Dr Hisham Ahamed
The last few decades have led to the identification of the genetic basis of a large number of cardiovascular diseases. They include dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) with mutations related to the sarcomere and structural genes, channelopathies with mutations in ion channel genes, arrhythmogenic cardiomyopathy with mutations in desmosomal genes and aortopathies with mutations in genes encoding for connective tissue elements. As a result, genetic testing has taken on an important role in managing families with the inherited cardiovascular disease. Various professional bodies have now included the recommendation of genetic testing for the management of patients with the disease as well as at-risk members in the family.
Why genetic testing in CVD?
- Diagnostic genetic testing : This can be performed to establish a specific genetic diagnosis. For example, the clinical phenotype may be shared among different disease entities, each with their own underlying cause, prognosis and treatment. In patients with left ventricular hypertrophy, genetic testing will help in characterizing it as sarcomeric HCM or an HCM phenocopy.
- Predictive Genetic Testing : This is done in apparently healthy relatives to determine who has inherited the causal variant in the family and is at risk for developing the disease. The majority of inherited cardiovascular diseases exhibit autosomal dominant inheritance pattern, with a 50 % chance of transmission to the offspring. This makes an evaluation of at risk healthy family members an important strategy. The aim of phenotypic and genotypic family evaluations are to identify individuals with the previously unrecognized disease and currently healthy family members who are at risk for future disease development.
When to perform genetic testing?
All patients diagnosed with an inherited cardiovascular condition should undergo a comprehensive evaluation which includes a full phenotypic assessment, a systematic family history with at least a 3 generation pedigree chart, genetic counseling and genetic testing.
The typical scenarios in which genetic testing may be done in cardiovascular disease is given below :
- High utility scenario: In this
situation, a definite diagnosis
along with familial inheritance pattern will increase the pre-test probability of identification of a disease-causing variant. This can then be used for predictive testing in other family members
- Intermediate utility scenario: Certain inherited cardiovascular diseases may exist without affected relatives and may be due to recessive inheritance, de novo mutations or reduced penetrance. Genetic testing in this group may be done if it will make a difference to the patient’s management and if other members of the family would benefit from predictive testing. It may be a challenge to determine whether the identified variant in this scenario is indeed that disease causing variant, especially since there is an absence of a family history of the disease.
- Low utility scenario: In these clinical situations, genetic testing has a low likelihood of a positive genetic test result and should not be pursued. For example, investigating a case of sudden cardiac death in a family with no living, affected individuals available for testing and no genetic sample available from affected descendants. Another scenario in which genetic testing is of low utility is when the identified genetic variant is not a reliable marker for the disease in question.
We have entered the genomic era of cardiovascular disease. Genetic testing constitutes a powerful tool in the diagnosis of inherited cardiovascular disease and identification of at-risk family members. Genetic testing is now becoming increasingly available and the cardiovascular physician would do well to familiarize himself with the appropriate indications, interpretations and related complexities of genetic testing in cardiovascular disease. Cardiovascular disease gene panels, as well as whole exome sequencing (via next-generation sequencing), have established themselves as validated methods of genetic testing. Integrating the results of genetic testing will definitely aid in the management and risk stratification of the patient and the patient’s family with the inherited cardiovascular disease.