Genetic Testing

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Genetic Testing




Major advances have been made over the past two decades that have defined the genetic basis of many medical diseases. Now, more than 40 different cardiovascular diseases are known to be directly caused by mutations in genes that encode cardiac proteins. These cardiovascular diseases include inherited cardiomyopathies, primary arrhythmogenic diseases, metabolic disorders, and congenital heart diseases. Identification of the genetic causes of cardiovascular disease has led to improved and earlier diagnosis in at-risk individuals and, in some cases, is helping to guide therapies as well as inform prognosis. This chapter provides an overview of current knowledge related to the role of genetic testing in cardiac disease, with a specific focus on arrhythmogenic diseases.



Basic Genetics



DNA, Genes, and Mutations


With the recent completion of the human genome sequence and subsequent advances in genetic technologies, we now have a clearer picture of our genetic makeup, and how variations in our genome can lead to cardiovascular disease.






Modes of Inheritance


The four major modes of inheritance are summarized in Figure 71-1. In most cardiovascular genetic diseases, inheritance is autosomal dominant, whereby the disease can be expressed when the mutation is present in just one allele. As a result, the chance of passing on the gene mutation from parent to offspring is 50%. Most primary arrhythmogenic diseases and inherited cardiomyopathies are inherited in this fashion. The other three modes of inheritance, shown in Figure 71-1, are significantly less common. Autosomal recessive inheritance requires the person to inherit the mutation on both alleles for disease to develop (i.e., one mutation is inherited from each parent). The chance of passing on the gene mutation from parent to offspring is 25%. The Jervell-Lange-Nielsen form of familial long QT syndrome is inherited in an autosomal recessive fashion. X-linked inheritance refers to the situation whereby the gene mutation is located on the X-chromosome. In this case, males develop the phenotype, while females most often are asymptomatic gene mutation carriers. Rare forms of dilated cardiomyopathy have been shown to have an X-linked pattern of inheritance. Mitochondrial inheritance is a non-Mendelian pattern in which transmission of disease occurs exclusively via females; it involves inheritance of mutant mitochondrial DNA by offspring. Although uncommon, this form of inheritance is often seen in mitochondrial diseases that can clinically manifest with a hypertrophic cardiomyopathy phenotype (or phenocopy).




Genetic Testing in Cardiovascular Disease



General Principles


Genetic testing is not a simple blood test. Many considerations arise with every family. A complete cardiogenetic evaluation is required, which includes confirming the clinical diagnosis in the proband, understanding the probabilistic nature of genetic testing and the need for genetic counseling, and taking a detailed family history to get a sense of disease penetrance and patterns of disease.1




Genetic Counseling and Informed Consent


In all patients and families with a genetic heart disease, genetic counseling is essential. Genetic testing options span all stages of life, from the preimplanted embryo or fetus, to children and adults. Appropriate pretest and posttest genetic counseling is a vital component of genetic testing. Apart from the diagnostic usefulness of genetic testing within families, a specific gene result may guide therapy and provide information about prognosis. The cardiac genetic counselor therefore plays a key role in the testing process, ensuring that the individual understands the clinical and psychosocial implications of every possible result and the limitations of the tests, including difficulties in interpretation of the results; and guiding discussion of other issues such as genetic testing of children, prenatal and preimplantation genetic diagnosis, and access to insurance.2



Commercially Available Genetic Testing


Over the past decade, commercially available genetic testing for inherited cardiac disease has expanded significantly. Many centers around the world now provide testing. In principle, genetic testing has moved from single gene testing to concurrent testing of multiple genes in “panels.” These panels may include 20 or more genes to be tested in a single process and reflect the genetic heterogeneity seen in many inherited cardiac diseases. As an example, recent developments have led to a “cardiomyopathy panel,” which tests for more than 40 cardiac genes involved in the pathogenesis of a variety of cardiomyopathies. Such approaches are likely to expand significantly in the future as the result of our increasing knowledge about causative genes and rapid advances in genetic screening technologies, such as next-generation and whole-genome sequencing.



Proband Genetic Testing


The genetic testing process most frequently begins with testing the proband (or index case). This is often the first person in the family who presents, and the clinical diagnosis is established. After genetic counseling and informed consent, genetic testing is performed. Outcomes can be divided into (1) those in which a mutation(s) is identified that is deemed to be pathogenic (disease-causing), (2) those for which no causative mutation is identified (an “indeterminate result”), and (3) those for which it is unclear whether the variant is pathogenic or is a benign variation in our genetic sequence (variant of uncertain significance [VUS]).



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Jun 4, 2016 | Posted by in CARDIAC SURGERY | Comments Off on Genetic Testing

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