What is the role of genetic testing in diagnosing cardiac (heart) issues?

From the Guidelines

Genetic testing for heart issues is recommended for patients with cardiomyopathy, particularly those with a family history of cardiac conditions or sudden cardiac death, as it can help identify specific mutations that guide personalized treatment approaches and potentially prevent serious cardiac events. This recommendation is based on the most recent and highest quality study available, which emphasizes the importance of genetic testing in patients with cardiomyopathy 1. The study highlights that genetic testing can facilitate patient management and family screening, and that cascade genetic testing of at-risk family members is recommended for pathogenic and likely pathogenic variants.

Some key points to consider when it comes to genetic testing for heart issues include:

• Genetic testing is recommended for the most clearly affected family member, and cascade genetic testing of at-risk family members is recommended for pathogenic and likely pathogenic variants 1
• The identification of at-risk family members is critical because the first presentation may be sudden death, and institution of therapy in asymptomatic affected individuals improves outcomes and decreases hospitalization and death due to heart failure 1
• Genetic testing and cascade screening for HCM have been shown to be cost-effective in Australia and the United States 1
• The identification of a molecular cause may also lead to critical gene-specific cardiac or extracardiac management recommendations, such as consideration of implantable cardioverter defibrillator (ICD) for primary prevention in carriers of LMNA pathogenic variants 1

In terms of the process of genetic testing, it typically involves a blood or saliva sample and consultation with a genetic counselor before and after testing. Common genetic tests include panel testing for cardiomyopathies, arrhythmias, and familial hypercholesterolemia. If a patient tests positive, their doctor may recommend specific medications, lifestyle modifications, and more frequent cardiac monitoring. Family members may also need testing, particularly if a pathogenic or likely pathogenic variant is identified in the proband 1.

It's worth noting that not all heart conditions have identified genetic markers, and a negative test doesn't completely rule out genetic heart disease. However, the value of genetic testing lies in its ability to identify specific mutations that can guide personalized treatment approaches, help with early intervention, and potentially prevent serious cardiac events 1. Overall, genetic testing for heart issues is a valuable tool that can help improve outcomes and reduce morbidity and mortality in patients with cardiomyopathy and their family members.

From the Research

Genetic Testing for Heart Issues

• Genetic testing can help identify individuals with hypertrophic cardiomyopathy (HCM), a common inherited cardiac disease, by detecting mutations in genes such as MYBPC3 2, 3, 4, 5, 6.
• The MYBPC3 gene is the most frequently mutated gene in HCM, and mutations in this gene can lead to truncated protein products or alterations in RNA splicing or protein stability, resulting in cMyBP-C haploinsufficiency 4.
• Comprehensive screening of MYBPC3, MYH7, and TNNT2 genes can identify mutations in 57% of HCM patients, supporting a combined analysis of these genes as a rational and cost-effective initial approach to molecular screening of HCM 3.
• Protein haploinsufficiency drivers, such as alterations in RNA splicing or protein stability, can identify MYBPC3 variants that cause HCM with high specificity 4.
• Patients with pathogenic MYBPC3 mutations can exhibit a range of clinical manifestations, from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes 6.

MYBPC3 Gene Mutation

• The MYBPC3 gene mutation is a major cause of HCM, and the type of mutation can influence the clinical manifestations and outcomes of the disease 2, 6.
• Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids 6.
• Disturbances in protein and transcript quality control systems, such as the ubiquitin-proteasome system and nonsense-mediated RNA dysfunctions, can also contribute to the onset of HCM 6.

Clinical Implications

• Genetic testing for MYBPC3 gene mutations can help identify individuals at risk of developing HCM and allow for early intervention and management of the disease 2, 5.
• Patients with pathogenic MYBPC3 mutations require regular monitoring and follow-up to prevent sudden cardiac death and other adverse clinical outcomes 6.
• RNA-based correction therapies are being developed to target the underlying cause of HCM, offering a potential cure for the disease 5.