Originally posted: December 19, 2022
Linnea M. Baudhuin, Ph.D.
Professor of Laboratory Medicine and Pathology
Division of Laboratory Genetics and Genomics
Mayo Clinic, Rochester, Minnesota
Hello, my name is Linnea Baudhuin. I am a professor of laboratory medicine and pathology at the Mayo Clinic and today I am going to be talking about genetic testing for inherited cardiovascular disorders.
I have nothing to disclose.
These are my learning objectives.
There are many different inherited cardiovascular disorders, and they can impact the heart in a variety of ways. They can affect the heart structurally, such as cardiomyopathies, or they can be nonstructural, such as arrhythmias. They can also be isolated, such as familial thoracic aortic disease, or syndromic, such as Marfan syndrome.
A large number of genes can be involved in these disorders and thus there is quite a bit of genotypic heterogeneity involved. These disorders also often display phenotypic heterogeneity and phenotypic overlap, for example, with Marfan syndrome and Loeys-Dietz syndrome, where clinical presentation alone may not provide a specific diagnosis. Due to genotypic and phenotypic heterogeneity and overlap, gene panel testing performed through next-generation sequencing is an ideal method for testing for these disorders.
While not all-inclusive, this slide depicts four major categories of inherited cardiovascular disorders. On the left, cardiomyopathies, such as hypertrophic and dilated cardiomyopathies; Arrhythmias, such as long QT and Brugada syndromes; Aortopathies, such as Marfan and Loeys-Dietz syndrome; and Dyslipidemias, such as familial hypercholesterolemia and familial hypertriglyceridemia.
There are many benefits to genetic testing for inherited cardiovascular disorders. First, genetic testing offers a confirmatory diagnosis. Second, it can help to clarify the diagnosis in cases that involve conditions with phenotypic overlap with other conditions. It can also provide prognostic insights, and in some cases, facilitate gene-based management strategies. If a variant is detected in a proband, targeted testing of that variant can be performed in at-risk family members. And finally, genetic testing for these disorders aligns with expert consensus guideline recommendations by, for example, the American Heart Association, the American College of Cardiology, and other expert groups in Europe and Asia.
At Mayo Clinic, we have been performing cardiovascular genetic testing since 2006, starting with familial hypercholesterolemia and Marfan syndrome, and expanding into cardiomyopathies, arrhythmias, and many other tests. Our tests are performed using next-generation sequencing-based targeted gene panels with supplemental PCR-based analysis for comprehensive analysis of each gene that we target. We can detect single nucleotide variants, deletion-insertion variants, and copy number variants. Our gene panels have been vetted for content by a team of experts so that clinically-significant genes are included in the panels.
The first group of disorders that I would like to discuss are the cardiomyopathies and arrhythmias. Cardiomyopathies are a heterogeneous group of diseases of the myocardium and are associated with mechanical and/or electrical dysfunction. The image to the right shows a normal heart on the left and a heart with hypertrophic cardiomyopathy on the right with a thickened ventricular septum and a small left ventricle.
Arrhythmias are nonstructural cardiovascular conditions due to dysfunction of the cardiac ion channel pathways, such as what is seen in long QT syndrome in the electrocardiogram in the image on the lower right.
The overall incidence of cardiomyopathies and arrhythmias is at least 1/250 in the general population. They can lead to fatigue, breathlessness, syncope, and sudden cardiac death, which contributes to 60% of sudden deaths and are important causes of sudden death in young athletes.
We offer 11 different gene panel tests for cardiomyopathies and arrhythmias. Our largest panel is our comprehensive arrhythmia and cardiomyopathy panel, with 105 genes. We also have separate comprehensive panels for arrhythmias and cardiomyopathies, and separate panels for each specific cardiomyopathy and arrhythmia. Additionally, we have panels for CPVT and Noonan syndrome and related disorders.
The next group of disorders that we are offering genetic testing panels for fall under the category of connective tissue and vascular fragility disorders. These can be characterized by aortopathies and other vascular fragility, including aneurysms and dissections, as shown in the figures. Aortic aneurysm and dissection, as seen in the lower figure, is often observed in Marfan syndrome and other aortopathies. The figure on the right shows many of the different vessels that can be impacted in Ehlers-Danlos, vascular type.
These disorders may also be characterized by joint hypermobility and dislocations, as well as having skeletal features such as arachnodactyly, scoliosis, and chest deformities including pectus excavatum and carinatum, as shown in the figures. The positive thumb sign on the bottom left is characteristic of both joint hypermobility and arachnodactyly.
