEOPARD, cardiofaciocutaneous, and Costello syndromes. The clinical sensitivity of this test is around 65 to75%.
The next set of disorders that I will talk about is long QT and Brugada syndromes. This figure gives a snapshot of our tests for long QT and Brugada syndromes which have some overlap in gene involvement.
Long QT Syndrome
Long QT refers to a condition which can be diagnostic utilizing a cardiac test called an ECG or EKG (short for electrocardiogram). The QT interval on the EKG can be measured and, if prolonged, can be diagnostic for long QT which can predispose an individual to potentially fatal arrhythmias. There are both inherited and acquired forms of long QT syndrome. Some medications can cause a prolonged QT interval in individuals either with or without inherited forms of long QT and therefore assessing what medications an individual was on when they experienced a cardiac event is important and avoiding certain medications if you have an inherited long QT is also necessary.
Long QT Syndrome Genetic Panel
Our test for long QT syndrome analyzes 13 genes, with KCNH2, KCNQ1, and SCN5A being most commonly involved. The clinical sensitivity of this test is around 75 to 80%.
Similar to long QT, Brugada syndrome can be diagnosed by EKG, as well as clinical and family history. Brugada is less common than long QT but expresses more frequently in males in the third to fourth decade of life.
Brugada Syndrome Genetic Testing Panel
Our test for Brugada syndrome analyzes 9 genes, with SCN5A being most commonly involved. The clinical sensitivity of this test is around 25 to 40%.
Marfan Syndrome and Related Disorders
The final test that I will cover in this presentation is our multi-gene panel for Marfan syndrome and related disorders. Marfan syndrome affects approximately 1 in 5,000 to 1 in 10,000 people. It can be characterized by cardiac, eye, skin, and skeletal findings and can be diagnosed clinically using the Ghent criteria. Marfan syndrome has significant overlap with Loeys-Dietz syndrome, Ehlers Danlos vascular type, and familial thoracic aortic aneurysm and dissection (or FTAAD), which are due to different and sometimes overlapping genetic causes. It is often times difficult to distinguish which genetic disorder a patient has based on clinical presentation alone. These patients all have increased risk for sudden cardiac death due to aortic aneurysm and dissection. Other types of aneurysms and dissections may also occur in other areas of the body depending on the gene involved, and thus implicate the importance of utilizing genetic testing to determine which gene is involved and then following the recommendations for gene-specific imaging. These disorders are mainly autosomal dominant and penetrance and expressivity are gene dependent.
Gene-Specific Management in Marfan and Related Disorders
Marfan syndrome and related disorders are a great example of how we can use genetic test results to help with patient management. As you can see in this table, dependent on the gene involved, there are various recommendations for frequency of echocardiogram, thresholds for aortic surgery, and extent of vascular imaging. For example, patients with an FBN1 mutation will have an echocardiogram annually whereas patients with Loeys Dietz syndrome will have more frequent echocardiograms. There are gene-specific management guidelines for determining when a patient should have prophylactic aortic surgery based on aortic diameter threshold. For example, surgery is recommended for Marfan patients at an aortic diameter of 5 cm, whereas progression of aortic dilatation and dissection is more aggressive in Loeys Dietz syndrome and the recommended aortic diameter threshold for surgery is 4 cm. Another example of gene-specific management for this group of disorders has to do with the extent of imaging. Due to the risk for aortic manifestations that are not limited to the thoracic aorta, patients with non-FBN1 related conditions are recommended to have more extensive imaging, from head to pelvis. Additionally, patients may be at risk for other manifestations dependent of the gene involved. For example, patients with ACTA2 involvement have a higher risk for coronary artery disease and stroke.
Marfan Syndrome and Related Disorders Genetic Testing
Our test for Marfan syndrome and related disorders analyzes 13 genes, with FBN1, TGFBR1, and TGFBR2 being most commonly involved. The clinical sensitivity of this test is around 90% for clinically diagnosed Marfan syndrome patients and around 20% for nonsyndromic thoracic aortic aneurysm and dissection patients.
This concludes my presentation. Thank you for your attention.