Download Genetic Testing for Inherited Cardiac Conditions

Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
Welcome to Mayo Medical Laboratories Hot Topics. These presentations provide
short discussion of current topics and may be helpful to you in your practice.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
1
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
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Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
Thank you for that introduction. I have nothing to disclose.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
3
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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?
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
4
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
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Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
6
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
7
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
8
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
9
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
10
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
11
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
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Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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%.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
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Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
6/15/2015
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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 Xlinked. Like HCM, DCM demonstrates reduced penetrance and variable expressivity,
and treatment includes pharmacologic therapy, pacemaker, ICD, and transplant.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
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Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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%.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
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Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
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Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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%.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
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Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
19
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
20
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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%.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
21
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
22
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
23
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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%.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
24
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
25
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
26
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
27
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
28
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
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.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
29
Multi-Gene Panel Testing For Inherited
Cardiovascular Disorders
6/15/2015
This concludes my presentation. Thank you for your attention.
©2015 Mayo Foundation for Medical
Education and Research. All rights reserved.
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