We offer seven different connective tissue/vascular fragility gene panels. These include a 48-gene panel for aortopathies, as well as a separate Ehlers-Danlos 22-gene panel; and a separate Marfan, Loeys-Dietz, aortopathy panel with 30 genes. Additionally, we offer a single gene analysis of FBN1 for Marfan syndrome and other FBN1-associated conditions. We also offer a hereditary hemorrhagic telangiectasia panel; a comprehensive cerebrovascular gene panel, which is 30 genes and is for monogenic causes of cerebrovascular accident or stroke; and an osteogenesis imperfecta 25-gene panel.
Hypercholesterolemia, characterized by elevated cholesterol levels in the blood, can be an inherited condition or can be acquired. Our hypercholesterolemia gene panel assesses for monogenic causes of hypercholesterolemia. Autosomal dominant familial hypercholesterolemia is the most common inherited hypercholesterolemia condition and is characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C), leading to increased risk of premature atherosclerosis and cardiovascular disease. Xanthelasmas, xanthomas, and arcus corneae can also be observed.
Another group of hereditary dyslipidemias can be characterized by hypobetalipoproteinemia, or low LDL-C. Monogenic causes of hypobetalipoproteinemia include familial hypobetalipoproteinemia, abetalipoproteinemia, chylomicron retention disease, loss of function variants in PCSK9, and familial combined hypolipidemia.
Hypertriglyceridemia is present in approximately 30% of adults in the United States. The majority of hypertriglyceridemia is secondary, due to a combination of lifestyle factors such as diet, obesity, diabetes, hypothyroidism, or certain medications. Primary hypertriglyceridemia, on the other hand, accounts for less than 5% of cases and is due to rare, monogenic conditions with disease-causing variants resulting in disordered triglyceride metabolism.
Lipodystrophies are rare conditions characterized primarily by the inability to properly store adipose tissue in the absence of nutritional deficit or catabolic state. The two most common forms of hereditary lipodystrophies are congenital generalized lipodystrophy and familial partial lipodystrophy. Lipodystrophies are associated with fat maldistribution and can include a dyslipidemia profile, with alterations in cholesterol and triglycerides associated with an increased risk of atherogenic progression.
Accordingly, we have four different gene panel tests for dyslipidemias, including a 12-gene panel for hypercholesterolemia, a 5-gene panel for hypobetalipoproteinemia, a 13-gene panel for hypertriglyceridemia, and a 12-gene panel for hereditary lipodystrophies.
Congenital heart disease or defects, or CHD, is a general term used to describe one or more problems with the heart's structure that exist at birth. CHD may involve one or more structures of the heart, including chambers, valves, arteries, and veins. Some examples are shown in the images to the right. CHD represents the most common birth defects in humans, with approximately 1% of births affected. CHD can be characterized as isolated (or nonsyndromic), or part of a systemic condition involving additional congenital anomalies (or syndromic).
It is estimated that a genetic etiology can be determined in around 20% to 30% of CHD cases, with increased likelihood of diagnostic findings in individuals with extracardiac anomalies and/or dysmorphic features. When an underlying genetic cause is detected, it is most often due to chromosomal copy-number variants, followed by aneuploidy, then single-gene variants. For this reason, chromosomal microarray analysis is often used as the first-tier test for individuals with CHD, followed by single- or multi-gene panel analysis, depending on the cardiac lesion, presence or absence of extra-cardiac features, and family history.
Our congenital heart disease gene panel includes 44 genes associated with both isolated CHD as well as syndromic conditions commonly involving CHD, such as Noonan syndrome and related disorders, CHARGE syndrome, Holt-Oram syndrome, and Alagille syndrome.
As you can see, Mayo Clinic Laboratories’ cardiovascular genetic testing is among the most comprehensive diagnostic testing available. These tests use next-generation sequencing to evaluate clinically relevant genes across several disease states.
These tests are high quality and provide the maximum depth of coverage, highest possible detection rates, and low false negative and false positive rates across all included genes. These tests detect both small variants and copy number variants. We utilize a combination of automated processes and manual review to ensure high efficiency and high quality in our results.
Our cardiovascular diagnostic testing utilizes a team of clinical and laboratory experts to provide an individualized results interpretation for clinical management on a patient-to-patient basis. Every result and report are reviewed by an expert in the context of the patient information provided.
In summary, Mayo Clinic Laboratories is pleased to be able to offer 23 up-to-date gene panel tests in the categories of cardiomyopathies and arrhythmias, connective tissue and vascular fragility disorders, dyslipidemias, and congenital heart disease. Thank you for your attention to this "Hot Topic" presentation.
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